Tabletability and compactibility of α-lactose monohydrate powders of different particle size. I. Experimental comparison.

In this paper, two types of parameters representing tabletability and compactibility profiles of a series of α-lactose monohydrate powders, ranging in particle size from approximately 3.5 to 203 µm, are derived and compared. By approximating the tabletability profiles using a three-stage model and the compactibility profiles using the Ryshkewitch-Duckworth equation, two compaction rate parameters and two compaction endpoint parameters were derived. The original median particle diameter had generally a strong effect on the tablet tensile strength and hence the tabletability and compactibility profiles. The experimental profiles were well approximated by the models used, and the compaction parameters were regarded as representative of the experimental profiles. The compaction endpoint parameters increased with decreased particle size and were controlled by the same structural feature as the compacts. The tabletability rate parameter also increased with decreased particle size and correlated well with the tabletability endpoint parameter. The compactibility rate parameter tended to increase with decreased particle size, but the effect was limited; moreover, no general correlation was obtained with the compactibility endpoint parameter. It is concluded that compactibility and tabletability parameters collectively provide a concentrated description of the compaction properties of a powder.

Atypical compaction behaviour of disordered lactose explained by a shift in type of compact fracture pattern.

The objective was to investigate tabletability and compactibility for compacts of a series of α-lactose monohydrate powders with different degree of disorder. Regarding the tabletability, the powders of high degree of disorder displayed similar behaviour that deviated markedly from the behaviour of the crystalline powders and the milled powder of modest degree of disorder. The Ryshkewitch-Duckworth equation, describing compactibility, was nearly linear for the crystalline powders, while for the disordered powders the model failed to describe the relationships, i.e. the disordered powders were characterised by a plateau in the Ryshkewitch-Duckworth plots over a relatively wide range of compact porosities. It was concluded that the difference in compaction behaviour of the milled particles compared to the crystalline powders was primarily explained by the increased particle plasticity of the disordered particles. The plateau in the Ryshkewitch-Duckworth plots obtained for the disordered powders was explained by a change in the fracture behaviour of the compacts, from an around grain to an across grain fracture pattern. This implied that the disordered particles can be described as a type of core-shell particles with an amorphous shell and a defective crystalline core.

Milling induced amorphisation and recrystallization of α-lactose monohydrate.

Preprocessing of pharmaceutical powders is a common procedure to condition the materials for a better manufacturing performance. However, such operations may induce undesired material properties modifications when conditioning particle size through milling, for example. Modification of both surface and bulk material structure will change the material properties, thus affecting the processability of the powder. Hence it is essential to control the material transformations that occur during milling. Topographical and mechanical changes in surface properties can be a preliminary indication of further material transformations. Therefore a surface evaluation of the α-lactose monohydrate after short and prolonged milling times has been performed. Unprocessed α-lactose monohydrate and spray dried lactose were evaluated in parallel to the milled samples as reference examples of the crystalline and amorphous lactose structure. Morphological differences between unprocessed α-lactose, 1 h and 20 h milled lactose and spray dried lactose were detected from SEM and AFM images. Additionally, AFM was used to simultaneously characterize particle surface amorphicity by measuring energy dissipation. Extensive surface amorphicity was detected after 1 h of milling while prolonged milling times showed only a moderate particle surface amorphisation. Bulk material characterization performed with DSC indicated a partial amorphicity for the 1 h milled lactose and a fully amorphous thermal profile for the 20 h milled lactose. The temperature profiles however, were shifted somewhat in the comparison to the amorphous reference, particularly after extended milling, suggesting a different amorphous state compared to the spray-dried material. Water loss during milling was measured with TGA, showing lower water content for the lactose amorphized through milling compared to spray dried amorphous lactose. The combined results suggest a surface-bulk propagation of the amorphicity during milling in combination with a different amorphous structural conformation to that of the amorphous spray dried lactose. The hardened surface may be due to either surface crystallization of lactose or to formation of a low-water glass transition.

Effect of milling on the plastic and the elastic stiffness of lactose particles.

The purpose of this study was to investigate the effect of degree of disorder of a series of α-lactose monohydrate powders, prepared by milling for different time periods, on the plastic and the elastic stiffness of the particles. As references, a series of physical mixtures consisting of original crystalline particles and amorphous particles obtained by spray-drying was used. In addition, the effect of powder pre-storage humidity on the mechanical properties was investigated. For milled particles of a low degree of disorder, a decreased particle size increased the particle plastic stiffness. For milled particles of constant particle size, the plastic stiffness decreased with an increased degree of disorder while the elastic stiffness seemed nearly independent of the degree of disorder. The presence of moisture caused a recrystallisation of milled particles with low degree of disorder which increased their plastic stiffness. For the physical mixtures of crystalline and amorphous particles, similar relationships between plastic stiffness and amorphous content as for the milled powders were obtained. A reasonable explanation is that the nature of the milled particles is represented by a two-state system with crystalline and amorphous domains.

Comminution-amorphisation relationships during ball milling of lactose at different milling conditions.

