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. For drug substances intended for use in solid or suspension drug product, PSD can have a significant effect on dissolution rates, bioavailability, and/or stability.

Crystallization Processes

Crystallization is the main separation and purification step for the manufacturing of drug substances. The PSD obtained during crystallization is influenced by a combination of various mechanisms that occur during crystallization, such as nucleation, growth, aggregation, attrition, breakage, etc. Control of PSD during crystallization is critical to achieving the desired product properties. When the particle size cannot be consistently controlled during crystallization to meet the desired specifications, an extra processing step such as dry milling is required. The PSD obtained during the crystallization step affects the efficiency of downstream operations such as filtration, drying, formulating, and product effectiveness such as bioavailability and shelf life. Thus, the control of PSD is an important objective during the operation of crystallization process.

Manufacturing

At the manufacturing stage, PSD has a critical effect on the content uniformity of solid dosage forms, where poor content uniformity would result if a drug powder were not dispersed evenly throughout a mixture with excipients. A leading cause of poor content uniformity is a mismatch of drug and excipient particle size and density leading to segregation during sampling and manufacture, especially for low drug to excipient ratio blends. However, the diversity of particle treatments, methods of particle size distribution (PSD) 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.

Particle Size Analysis

Essentially all automated determinations of particle size are obtained indirectly from direct measurements of some parameter other than the complete geometry. These parameters are associated with a physical phenomenon in which the particle is involved. The parameter being directly measured is related to particle geometry by some law, theory or model describing the physical phenomenon. If the particles under test are of irregular shape, then the most probable outcome is that the results will differ. Two particles that, for example, settle with the same velocity (therefore, are the same Stokes size) can scatter light differently (therefore, have different Mie sizes). Two particles that pass through the same screen mesh have the same sieve size, but may have very different volumetric size as determined by electrozone sensing.

The apparent simplicity of particle size analysis is deceptive. Particle sizing is a poorly posed problem. As a matter of fact, only objects of simple geometry, namely spheres, can be unambiguously described by a single numerical descriptor. The size of irregularly shaped particles is typically expressed in terms of equivalent spherical diameters. However, different particle-sizing instruments use various algorithms based on surface area, volume, or linear dimension to calculate equivalent spherical diameters. The difficulties encountered when relating empirical information derived using different methods would not exist if the component particles were spherical. In the real world of pharmaceutics, particles are rarely (if ever) spherical, and consequently it is important to understand the importance of particle shape and morphology.

Often, manufacturers producing a particulate product need to identify and understand the differences between batches, either for product development reasons or for quality control purposes. For some applications particle size analysis generates enough data for sample differences to be fully rationalized, but for applications where samples are very close in size, measurement of subtle variations in shape may be necessary. For instance, the PSD for two materials could be the same, but they could be clearly not identical under the microscope. It is likely that these two materials would behave differently during processing, or in their final product form. For example, their flow and abrasion characteristics would be dramatically different. Therefore, particle size data alone would not allow differentiation between them. As the result, the measurement and expression of particle size is intimately bound with the shape and morphology of the constituent units that make up the ensemble of particles.

The Physical Characterization team at Exova is equipped with variety of instrumentation for complete characterization of particulate for pharmaceutical applications, such as laser diffraction, liquid particulate counter, specific surface area (BET), helium pycnometry, optical and electron scanning microscopy combined with digital image analysis software.