(298d) Surface Engineering of Lactose Particles By Atomic Layer Deposition for Modified Release

Authors: 
van Ommen, J. R., Delft University of Technology
La Zara, D., Delft University of Technology
Zhang, D., AstraZeneca R&D Gothenburg
Quayle, M. J., AstraZeneca R&D Gothenburg
Petersson, G., AstraZeneca R&D Gothenburg
Folestad, S., AstraZeneca R&D Gothenburg
Atomic layer deposition (ALD) is an established technique for the synthesis of thin films for various applications ranging from semiconductors to energy storage devices. Recently, it has been gaining attention in the pharmaceutical field to modify the particle properties, for example the drug release. Compared to the conventional methods of drug particle coating, ALD has a number of advantages: control over the amount of deposited material, conformality, and its solventless nature. A few studies about ALD of metal oxides, including Al2O3, TiO2 and ZnO, on acetaminophen, lactose and budesonide particles showed that the deposition of nanoshells can effectively slow down the drug release [1, 2, 3]. However, the dependence of the film growth on pharmaceutical particles on the ALD operating conditions has not yet been investigated. Furthermore, the relationship between the properties of the coating (e.g, uniformity, conformality) and the dissolution behaviour of the resulting core-shell structures is not clear. Therefore, as the dissolution profile strongly depends on the coating quality, understanding how process parameters (e.g., number of cycles, co-reactants and substrate surface) affect the coating uniformity and conformality is crucial.

In this work, we study the effect of co-reactants, namely H2O and O3, on the Al2O3 growth on two kinds of lactose particles (i.e., fully crystalline lactose and crystalline lactose with micronization-induced amorphous surfaces) and evaluate the dissolution behaviour. The ALD process is carried out at ambient conditions in a fluidized bed reactor for a low number of cycles (i.e., from 4 to 14) using trimethylaluminum (TMA) as a metal precursor. Time-of-flight secondary ion mass spectrometry and Transmission Electron Microscopy (TEM) show that TMA/O3 ALD on crystalline lactose particles offers greatly improved control over the coating uniformity and conformality compared to TMA/H2O ALD. In fact, by causing severe agglomeration of the particles, water deteriorates the fluidization quality and thus the homogeneity of the coating process. In-vitro dissolution tests reveal more sustained release for the O3-based process than for the H2O-based one, thus underlining the benefit of O3 in providing uniform and conformal coatings. However, little to no difference between TMA/O3 and TMA/H2O ALD is observed on lactose particles with amorphous surfaces. In fact, such amorphous surfaces firstly are inherently inhomogenous across the particles and secondly present micropores, as suggested by BET measurements. This inevitably leads to non-conformal films regardless of the co-reactant and moreover results in both surface and subsurface growth.

[1] Tommi O. Kääriäinen, Marianna Kemell, Marko Vehkamäki, Marja-Leena Kääriäinen, Alexandra Correia, Hélder A. Santos, Luis M. Bimbo, Jouni Hirvonen, Pekka Hoppu, Steven M. George, David C. Cameron, Mikko Ritala, Markku Leskelä, Surface modification of acetaminophen particles by atomic layer deposition, International Journal of Pharmaceutics, 525 (1), 2017, 160-174

[2] Joel Hellrup, Mårten Rooth, Anders Johansson, Denny Mahlin, Production and characterization of aluminium oxide nanoshells on spray dried lactose, International Journal of Pharmaceutics, 529 (1–2), 2017, 116-122

[3] Di Zhang, Mike J. Quayle, Gunilla Petersson, J. Ruud van Ommen and Staffan Folestad, Atomic scale surface engineering of micro- to nano-sized pharmaceutical particles for drug delivery applications, Nanoscale, 2017, 9, 11410-11417