Structure, Morphology and Surface Properties of α-Lactose Monohydrate in Relation to its Powder Properties

Thai T H Nguyen; Cai Y Ma; Ioanna D Styliari; Parmesh Gajjar; Robert B Hammond; Philip J Withers; Darragh Murnane; Kevin J Roberts

doi:10.1016/j.xphs.2024.10.031

Structure, Morphology and Surface Properties of α-Lactose Monohydrate in Relation to its Powder Properties

J Pharm Sci. 2024 Oct 29:S0022-3549(24)00482-9. doi: 10.1016/j.xphs.2024.10.031. Online ahead of print.

Authors

Thai T H Nguyen¹, Cai Y Ma¹, Ioanna D Styliari², Parmesh Gajjar³, Robert B Hammond¹, Philip J Withers³, Darragh Murnane², Kevin J Roberts⁴

Affiliations

¹ Centre for the Digital Design of Drug Products, School of Chemical and Process Engineering, Institute of Process, Research & Development, University of Leeds, Leeds, LS2 9JT, UK.
² School of Life and Medical Sciences, University of Hertfordshire, Hertfordshire, AL10 9AB, UK.
³ Henry Moseley X-ray Imaging Facility, Department of Materials, The University of Manchester, Manchester, M13 9PL, UK; Henry Royce Institute for Advanced Materials, Department of Materials, The University of Manchester, Manchester, M13 9PL, UK.
⁴ Centre for the Digital Design of Drug Products, School of Chemical and Process Engineering, Institute of Process, Research & Development, University of Leeds, Leeds, LS2 9JT, UK. Electronic address: k.j.roberts@leeds.ac.uk.

PMID: 39481472
DOI: 10.1016/j.xphs.2024.10.031

Abstract

The particulate properties of α-lactose monohydrate (αLMH), an excipient and carrier for pharmaceuticals, is important for the design, formulation and performance of a wide range of drug products. Here an integrated multi-scale workflow provides a detailed molecular and inter-molecular (synthonic) analysis of its crystal morphology, surface chemistry and surface energy. Predicted morphologies are validated in 3D through X-ray diffraction contrast tomography. Interestingly, from aqueous solution fastest growth is found to lie along the b-axis, i.e. the longest unit cell dimension of the αLMH crystal structure reflecting the greater opportunities for solvation on the prism compared to the capping faces leading to their slower relative growth rates. The tomahawk morphology reflects the presence of β-lactose which asymmetrically binds to the capping surfaces creating a polar morphology. The crystal lattice energy is dominated by van der Waals interactions (between lactose molecules) with electrostatic interactions contributing the remainder. Predicted total surface energies are in good agreement with those measured at high surface coverage by inverse gas chromatography, albeit their dispersive contributions are found to be higher than those measured. The calculated surface energies of crystal habit surfaces are not found to be significantly different between different crystal surfaces, consistent with αLMH's known homogeneous binding to drug molecules when formulated. Surface energies for different morphologies reveals crystals with the elongated crystal morphologies have lower surface energies compared to those with a triangular or tomahawk morphologies, correlating well with literature data that the surface energies of the lactose carriers are inversely proportional to their aerosol dispersion performance.

Keywords: Inhalation Powdered Drug Formulations; Mechanical Properties; Morphological Characterisation; Surface Energy; Surface physical Chemical Properties; Synthons and Intermolecular Interactions; X-ray Computed Tomography; α-Lactose Monohydrate.