Exploring co-milling of poorly water-soluble drugs with swellable polymers to enhance the dissolution rate

Co-milling with excipients offers an effective solvent-free strategy to enhance the dissolution of drugs in the pharmaceutical industry. Nonetheless, the range of excipients available for co-milling, as well as the selection criteria, remains relatively unexplored. Therefore, this study aims to evaluate the effect of co-milling with crosslinked swellable polymers on the dissolution of poorly water-soluble drugs. A structurally diverse set of crystalline compounds (n = 13) were co-milled with the three commonly used tablet disintegrants: Croscarmellose sodium, sodium starch glycolate and crospovidone. In vitro dissolution profiles were assessed to evaluate the excipient performance and identify crucial drug descriptors relating to co-milling induced dissolution enhancement. All 39 co-milled formulations showed an increased drug intrinsic dissolution rate (IDR), with drug properties such as molecular size and polar surface area showing a positive correlation with the extent of IDR enhancement following co-milling. Moreover, co-milling consistently yielded greater initial dissolution (AUC_{0-5 min}) across all excipients compared to milling the drug without an excipient. On average, milling with croscarmellose sodium produced the greatest improvement in the early stages of dissolution for neutral and basic compounds, while sodium starch glycolate was more effective in enhancing the dissolution of co-milled acidic drugs. Furthermore, an assessment within the refined Developability Classification System (rDCS) revealed that co-milling was effective to overcome dissolution rate limitations for all rDCS class IIa drugs. This study establishes a practical framework for the broader application of co-milling with tablet disintegrants and demonstrates its relevance within the latest rDCS paradigm for overcoming dissolution rate-limited absorption.