Use of Mercury Porosimetry and Nitrogen Adsorption in Characterisation of the Pore Structure of Mannitol and Microcrystalline Cellulose Powders, Granules and Tablets

USE OF MERCURY POROSIMETRY AND NITROGEN ADSORPTION IN CHARACTERISATION OF THE PORE STRUCTURE OF MANNITOL AND MICROCRYSTALLINE CELLULOSE POWDERS, GRANULES AND TABLETS Sari Westermarck, 2000, University of Helsinki (FIN), pp. 50. ISBN952-91-2534-8 The effects of pretreatment and scanning speed of mercury porosimetry on the mercury porosimetry results of non-hygroscopic mannitol and hygroscopic microcrystalline cellulose powder, granule and tablet samples were studied. Behaviour of water in the structure of these samples during mercury porosimetry was evaluated. The effect of granulation and tableting on the pore structure of mannitol and microcrystalline cellulose was investigated. Furthermore, mercury porosimetry and nitrogen adsorption methods were compared. Granules were manufactured by wet granulation with a high-shear mixer. Tablets were prepared both by direct compression and from granules with an instrumented rotary press using three compression pressures. Porosity parameters were determined with mercury porosimetry and nitrogen adsorption. Pretreatment has an effect on mercury porosimetry results of non-hygroscopic mannitol and hygroscopic microcrystalline cellulose samples. Water affects with different mechanisms the results of samples of different physical structures, i.e. powder, granule and tablet samples. Water surprisingly increases the volume of the smallest pores of both mannitol and microcrystalline cellulose granules in high-pressure mercury porosimetry. Similarly, water increases the volume of the smallest pores of microcrystalline cellulose tablets compressed from granules with the highest compression pressure used in the study. Water condenses into the smallest pores of microcrystalline cellulose tablets manufactured by direct compression, hinders the intrusion of mercury and decreases the volume of the smallest determined pores. Water settles into the structure of mannitol and microcrystalline cellulose tablets in the pore diameter range of 50 – 2000 nm and 500 – 2000 nm, respectively. Maximum of the volume pore size distribution at this pore size range shifts towards larger pores with increasing moisture. Proper pretreatment and determination of water content of the samples before mercury porosimetry measurement is important. Due to low scanning speeds used in the measurements, scanning speed does not have an effect on the result of low-pressure porosimetry analysis. Total pore volume determined with high-pressure porosimetry is unaffected by scanning speed, too. However, other porosity parameters determined with high-pressure porosimetry were influenced when different scanning speeds were used in determinations. The smallest pores of the samples were not accurately determined with fast scanning. In tablet samples, scanning speed affected the pore structure determinations even in the larger pore size range. Therefore, slow scanning speed in the measurements is preferable. Wet granulation increased the compactibility of mannitol, but decreased that of microcrystalline cellulose. Mannitol granules had a porous structure, whereas microcrystalline cellulose granules were hard, dense and non-porous. Mannitol powder and granules deformed by fragmentation and plastic deformation under compression. Microcrystalline cellulose powder deformed plastically, and the structure of hard granules was destroyed when compressed with the highest compression pressure. The pore structure obtained with mercury porosimetry describes the behaviour of powder and granules and the voids between them in granulation and compression. Nitrogen adsorption emphasizes the changes in the intraparticular structure of the particles during compression. Due to the low porosity of pharmaceutical samples and the different measurement ranges of these methods, total pore volume, specific surface area and intensities of volume pore size distributions obtained with these two methods are not equivalent. Pores of mannitol samples are detected at the same pore size range with both methods. However, microcrystalline cellulose samples may be deformed during mercury porosimetry measurement, because the pores are not determined at the same pore size range as with nitrogen adsorption. Volume pore size distribution is a useful parameter showing where the changes in the structures of the samples occur during processing. Specific surface area obtained with nitrogen adsorption describes well the behaviour of pharmaceutical materials during compression. Together mercury porosimetry and nitrogen adsorption describe well the behaviour of materials in pharmaceutical processes. LIST OF ORIGINAL PUBLICATIONS This thesis is based on the following original papers, which are referred to in the text by the Roman numerals I – V. I Westermarck, S. , Juppo, A.M., Koiranen, K. and Yliruusi, J., 1998. Mercury porosimetry of pharmaceutical powders and granules. J. Porous Mater. 5, 77-86. II Westermarck, S. , Juppo, A.M., Kervinen, L. and Yliruusi, J., 1998. Pore structure and surface area of mannitol powder, granules and tablets determined with mercury porosimetry and nitrogen adsorption. Eur. J. Pharm. Biopharm. 46, 61-68. III Westermarck, S. , Juppo, A.M., Kervinen, L. and Yliruusi, J., 1999. Microcrystalline cellulose and its microstructure in pharmaceutical processing. Eur. J. Pharm. Biopharm. 48, 199 – 206. IV Westermarck, S. , Juppo, A.M. and Yliruusi, J., 2000. Mercury porosimetry of mannitol tablets: effect of scanning speed and moisture. Pharm. Dev. Technol. 5 (2), 181 – 188. V Westermarck, S. , 2000. Mercury porosimetry of microcrystalline cellulose tablets: effect of scanning speed and moisture. Eur. J. Pharm. Biopharm. 50, 319 – 325.