The micro-structure of lactose powder compacts studied by small-angle and ultra small-angle X-ray scattering
Abstract
The objective was to derive indications of the microstructure of lactose powder compacts was studied by small-angle and ultra small-angle X-ray scattering experiments (SAXS/USAXS). Measurements were performed on a series of lactose powder compacts formed at four different pressures in the interval 300–1000 MPa. Porod analyses of the 1-D scattering profiles, i.e. intensity vs. magnitude of scattering vector (q), enabled accurate determinations of the specific surface area. From these, the interparticle contact area was estimated and compared to the compact tensile strength. Measures of the volume fraction and sizes of the voids were obtained from a fit of a model of polydisperse cylindrical pores. These were found to be approximately disc-shaped, with one dimension significantly smaller than the other two. The scattering data were consistent with an isotropic distribution of pores. The void volume fractions, void sizes and specific surface areas showed anti-correlating trends with the pressure applied.
Highlights
- SAXS used in a novel way to study microstructure in lactose powder compacts.
- Reliable values of surface area and SAXS determined porosity.
- USAXS used to indicate shape of pores.
- Linking particle contact area, mechanical strength and SAXS determined porosity.
Introduction
Tablets for pharmaceutical applications are formed by confined compaction of a powder and the quality of the tablet is specified by various so-called critical quality attributes. These include, for example, tablet mechanical strength and tablet disintegration time, attributes that certify that the tablets can be handled without breakage and that they will disintegrate after administration so that the drug provides an adequate therapeutic effect. These attributes are linked to the microstructure of the tablet; one important quantity being the porosity, which is the total relative volume of air present in the tablet. The air is located in pores that can be present both within the particles and between the particles, the latter sometimes referred to as voids. These pores can differ in size, shape and availability to the surroundings, i.e. the pores can be open or closed. As the microstructure is affected by particle size, packing and deformation and processing conditions, the tablet microstructure is important to determine during formulation development. Traditionally, this has been done by mercury porosimetry [[1], [2], [3]], a technique that gives information about both total porosity and the size distributions of open pores [[4], [5], [6]]. Similar information can be obtained from gas adsorption [7,8], however the accessible pore-size range is smaller compared to that determined by mercury porosimetry [[7], [8], [9]].
More recent techniques for measuring porosity are terahertz spectroscopy [[10], [11], [12], [13]] and X-ray microtomography [[14], [15], [16]]. These methods use electromagnetic radiation to measure pore volume and have the advantage of assessing not only open pores but also closed pores. Compared to X-ray microtomography, terahertz spectroscopy provides quick measurements and thus provides the possibility for use at-line or on-line during tablet manufacturing for assessing total porosity [13] but gives no direct information of e.g. surface area or pore size distributions.
Small-angle X-ray scattering (SAXS) and ultra small-angle X-ray scattering (USAXS) are well-established techniques to study structures and objects on the ∼1–1000 nm scale. They can be applied to solids, powders, solutions and suspensions. The scattering data are considered as a function of the momentum transfer vector, q, that is given by q = (4π/λ) sin (θ/2) where λ is the wavelength of the radiation and θ is the scattering angle. Basically, the techniques rely on scattering of X-rays from regions of different electron density in the sample under study and structural information is obtained from an analysis of the interference patterns caused by X-ray scattered over a range of angles. Even though the scattering pattern originates from density correlations in the sample under study, it is not always straightforward to draw full conclusions about the structure, size, and geometry from the scattering data alone. Often, some additional information about the sample is needed for quantitative analysis. More detail can sometimes be obtained by using a parameterized model that describes assumed shape, size and structure from which a simulated scattering with the parameters adjusted to fit the measured data can be used. However, model independent interpretation of scattering data is possible in some cases [[17], [18], [19]]. For example, within a range , it is possible to determine the average radius of gyration, of the scattering objects according to Guinier’s formula. For a two-phase system, comprising solid material and pores, there are two relevant model-independent quantities. First, the Porod invariant, obtained as the second moment of the absolute intensity, that is directly related to the porosity of the system. It is important to note, however, that the total porosity is not accessible, since this would require access to data for ranging from zero to infinity. Rather, an ‘incomplete’ Porod invariant can be computed that reflects the volume of pores in a size-range corresponding to the experimentally accessible range [20]. Secondly, the absolute intensity decreases as at larger momentum transfer, and the constant is directly related to the specific surface area of the boundary between the phases.
As in crystallographic diffraction, SAXS and USAXS analyses the interference of X-rays that are scattered from samples. While wide-angle diffraction is used to determine distances between crystal planes and the local arrangement of atoms and molecules, SAXS is primarily used to observe the size and the shape of larger scattering objects.
SAXS has been used previously to study dry pharmaceutical excipients. In a series of related studies [[21], [22], [23], [24], [25]], SAXS was used to investigate pharmaceutical excipients intended for tabletting such as different cellulose and starch grades. From the two-dimensional (2D) scattering patterns, relations were established for properties such as density, particle strain and strain directions in tabletted powders, granules and pellets. In another study [26], diffraction patterns in the low-angle range were measured during drying of extruded and spherical pellets of calcium stearate/ibuprofen mixtures and related to potential changes in solid-state properties. Hodzic et al. [27] extracted parameters related to the internal surface area from SAXS patterns and correlated these parameters with the hardness of tablets formed from lactose/cellulose/silicon dioxide powder mixtures, demonstrating that parameters obtained from SAXS could be used as empirical predictors for the tablet-forming ability.
The previous studies indicate the feasibility of SAXS to provide structural information about powder compacts. The present work investigates cylindrical tablet-like lactose powder compacts that present some differences to the fibrillar microstructure of the cellulose compacts described in many of the previous studies. The present work also extends the q-range of the scattering data to lower values by measuring also USAXS, which provides the possibility to detect features arising from larger structures. Specifically, the work quantifies the pores and porosity in the powder compacts. This includes determination of specific surface area, pore size and shape and their dependence on the compaction pressure.
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Materials
Crystalline α-lactose monohydrate powder Lactohale® LH300 (hereinafter referred to as LH300) with an apparent density of 1.547 g/cm3 and a median particle diameter of 3.46 μm [28,29] was received as a gift from DFE Pharma, the Netherlands. The powder was stored in a humidity-controlled room at relative humidity 33 ± 2 % and room temperature (21 ± 1 °C) for a minimum of one week before powder compaction.
The volume specific surface area of the lactose powder was measured with air permeametry using the Blaine apparatus [30]. A powder amount of 1.29 g was manually compressed in a sample holder to form a cylindrical powder plug (1.27 cm diameter and 1.47 cm height) with a porosity of 55 %. The time of a specific volume of air to pass through the powder plug was recorded. Three independent measurements were made and each measurement was an average of three recordings of flow time.
Johan Gråsjö, Ann-Sofie Persson, Göran Alderborn, Göran Frenning, Per Hansson, Adrian R. Rennie, The micro-structure of lactose powder compacts studied by small-angle and ultra small-angle X-ray scattering, Powder Technology, Volume 460, 2025, 121090, ISSN 0032-5910, https://doi.org/10.1016/j.powtec.2025.121090.
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