QbD-based optimization of wet milling for the synthesis of glimepiride-metformin HCl nano-cocrystal suspension using various stabilizers

Glimepiride (GLI) and metformin HCl (MET) are widely co-administered as oral antidiabetic agents for type 2 diabetes mellitus (T2DM). From a crystal engineering perspective, this combination can be developed into a multidrug cocrystal (CC) to improve physicochemical properties. With appropriate stabilizers, the CC can be further processed into a nano-cocrystal (NCC), potentially enhancing physicochemical properties, which in turn improve oral bioavailability and facilitate better manufacturability. The main objective of this research was the screening of cocrystal formation to produce GLI–METCC powder, which was further synthesized into GLI–METNCC. This process began with a Box–Behnken design (BBD) to optimize formulation variables for NCC suspension preparation using various stabilizers such as poloxamer 188 (P188), poloxamer 407 (P407), Tween 80 (T80), and sodium dodecyl sulfate (SDS) by a top-down wet milling method using Quality by Design (QbD) principles. The GLI–METCC, prepared via solvent evaporation at an equimolar ratio, showed improved solubility and dissolution of GLI. It was further processed into an NCC suspension using a dual stabilizer combination of P188 (0.2% w/v) and T80 (1.0% w/v), identified as the optimal formulation by wet milling with a reciprocating ball mill. Milling was conducted with three balls at 350 rpm for 30 min. The resulting NCC suspension exhibited a particle size of 452.6 ± 7.8 nm, a polydispersity index of 0.482 ± 0.012, and a zeta potential of –31.30 ± 0.26 mV. The formulation demonstrated good stability over 3 months at room temperature.