The purpose of the study was to investigate the relationship between comminution and amorphisation of α-lactose monohydrate particles during ball milling under different milling conditions, including ball-to-powder mass ratio, milling time and ball diameter. The results revealed that at a constant ball filling ratio, ball-to-powder mass ratio of 25:1 resulted in the lowest minimum particle diameter of ∼5µm and the highest degree of apparent amorphous content of 82%. The rate of comminution was high during early stage of milling whereas the degree of apparent amorphous content increased gradually at a slow rate. An increased ball-to-powder mass ratio during milling increased both the rate of comminution and the rate of amorphisation. Using a given ball-to-powder mass ratio, the ball diameter affected the degree of apparent amorphous content of the particles while the particle diameter remained unchanged. The relationship between comminution and amorphisation could be described as consisting of two stages, i.e. comminution dominated and amorphisation dominated stage. It was proposed that the rate constant of comminution and amorphisation are controlled by stress energy distribution in the milling jar and the stress energy distribution is regulated by the ball motion pattern that can be affected by the process parameter used.

Determination of Interfacial Amorphicity in Functional Powders.

The nature of the surfaces of particles of pharmaceutical ingredients, food powders, and polymers is a determining factor for their performance in for example tableting, powder handling, or mixing. Changes on the surface structure of the material will impact the flow properties, dissolution rate, and tabletability of the powder blend. For crystalline materials, surface amorphization is a phenomenon which is known to impact performance. Since it is important to measure and control the level of amorphicity, several characterization techniques are available to determine the bulk amorphous content of a processed material. The possibility of characterizing the degree of amorphicity at the surface, for example by studying the mechanical properties of the particles' surface at the nanoscale, is currently only offered by atomic force microscopy (AFM). The AFM PeakForce QNM technique has been used to measure the variation in energy dissipation (eV) at the surface of the particles which sheds light on the mechanical changes occurring as a result of amorphization or recrystallization events. Two novel approaches for the characterization of amorphicity are presented here. First, since particles are heterogeneous, we present a methodology to present the results of extensive QNM analysis of multiple particles in a coherent and easily interpreted manner, by studying cumulative distributions of dissipation data with respect to a threshold value which can be used to distinguish the crystalline and amorphous states. To exemplify the approach, which is generally applicable to any material, reference materials of purely crystalline α-lactose monohydrate and completely amorphous spray dried lactose particles were compared to a partially amorphized α-lactose monohydrate sample. Dissipation data are compared to evaluations of the lactose samples with conventional AFM and SEM showing significant topographical differences. Finally, the recrystallization of the surface amorphous regions in response to humidity was followed by studying the dissipation response of a well-defined surface region over time, which confirms both that dissipation measurement is a useful measure of surface amorphicity and that significant recrystallization occurs at the surface in response to humidity.

Considerations on the quantitative analysis of apparent amorphicity of milled lactose by Raman spectroscopy.

The main purpose of the study was to evaluate various pre-processing and quantification approaches of Raman spectrum to quantify low level of amorphous content in milled lactose powder. To improve the quantification analysis, several spectral pre-processing methods were used to adjust background effects. The effects of spectral noise on the variation of determined amorphous content were also investigated theoretically by propagation of error analysis and were compared to the experimentally obtained values. Additionally, the applicability of calibration method with crystalline or amorphous domains in the estimation of amorphous content in milled lactose powder was discussed. Two straight baseline pre-processing methods gave the best and almost equal performance. By the succeeding quantification methods, PCA performed best, although the classical least square analysis (CLS) gave comparable results, while peak parameter analysis displayed to be inferior. The standard deviations of experimental determined percentage amorphous content were 0.94% and 0.25% for pure crystalline and pure amorphous samples respectively, which was very close to the standard deviation values from propagated spectral noise. The reasonable conformity between the milled samples spectra and synthesized spectra indicated representativeness of physical mixtures with crystalline or amorphous domains in the estimation of apparent amorphous content in milled lactose.

Mechanism of amorphisation of micro-particles of griseofulvin during powder flow in a mixer.

The purpose of the research was to investigate the degree of solid-state amorphisation during powder flow and to propose a mechanism for this transformation. Micro-particles of griseofulvin (about 2 µm in diameter) were mixed in a shear mixer under different conditions to influence the inter-particulate collisions during flow, and the degree of amorphisation was determined by micro-calorimeter. The amorphisation of griseofulvin particles (GPs) during repeated compaction was also determined. The GPs generally became disordered during mixing in a range from about 6% to about 86%. The degree of amorphisation increased with increased mixing time and increased batch size of the mixer, whereas the addition of a lubricant to the blend reduced the degree of amorphisation. Repeated compaction using the press with ejection mode gave limited amorphisation, whereas repeated compaction without an ejection process gave minute amorphisation. It is concluded that during powder flow, the most important inter-particulate contact process that cause the transformation of a crystalline solid into an amorphous state is sliding. On the molecular scale, this amorphisation is proposed to be caused by vitrification, that is the melting of a solid because of the generation of heat during sliding followed by solidification into an amorphous phase.