Fabrication of Second-Generation Acalabrutinib Nanocrystals by Employing the Nano-Edge Method for Improving the Physico-Chemical Properties and Forecasting their In-Silico Pharmacokinetic Behaviour.

Acalabrutinib (ACL) is approved by the USFDA and classified as a BCS class II drug, primarily used for treating chronic lymphocytic leukaemia. It is characterised by low solubility, particularly at higher pH levels, which results in reduced systemic absorption. Our current research aims to repurpose ACL for breast cancer treatment by enhancing its solubility and overall bioavailability through a second-generation nanocrystal formulation (SGACNCs). SGACNCs were prepared using the Nano-Edge method, which combines microprecipitation and high-pressure homogenization. The prepared SGACNCs with a mean particle size of 250.5 ± 17nm were characterised by solid-state techniques such as FTIR, DSC, PXRD, SEM, and BET analysis. In vitro dissolution studies indicated that at pH levels of 6.8 and 7.4, there was a 99 ± 0.2% and 99 ± 0.1% release after 6 h, respectively. Furthermore, the apparent permeability of the SGACNCs were observed to be two times greater than that of ACL. The stability studies indicated that the SGACNCs remained stable for 3 months at 5 ± 3 °C. Gastroplus 10.1 software was utilized to predict the pharmacokinetic profiles of SGACNCs based on their in vitro dissolution characteristics. In vitro biological studies on MDA-MB-231 cell lines showed a 1.55-fold reduction in IC value in SGACNCs (36.08 ± 2.5 μM) compared to the ACL. SGACNCs showed higher cell internalisation, MMP depolarisation, ROS generation, apoptosis, reduced cell migration, and colony formation. The Nano-Edge technique for the nanonization of ACL showcased its potential to increase both the solubility and dissolution rate of ACL, which will boost its therapeutic efficacy in treating breast cancer.