Drug Discovery & Pharmaceuticals


The Importance of Comminution in Pharmaceutical Analysis Leos Benes, B.Sc.Pharm. Technology, Fritsch GmbH, Email: benes@fritsch.de


The determination of substances contained in tablets after the production process is mandated according to the analytical rules of the German and European Pharmacopoeia. These rules include an analysis in regards to quality, effectiveness and safety of all contained active components and auxiliary materials.


The importance of Comminution


The process steps are divided into comminution, dissolution and ensuing analysis. In the analytical pharmacopoeia are besides the direct titration, especially the chromatographic methods such as ion chromatography, HPLC and gas chromatography utilised. A prerequisite for these technologies is that the samples have to be in liquid and fi ltrated form before they can be added onto the column. The dissolution of the tablets proves to be very diffi cult with certain active components. Therefore it is during the comminution process extremely important to keep the particle size possibly small or obtain a suspension by a wet grinding, which can be diluted even further.


Classical methods of the comminution with the mortar mill offer the advantage of a gentle comminution i.e. the thermal load of the sample is kept at a minimum. This comminution is utilised with especially sensitive analytes in order not to destroy these during sample preparation. But the obtainable fi nal fi neness is limited and the ensuing dissolution afterwards can also be a problem. The innovative manner of the comminution with some planetary micro mills achieves particle sizes below the critical area within a short time, even with problematic compositions of active ingredients. The dissolution already begins during the wet grinding process, so the obtained suspension can be diluted without any problems for the ensuing analysis.


Introduction


The production of medication is subject to very stringent guidelines and must therefore in regards to the product quality meet highest standards. During the production of the various active and auxiliary components each process step is precisely monitored. In order to guarantee an accurate analysis the repetition of mistakes must be stopped directly in the fi rst process chain. Here the fi rst step is always the sample preparation. In the analysis of tablets it is specifi cally the comminution. The further success of the analysis also depends directly on the selection of the method and the parameters to be adjusted [1].


Classical vs. Innovative Methods


The comminution process belongs to the basic operations in pharmacy. Since humans produced their fi rst phytopharmaceuticals themselves, they realised that the extraction of an active component is more optimal in fi ner substances. Dissolving depends on the interplay of solvent particles and the particles which the substances form.


The dissolving occurs on the surface of the substance. The larger the surface of a certain amount of a substance is, the faster it is dissolved. Therewith the relationship between particle size for example of a powder and its dissolving ability in the solvent could be proven. Mathematically the facts can be expressed with the Noyes-Whitney-Equation [1,2,3].


Figure 2. Obtained particle size with the Fritsch Mortar Mill PULVERISETTE 2 after 30 minutes of grinding (black curve) and achieved particle size of the Fritsch Planetary Micro Mill PULVERISETTE 7 premium line after grinding 5 minutes (yellow curve).


The grinding technology in detail Figure 1. Noyes-Whitney-Equation Classic Comminution


The classical method used in earlier days used to be the manual comminution with a mortar. Today this process step is substantially alleviated with the automatic mortar mill. The adjustment of the most various parameters makes it possible to obtain reproducible results. This is almost impossible with a hand mortar since the application of energy fl uctuates between users and can’t be constant. A mortar grinder with an exact to the second adjustable grinding duration is desirable for the comminution so it is easier to integrate the results into the validation. The grinding should be gentle to ensure only a slight rise in temperature is induced and therefore the sample in its basic structure not altered.


The sample is added along with the grinding balls in a grinding bowl in a planetary ball mill. The grinding bowls are fastened to a so called sun disk and turn counter clockwise around the centre of the disk. Due to impact, blow and friction effects of the grinding balls, the sample is comminuted effectively. The maximal possible rotational speed for planetary mills is limited to approximately 800 rpm. The decisive difference of a premium mill as opposed to a conventional mill is the tensioning of the grinding bowls. Instead of fastening them to the sun disk, here the grinding bowls are lowered into the disk (SelfLOCK technology). This now allows a maximum rotational speed inside of 1100 rpm and therefore an increase of the kinetic energy of the grinding medium by 150%. The grinding duration into the nano range is drastically reduced respectively making the comminution of nano particles for certain materials actually possible [4].


The most important parameters


In order for the sample preparation to remain faultless, several rules have to be observed. The coarse comminution should always be conducted as a dry grinding. Only in the second step, with slight sticking of the produced powder, the liquid, the solvent is added. This is due to possible fl oating effects of the sample parts which would cause an inhomogeneous sample. Additionally, the amount of liquid for the wet grinding must be selected in regards to the sample material. The optimal comminution is achieved in liquid-pasty suspensions.


Innovative Comminution


Inevitably there are limits with regards to the obtainable particle size. Due to the lower grinding energy only particles with a fi neness of approximately 10 - 20 µm can be produced. The end of the dry grinding process is marked by the sticking of the samples. Here the Van der Waals forces and the electrostatic interplays of the small particles cause the agglomeration of the sample. In order to obtain a smaller particle size liquid is added in the next step in order to continue with the wet grinding. During this process, after a certain period a constant particle size will be obtained, since the particles in the suspension are not touched by the pestle any longer and fl oat past it.


For a planetary micro mill to allow a comminution far below the required range of particle size for chromatographic methods important parameters will have to be considered, such as, amount of liquid, grinding ball size as well as grinding duration and rotational speeds.


Figure 4. Formula degree of comminution


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