Frank M. Etzler

Particle size analysis: AAPS workshop report, cosponsored by the Food and Drug Administration and the United States Pharmacopeia

The concepts of particle engineering and dosage form design have become dominant themes in pharmaceutical manufacturing. This trend is not simply a reflection of the development of new, more sophisticated manufacturing methods of particles or dispersed systems but also recognition of the importance of quality control even in more traditional manufacturing processes. However, the diversity of particle treatments, methods of particle size analysis, expression and interpretation of data, and process applications results in complicated and sometimes confusing criteria for selection, adoption, or relevance of the available techniques.

Direct adhesion measurements of pharmaceutical particles to gelatin capsule surfaces

Scanning probe microscopy (SPM) was used to measure directly the adhesion of individual lactose particles to the surface of gelatin capsules employed in dry powder inhalant drug delivery systems. In this study, SPM shows that gelatin capsule surfaces with high surface heterogeneity and high-contrast friction exhibit high adhesion and that gelatin capsule surfaces with low surface heterogeneity and low-contrast friction exhibit low adhesion. The adhesion of lactose particles to gelatin capsules was also determined by measuring the retention of lactose particles in the capsules. The adhesion trend obtained with individual lactose particles using the colloidal probe technique agrees with the macroscopic retention results. The adhesion appears to be proportional to the particle size for homogeneous capsule surfaces. In dry powder inhalation products, the Lifshitz-van der Waals forces and acid-base interactions appear to be the principal forces contributing to particle-surface adhesion. The physicochemical nature of the capsule surface seems to dictate the spatial variation of adhesion across the surface. The SPM results clearly show that the surface physicochemical properties depend on the gelatin and mold release agent utilized in the manufacture of gelatin capsules. One of the practical implications of this study is that extraneous surface contamination of gelatin capsules by chemical processing aids such as mold release agents appears to be a key factor affecting the respirable fraction in dry powder inhalation products.

Prediction of inter-particle adhesion force from surface energy and surface roughness

Fine powder flow is a topic of great interest to industry, in particular for the pharmaceutical industry; a major concern being their poor flow behavior due to high cohesion. In this study, cohesion reduction, produced via surface modification, at the particle scale as well as bulk scale is addressed. The adhesion force model of Derjaguin–Muller–Toporov (DMT) was utilized to quantify the inter-particle adhesion force of both pure and surface modified fine aluminum powders (∼8 μm in size). Inverse Gas Chromatography (IGC) was utilized for the determination of surface energy of the samples, and Atomic Force Microscopy (AFM) was utilized to evaluate surface roughness of the powders. Surface modification of the original aluminum powders was done for the purpose of reduction in cohesiveness and improvement in flowability, employing either silane surface treatment or dry mechanical coating of nano-particles on the surface of original powders. For selected samples, the AFM was utilized for direct evaluation of the particle pull-off force. The results indicated that surface modification reduced the surface energy and altered the surface nano-roughness, resulting in drastic reduction of the inter-particle adhesion force. The particle bond number values were computed based on either the inter-particle adhesion force from the DMT model or the inter-particle pull-off force obtained from direct AFM measurements. Surface modification resulted in two to three fold reductions in the Bond number. In order to examine the influence of the particle scale property such as the Bond number on the bulk-scale flow characterization, Angle of Repose (AOR) measurements were done and showed good qualitative agreements with the Bond number and acid/base surface characteristics of the powders. The results indicate a promising method that may be used to predict flow behavior of original (cohesive) and surface modified (previously cohesive) powders utilizing very small samples, and that the surface modification can drastically improve the powder flow for industrially relevant materials.

Tablet Tensile Strength: An Adhesion Science Perspective

Tablets are the most common dosage form employed by the pharmaceutical industry. They are both inexpensive to produce and convenient to patients. Active pharmaceutical ingredients, particularly those incorporated into innovator company products, are new chemical substances whose chemical and physical properties are incompletely known and are sometimes present in large amounts in the manufactured products. Excipients present in the formulation can, at least partially, offset undesirable properties of active ingredient. Successful tablet formulations must, in addition to having desirable medicinal properties, must be manufacturable. In order to be manufacturable tablets must have sufficient tensile strength to survive handling, processing and packaging. In this paper the tensile strength of common pharmaceutical excipients mixed with sodium dodecyl sulfate is investigated. Sodium dodecyl sulfate, if incorporated into formulations, usually has an undesirable effect on tensile strength. A model, based on adhesion science principles is proposed that allows the tensile strength of candidate formulations to be calculated from the Ryshkewitch–Duckworth parameters of the component materials. Both the model and the Ryshkewitch–Duckworth equation suggest that tablet porosity is the principal measure of the outcome of the tableting process.

Adhesion of pharmaceutical particles to gelatin capsules having variable surface physicochemical properties: evaluation using a combination of scanning probe microscopy techniques

Abstract The adhesion of particles to solid surfaces is an important factor in the performance of a number of technologically significant systems. A combination of scanning probe microscopy (SPM) techniques, including adhesion mapping and force integration to equal limits imaging, is used to correlate the adhesion of particles with areas of distinct surface physicochemical properties. The utility of this approach is demonstrated using lactose particles and a gelatin capsule from a pharmaceutical dry powder inhalant drug delivery system. The particle adhesion forces were found to be higher on specific domains of the gelatin capsule identified as extraneous surface contamination. Furthermore, the dynamic nature of these contaminant domains on the capsule surface was found to result in a variance in the particle adhesion over time.