Drastic Modulation of Molecular Packing and Intrinsic Dissolution Rates by Meniscus-Guided Coating of Extremely Confined Pharmaceutical Thin Films

Nanosizing has emerged as one of the most effective formulation strategies for enhancement of dissolution properties of active pharmaceutical ingredients (APIs). In addition to enhancing the specific area of the dissolving solids, nanosizing can also capture and stabilize the metastable form of the API, which can further enhance the solubility by drastic modulation of surface energies. Herein, we employ meniscus-guided coating to fabricate nanothin films of three APIs that show anticancer properties and are poorly soluble: 10-HCPT, SN-38, and amonafide. By modulating the coating speed, we systematically deposited the APIs in films ranging from similar to 200 nm thickness to extreme confinement of similar to 10 nm (<10 molecular layers). In all three APIs, we observe a general order-to-disorder transition with semicrystalline (10-HCPT and amonafide) or amorphous (SN-38) form of API solids trapped in thin films when the thickness decreases below a critical value of similar to 25-30 nm. The existence of a critical thickness highlights the importance of nanoconfinement in tuning molecular packing. In the case of 10-HCPT, we demonstrate that the disordered form of the API occurs largely due to lack of incorporation of water molecules in thinner films below the critical thickness, thereby disrupting the three-dimensional hydrogen-bonded network held by water molecules. We further developed a dissolution model that predicts variation of the intrinsic dissolution rate (IDR) with API film thickness, which also closely matched with experimental results. We achieved drastic improvement in the IDR of similar to 240% in 10-HCPT by decreasing film thickness alone. Further leveraging the order-to-disorder transition led to 2570% modulation of the IDR for amonafide. Our work demonstrates, for the first time, opportunities to largely modulate API dissolution by precisely controlling the dimensionality of thin films.

Automated summary

Nanosizing has been effective in improving the dissolution properties of APIs, especially for poorly soluble anticancer compounds. By using meniscus-guided coating, nanothin films of three APIs were fabricated, demonstrating a transition from order to disorder in solid forms with decreasing film thickness. The critical thickness highlights the importance of nanoconfinement in molecular packing, leading to significant improvements in dissolution rates.