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Selecting a Particle Sizer for the Pharmaceutical Industry

Margarida Figueiredo1, M. José Moura1,2, and Paulo J. Ferreira1

1CIEPQPF, Department of Chemical Engineering, University of Coimbra, Portugal

2Department of Chemical and Biological Engineering, Polytechnic Institute of Coimbra, Portugal

1.1 Introduction

1.1.1 Relevance of Particle Size in the Pharmaceutical Industry

Knowledge and understanding of particle size data is crucial in a wide range of industries, being vital for the pharmaceutical industry, with applications from drug development to production and quality control. The purpose of particle size analysis is to obtain quantitative data on the mean size, particle size distribution and, sometimes in addition, particle shape of the compounds used in pharmaceutical formulations. It is well known that particle size highly affects not only the final product performance (e.g., dissolution, bioavailability, stability and absorption rates), but also every step of the manufacturing process of both drug substances and excipients (like mixing, flowability, granulation, drying, milling, blending, coating and encapsulation) [1-8]. For example, particle size is often directly related to dissolution/solubility characteristics of solid or suspension delivery systems, which have a direct impact on the bioavailability of pharmaceutical products. Dissolution is directly proportional to particle surface area, which in turn is inversely proportional to particle size (i.e., finer particles promote faster drug dissolution). The same applies to the suspensions where precipitation is highly controlled by particle size (in practice, finer particles generally give more stable suspensions), equally affecting viscosity and flow (Stokes' law relates the settling velocity of particles to the square of particle diameter). Distribution of sizes is another key characteristic that influences, for instance, handling and processing (powder handling characteristics are profoundly affected by changes in flow properties and tendency to segregate, which are both highly dependent on powder size distribution). Ultimately, particle size also has a critical effect on the content uniformity of solid dosage forms. Size analysis also becomes of significant importance with new drug delivery formats such as liposomes and nanoparticles whose characterization requires sophisticated analytical techniques [9-12].

In brief, particle size simultaneously affects safety, efficacy and quality of the drug, and regulatory agencies are becoming increasingly aware of the importance of particle sizing, requiring developers to have greater control and understanding of this aspect of their drug products [3,13-15].

1.1.2 Main Goals

This chapter intends to introduce the problem of particle sizing in the domain of the pharmaceutical industry, especially to those who are not very familiar with this topic. It is by no means an exhaustive description of particle sizing methods, but addresses the basic concepts associated with particle sizing, providing a basis to understand the most important details associated with particle sizing data and its interpretation. It was conceived not only to help the reader to select the most suitable techniques for your particle characterization needs, but also to be a valuable tool in daily work situations.

A considerable effort was made to condense in a single chapter topics that range from the interpretation of sizing data to the working principles, applications and limitations of some selected methods, including their selection criteria, subjects that are normally treated in separate publications/chapters. The idea was to provide the essential information to enable the reader to completely follow all the topics covered here. After discussing the reasons why choosing a particle sizer is not an easy task, some basic definitions of particle size, size distribution and their representations will be given in a concise manner, before addressing some of the most relevant parameters to be taken into consideration when selecting a particle sizing method. Finally, the underlying principles of some selected methods will be presented, together with their strengths and weaknesses. Naturally, the number of addressed methods had to be limited. Hence, this discussion will mainly be directed to sizing techniques normally available for routine analyses in the pharmaceutical field, from nanoparticles to some hundred micrometer particles. In order to encompass one of each class of particle sizing methods, the following techniques were selected: optical microscopy/image analysis and time-of-flight, representative of the counting techniques; static and dynamic light scattering, widely used ensemble techniques; and the cascade impactor, a separation technique frequently used for aerosol samples (nasal products). As mentioned, the ultimate goal will be to stimulate the reader's curiosity to consult other sources of information to complement this analysis.

1.1.3 Why it is So Difficult to Select a Particle Sizer

The apparent simplicity of particle size analysis is deceptive as particle sizing is a poorly posed problem. As is well known, only objects of simple geometry, namely spheres, can be unambiguously described by a single linear dimension. Non-spherical particles, as discussed below, are most conveniently described in terms of derived diameters calculated by measuring a size-dependent property of the particle and relating it to a linear dimension. As a result, different sizing methods, based on the measurement of different particle properties, might give different sizing data for the same sample. Moreover, the same measuring technique can also generate different sizing results as a consequence of distinct data processing algorithms used by the equipment manufacturers [2,3,16,17]. Complicating this, a wide range of size distributions normally have to be analysed, being not uncommon that the size range of the particles is too wide to be measured with a single device. Besides, particles, namely pharmaceuticals, include dry powders, suspensions, aerosols, emulsions and nanoparticles, which in turn can be presented as primary (individual) particles, aggregates or agglomerates (in aggregates the primary particles are bound strongly by covalent bonds, whereas agglomerates are collections of aggregates loosely held together by weak forces). Also, the recent interest in measuring nanoparticles resulted in a burst of new techniques (or new applications of old techniques) for the nanometer range, being that the smaller the particles, the more difficult it is to characterize them. Accordingly, there has never been so much diversity of sizing equipment (hundreds of commercially available instruments), sample and data treatments.

Additionally, it should be pointed out that formal training in the field of particle technology is not often as widespread as in other fields. Further, the technical information available in particle technology, namely particle sizing vocabulary, is unique and complex, and a clear domain of fine particle technology terminology is indispensable for correct data interpretation.

As a final point, it should be highlighted that the determination of particle size distribution seldom is the ultimate objective: indeed, a particle size measurement is often carried out with the aim of relating particle sizing data to a particular property or behavior of the material, and this relationship should be taken into consideration when choosing a sizing instrument. For example, if we are studying the particles of an airborne aerosol and their deposition in the lungs, a sizing method based on the measurement of the aerodynamic diameter would be more appropriate; furthermore, if a drug product is to be administered as a dry powder, a particle characterization technique capable of measuring the sample as a dry powder dispersion should be used.

Sizing equipment is not often restricted to a specific application, being normally used for more general purposes. Nonetheless, it should be borne in mind that no single technique is superior in all applications. All these reasons render the selection of the most appropriate particle sizing method a challenging process.

1.2 Particle Size Distribution

1.2.1 Equivalent Diameter

It is not possible to rationally discuss the size of a particle without considering the three-dimensional characteristics of the particle itself (length, breadth, and height). In fact, only the sphere can be fully described by a single dimension, its radius or diameter. However, most real-world particles are far from round or uniform, and with regard to particle sizing, it is often most convenient to express particle size in terms of derived diameters such as equivalent spherical diameter (ESD). ESD is defined by ISO 9276-1:1998 [18] as the diameter of a sphere that produces a response by a given particle-sizing method that is equivalent to the response produced by the particle being measured. In many cases the equivalent sphere is the one with the same volume as the particle, the so-called volume-equivalent spherical diameter (a cube of length 1?µm has a volume-equivalent spherical diameter of 1.24?µm). However, the method of measurement and the property of interest of the particle can lead to the use of other diameters, such as, for instance, the surface-equivalent spherical...