Medication production follows rigorous guidelines to achieve products of highest standards. Each process step is accurately monitored during the manufacture of various active and auxiliary components. It is necessary to stop the repetition of mistakes directly in the first process chain to ensure an accurate analysis, for which sample preparation is always the first step. In the case of tablet analysis, it is specifically the comminution. The selection of the appropriate technique and the parameters to be adjusted also play a key role in the success of the analysis.
Classical Versus Innovative Comminution Methods
Dissolution relies on the interaction of solvent particles and the particles formed by the substances. The dissolving takes place on the surface of the substance. The rate of dissolution can be stated by the Noyes-Whitney-Equation (Figure 1).
Figure 1. Noyes-Whitney-Equation
In earlier days, classic comminution involved manual comminution with a mortar. At present, this process is significantly improved with the automatic mortar mill. Reproducible results can be achieved by adjusting the different parameters. This is virtually not possible with a hand mortar as it is operator-subjective.
The basic structure of the sample is not changed when comminution is performed using the Mortar Grinder PULVERISETTE 2, which induces only a slight increase in temperature thanks to its gentle grinding. However, the classical method can yield only particles finer to roughly 10-20µm because of the lower grinding energy. The limit of the dry grinding process is manifested by the agglomeration of the sample due the Van der Waals forces and the electrostatic interplays of the small particles.
The addition of liquid in the case of wet grinding helps to obtain a smaller particle size. Nevertheless, the particle size will be constant after a certain period because the suspended particles are not contacted by the pestle any longer and floats past it. The innovative comminution of the Planetary Micro Mill PULVERISETTE 7 premium line produces particles of size far below that for chromatographic methods when considering factors such as grinding ball size, amount of liquid, grinding duration and rotational speeds. Figure 2 compares the obtainable particle size with a Mortar Grinder PULVERISETTE 2 after 30 minutes of grinding and with the Planetary Micro Mill PULVERISETTE 7 premium line after 5 minutes of pulverization.
Figure 2. Comparison of Obtainable Particle Size with Mortar Grinder PULVERISETTE 2 and Planetary Micro Mill PULVERISETTE 7 Premium Line.
Working Principle of Planetary Ball Mill
In a planetary ball mill, pulverization starts with the addition of a sample along with the grinding balls in the grinding bowl fastened to a sun disk. The grinding bowl turns counter clockwise around the disk center. Effective comminution takes place due to impact, friction and blow effects of the grinding balls (Figure 3). For planetary mills, the optimum rotational speed is limited to roughly 800rpm.
Figure 3. Working Principle of the Planetary Ball Mill.
Tensioning of the grinding bowls is the key variation of the premium line to a traditional mill. In the premium line, the lowering of the grinding blows into the disk (SelfLOCK technology) enables an optimal rotational speed of 1100rpm. This, in turn, increases the kinetic energy of the grinding medium by 150% and considerably shortens the grinding duration into the nano range, thereby facilitating the comminution of nano particles for certain materials.
Rules of Effective Sample Preparation
Dry grinding must be used for coarse comminution. If the produced powder becomes slightly sticky, wet grinding is started with the addition of the liquid. Floating effects of the sample particles would result in an inhomogeneous sample. Moreover, the quantity of liquid for the wet grinding needs to be selected relating to the sample material. The optimal comminution is attained in liquid-pasty suspensions.
Perfect Sample Processing
The sample particles float past the grinding balls if the suspension is too runny. Conversely, the energy of the grinding balls is decelerated if the suspension is highly viscous. During the comminution process, the amount of the liquid must be adjusted anew due to the necessity to wet the newly formed surfaces. The critical temperature of the grinding sample must not be exceeded and the impact of the increased agglomeration with high temperatures needs to be monitored.
In further processing, the grinding balls are replaced step by step for smaller grinding balls to achieve a smaller sample size. At this stage, the degree of comminution needs to be verified by particle size analysis. The degree of comminution ‘Z’ is the ratio of largest particle diameter D in the base sample to the largest particle diameter 'd' in the comminuted product (Figure 4). It provides information relating to the performance of a comminution process.
Figure 4. Degree of Comminution Formula.
Comminution Process in Antibiotics Analysis
The comminution process can be applied to analyze the quality of antibiotics as outlined in the guidelines of U.S. Pharmacopoeia and European Pharmacopoeia. Detecting the possible inorganic contaminations during production is part of the analysis. Using stripping voltammetry, the comminuted supplement can be analyzed for metal ions, which mostly arise from mercury containing thimerosal used as a preserving agent for pharmaceuticals and cosmetics. These delicate samples in their complex composition need an appropriate sample preparation in a system that transports the samples under optimal conditions without falsifying them.
The selection of a comminution technology must be based on the task and analysis to be performed in order to achieve optimum results. If the focus is only on the particle size, nano mills are suitable as they take much briefer grinding durations and can produce a particle size less than 0.1µm.
This information has been sourced, reviewed and adapted from materials provided by FRITSCH GMBH - Milling and Sizing.
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