User of ordered mixtures to obtain high dose homogeneity in mini-tablets : studies of orally disintegrating systems for children

Abstract

Studies have shown that homogeneity is higher in ordered mixtures compared to random mixtures. Based on this ordered mixtures should be particularly suitable for the preparation of mini-tablets. The overall aim of the study was to compare the homogeneity of ordered mixtures prepared using different particle size of carrier particles, and test their suitability for preparation of mini-tablets. The mini-tablets are intended for use as orally disintegrating systems (ODT) for children. Granulated, spray dried and co-processed mannitol samples were used as carrier particles and sodium salicylate and ibuprofen were studied as fine particulate drug for preparation of ordered mixtures. For compression of mini-tablets, ordered mixtures were prepared using mannitol samples, Pearlitol 200SD,300DC,400DC and 500DC (Pearlitol, France) in combination with sodium salicylate (Sigma Aldrich, Germany). The drug substances were grinded manually in mortar with pestle and screened through a sieve of 45 μm in mesh size. Also the carrier materials were sieved in order to collect the following fractions; 180-250 μm (Parteck ODT, Pearlitol (Flash, 200SD and 300DC)), 250-355 μm (Pearlitol 400DC) and 355- 500 μm Pearlitol 500DC. The raw materials were characterised using microscopic methods, Helium pycnometry, steady state and Blaine permeametry, particle size analysis (laser diffraction and sieving analysis), bulk and tapped density. Micronized sodium salicylate was mixed with selected carrier (1% w/w) in a Turbula mixer for 24 and 48 hours (n=2).The homogeneity of the ordered mixtures were examined by withdrawing 30 random sample units from the powder mixtures using a micro-thief (20± 2mg). The sample units were quantified by direct UV-assay. The amount of drug in each sample was normalised by dividing the experimentally determined content by the theoretically calculated content. The homogeneity of the mixtures was expressed as the relative standard deviation of the normalised values. A conventional mixture (drug particles screened through 500 μm mesh size, mixed with mannitol sample in Turbula mixer for 10 min), was made for a comparison of the relative standard deviation with the relative standard deviations of the ordered mixtures. All the ordered mixtures resulted in high dose homogeneity after 48 hours of mixing. The lowest particle size fraction resulted in ordered mixture after 24 hours and the larger particle size fractions needed 48 hours. The high dose homogeneity was proven also in the minitablets. The conventional mixture showed poor homogeneity, but resulted in better homogeneity when sample size increased. This proved ordered mixtures ideal solutions for mini-tablets, as the production is dependant on homogenous powder mixtures. All minitablets complied with the requirements for uniformity of mass and content for single dose 8 preparations. The mini-tablets demonstrated low friability’s, high crushing strengths and suitable simulated wetting times with respect to European Pharmacopoeia requirements, which made them possible to use as ODTs.