Jason Zhanjie Liu^a , Saurin H. Rawal^a, Sandra Dela Torre, Kyle Blakely^a, Aditya Singaraju^a, Kaushalendra Chaturvedi^b, Yuanhao Yu^b, San Kiang^b and Jeremy Merritt^a

^aSynthetic Molecule Design and Development, Eli Lilly and Company

^bJ-Star Research Inc.

Presenter: Jason Zhanjie Liu

Introduction: A high drug load formulation is often warranted when a higher dose strength must be delivered. However, this has been challenging as a large number of API molecules tend to have an acicular morphology and small particle size. Such APIs typically present very poor physical properties which make it significantly challenging to enable the high drug load formulation. Given the high requirement on physical properties and short development timeline for API drug substance, developing a technique to improve API physical properties to enable direct compression and high drug load formulation have gained significant interests. Method: We performed an industrial case study including three approaches to implement the co-processing of API with an excipient: 1) Heterogeneous nucleation (HN); 2) In-Situ granulation (ISG); 3) Mesoporous carrier loading (MC). Formulations up to 70% drug load are assessed on both manufacturability and chemical stability at stressed conditions. Results: The co-processed API present improved bulk density and flowability. The high drug load formulation has been demonstrated to be feasible with acceptable tablet tensile strength, disintegration and dissolution. Due to the significant advantages of ISG techniques in maintaining API chemical stability (Less than 1% impurity after 120 days at stressed condition), we have further explored the particle engineering options, process scaling up, as well as formulation space to enable the high-drug load immediate-release tablets. Conclusion: The co-processed API presents promising physical properties and tableting performance to enable high-drug-load direct compression tablets. Particularly, the API from in-situ granulation (co-precipitation) demonstrated superior stability in a formulation at stressed conditions.