Structure, morphology and surface properties of α-lactose monohydrate in relation to its powder properties

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 (XCT) contrast tomography. Interestingly, from aqueous solution the 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 the former's 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 that 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. A predictive workflow for inhalation drug formulation highlighting the 4-stage pathway from the molecular state through solid-state and surface properties to the blended powder. [Display omitted] •Lattice energy dominated by van der Waals interactions with electrostatic interactions contributing about 13%.•Predicted 3D crystal morphology agrees with aqueous solution grown data as measured using X-ray Computed Tomography.•Polar “tomahawk” morphology reflects differential adsorption of β-lactose molecules between {010} and {0-10} surfaces.•Predicted surface energies agree with IGC data albeit with higher predicted dispersive energies co