With rapid advancement in measurement technology, together with FDA’s PAT (Process Analytical Technologies) initiatives, pharmaceutical companies considered the importance of particle shape and size, and therefore increased its use in their day to day manufacturing process. It has been observed that by altering particle shape and size, the performance of the product can be improved. It is also observed that particle shape and size can directly determine the product performance and its regular measurement can lead to improved process and product understanding.
Why there is a need to Measure Particle Shape and Size?
Bulk drug manufacturer producing a specific product need to distinguish and understand the differences between their present and previous batches, either for product development or for quality control reasons. For some applications particle shape and size analysis shows enough data for sample differences to be fully rationalized, but while coming to other applications where samples are very close in size, measurement of subtle variations in shape may be necessary.
Process Analytical Technologies (PAT):
PAT, an initiative taken by FDA to improve cGMP by providing a regulatory framework for the introduction of new manufacturing technologies for pharmaceutical companies, is soulfully designed to enhance process control in the Pharmaceutical sector. Stepped-up process control delivers greater efficiency, less waste and lower production costs and therefore allows pharmaceutical companies to respond more efficaciously to economic challenges.
Presently, most of the manufacturing units are soulfully based on time-defined endpoints. The main aim of PAT initiative is to deviate from this approach, to one where endpoint is defined in relation to a property that is closely linked to product quality – granule size, morphic form or blend uniformity for example. Material with the desired properties is then produced more consistently and waste is minimized. This approach involves identification of an appropriate variable, with effective monitoring and control of the selected specifications.
Particle Characterization using Image Analysis:
Particle shape and size data can be concluded using automated image analysis technology, complementing both microscopy and laser diffraction for particle characterization. Unlike manual microscopy, image analysis develops statistically relevant data with no subjective bias, allowing shape, and its effects, to be studied systematically. Image analysis generates number-based distributions and is therefore extremely sensitive to the presence of fine or small numbers of foreign particle. It also record individual particle images along with visual detection and verification of agglomerates or contaminants.
Image analysis includes the capture of images using transmitted or reflected light, a lens system, and a CCD. Movement between the sample particle and the magnification lens allows scanning of a large number of particles for the production of statistically relevant data; typically several thousand particles are measured per minute. Multiple shape parameters are calculated for each individual particle and collated into distributions with all the associated distribution parameters.
Defining Particle Shape:
It has been observed that for many applications not only the particle size but also the shape is of importance, e.g. toner powders should be spherical while polishing powders should have sharp edges. With the advancement of computing technology, instruments have become available which develops the projected area of many particles in a short span of time.
Particle shape and size is an important property in detrital sediments. There are many descriptive terms that are applied to particle shape and size. The initial shape of weathered particles is effected by mineralogy: micas tend to platey, feldspars are often tabular, quartz tends to be equant. Ellipsoidal, cylindrical and spherical particles are generated by abrasion.
Elongation provides information regarding length/width ratio of the particle and is defined as (1-[width/length]).
Convexity is a measurement of the surface roughness of a particle. Convexity=(particle area/‘total area’, best visualized as the area enclosed by an imaginary elastic band placed around the particle). A smooth shape has a convexity of 1, while a very ‘spiky’ object has a convexity near to 0
Circularity is a measurement of the ratio of the actual perimeter of a particle to the perimeter of a circle of the same area. A perfect circle has a circularity of 1 while a very ‘spiky’ or irregular object has a circularity closer to 0.
Frequently used specifications in particle characterization is:
Circle Equivalent Diameter:
Circle equivalent diameter is calculated by measuring the area of a 2D image of a particle and back-calculating the diameter of a circle with the same area. It is the one that defines particle size and is calculated from image analysis data.
Virtual example showing the importance of particle shape and size
The following paragraph describes the importance of particle shape and size to a pharmaceutical company.
There was a pharmaceutical company, whose one among the four batches of a pharmaceutical excipient was repeatedly failing during the tablet preparation stage of a manufacturing process. This failure was proving to be very expensive since the tablet preparation process was at the very end of the manufacturing process where all the value has been locked into the product.
The tablet manufacturer wanted some way out to identify the failed batch much earlier as a raw material. Though the traditional microscopy or ensemble sizing method was available, they could not distinguish between the four batches which being used. So, in order to distinguish between the four batches automated image analysis was used. Automated image analysis evaluate the average convexity of each of the four batches. Convexity is a measure of surface roughness or ‘spikeyness’ of the particle surface and the failed batch was found to consistently exhibit a lower average convexity than the other three good batches.
It has been observed that the need for the best quality and higher sensitivity analytical techniques for better process understanding within the pharmaceutical industry has been spotlighted by PAT initiatives.
With the rapid advancement in digital camera technology, computing and processing power of a computer, image analysis became one of the best and an increasingly accessible alternative to analyze shape and size of the particle and is also an important tool for the pharmaceutical sector.
Availability of particle shape and size data from the above mentioned technology has made the task of identifying the differences in the behaviour of different batches easier. Therefore particle shape and size analysis through image analysis technology is coming up as one of the best way in bringing significant improvements in process efficiency and product quality in pharmaceutical sector.