Exploring co-milling as a strategy to improve the dissolution of poorly water-soluble drugs

Poor dissolution in gastrointestinal fluids remains a critical limitation to the oral absorption of many poorly water-soluble drugs. Co-milling offers a solvent-free and industrially scalable technology to overcome dissolution rate limited absorption. However, its broader application has been constrained by the complexity of mechanochemical transformations, particularly in the presence of excipients, and the limited predictive understanding of these processes. Therefore, this thesis aimed to establish a data-driven framework to enhance both the mechanistic understanding and predictability of co-milling outcomes for poorly water-soluble drugs. A series of experimental co-milling studies was carried out using a diverse selection of drugs and excipients. These investigations incorporated biorelevant dissolution testing, multivariate data modelling, solid-state and thermal analyses, as well as particle size characterization. The first major finding of this thesis was the development of a predictive model to quantify the dissolution enhancement achievable through co-milling. Using data from 29 crystalline drugs co-milled with PVP K25, key molecular and physicochemical properties, such as particle size, logD6.5, molecular complexity (Kappa 3) and apparent solubility, were identified as reliable predictors of the co-milling induced dissolution improvement. The models achieved high predictive accuracy, offering a practical computational tool to support early formulation development. Secondly, the influence of the drug glass transition temperature (Tg) on co-milling performance was examined. A distinct difference was observed between low Tg (fenofibrate) and high Tg (apremilast) drugs. Apremilast, milled below its Tg, exhibited progressive amorphization and supersaturation during dissolution testing. A strong linear correlation between melting point depression and maximum drug concentration (cmax) in vitro (R2 > 0.98) highlighted melting point depression as a promising critical quality attribute to anticipate drug supersaturation and for stability purposes. Fenofibrate, in contrast, retained its crystallinity and showed signs of recrystallisation upon storage, emphasising the central role of Tg in predicting both performance and stability. Thirdly, the role of tablet disintegrants in co-milling performance and biopharmaceutical relevance was investigated. Thirteen drugs were co-milled with three widely used crosslinked excipients: croscarmellose sodium, sodium starch glycolate, and crospovidone. All 39 co-milled formulations showed increased intrinsic dissolution rates (IDR), with molecular descriptors such as polar surface area and size correlating positively with enhancement. Excipient performance varied with drug type, with sodium starch glycolate more effective for acidic drugs and croscarmellose sodium for neutral or basic compounds. Co-milling with tablet disintegrants successfully addressed dissolution rate limitations in all rDCS class IIa drugs, confirming its utility as a biopharmaceutically meaningful formulation approach. Lastly, the issue of process variability in particle size reduction was addressed. Milling without excipients often led to particle aggregation and inconsistent size distributions. In contrast, co-milling with PVP yielded significantly improved and highly reproducible particle size reduction across all tested drugs. Notably, the extent of size reduction was accurately predicted based solely on the initial particle size. These findings underscore the suitability of PVP based co-milling as a robust and scalable approach for early-stage drug formulation. In conclusion, this thesis demonstrates that co-milling can be transformed from an empirical technique into a scientifically grounded and predictable formulation strategy. The models and mechanistic insights developed here offer practical guidance for the rational design of oral dosage forms and support the advancement of more sustainable pharmaceutical development.

Grantor dc:publisher

University College Cork

Year dc:date.issued

2025

Author dc:creator

• Pätzmann, Nicolas

Advisors dc:contributor.advisor

• Griffin, Brendan T.
• O'Dwyer, Patrick

• Co-milling
• Dissolution
• Formulation development
• Oral solid dosage forms

Statement dc:rights

• © 2025, Nicolas Pätzmann.

Licence dc:rights.uri

• https://creativecommons.org/licenses/by/4.0/

Language dc:language.iso

en

Handle dc:identifier.uri

https://hdl.handle.net/10468/18863

OAI identifier oai:identifier

oai:cora.ucc.ie:10468/18863