A study of the mechanisms of milling-induced enhancement of solubility and dissolution rate of poorly soluble drugs

Milling and co-milling are well known techniques that have potential to enhance the solubility and/or dissolution rate of poorly soluble drugs. There are broadly two aims for this project. The first was to develop an understanding of how individual and combination of techniques may be used to explore the impact of milling on particle characteristics (including phase changes, fractures and change in particle size) as a function of milling time/speed, for a range of single powder materials. Anhydrous (lactose, sucrose), monohydrate (lactose) and dihydrate (trehalose) excipients and a poorly soluble drug (ibuprofen), were chosen as model substrates. Each material was micronized by ball-milling (for various time durations and milling speeds) and then characterized by a range of techniques, specifically, SEM, DSC, TGA, THz and dielectric spectroscopy. The second aim of the project was to investigate the impact of milling and co-milling on the solubility and dissolution rate of ibuprofen after co-milling with a variety of excipients (polymer and surfactants). The principle findings of this programme of work can be summarized as follows: i) ball milling of lactose monohydrate produces nano-structured systems with a mixture of damaged crystals and amorphous phase, that can be characterised by dielectric relaxation spectroscopy (DRS), ii) THz spectroscopy provides estimates for residual crystallinity in lactose monohydrate that were much lower than the estimates from the thermal techniques. Such estimates of residual crystallinity are considered to be more reliable given the fact that the spectroscopic measurement characterizes the material in its native state, whereas thermal techniques require a heating process, which tend to induce de-vitrification and mutarotation of lactose. In case of anhydrous materials, while there was agreement between thermal and THz techniques at long milling times, it was shown that the THz technique was susceptible to moisture absorption and crystallization at short milling times, iii) In the molecular dynamics of milled sugars studied by DRS, the structural relaxation is not visible in the vicinity of glass transition, however the secondary relaxation (β) process is equally capable and provided molecular dynamics in term of activation energy changes. The activation energies of beta process of both lactose and sucrose are least affected by milling time, but the higher activation energies for sucrose as compared with lactose show that sucrose has lower propensity to re-crystallize than lactose during post milling storage, iv) Ibuprofen can be assayed by UV-method in the presence of interfering (in absorption) substance by applying multivariate method involving the calculation of concentration factors and v) Co-milling with soluplus has increased the in the solubility of ibuprofen by ~20% and dissolution rate ~50% in 30 min, while these values are ~5% and 30%, respectively in case of co-milling with HPMC.