@conference{
author = "Grujić, Branka and Jelić, Vesna and Medarević, Đorđe",
year = "2022",
abstract = "Introduction The study examined the development of barium sulphate tablets that do not dissolve in the digestive tract
and are used as a contrasting agent for measuring transit time through the column. The main problem for obtaining non-degradable tablets is the formation of a compact
polymer matrix that does not disintegrate in digestive fluids over a long period of time (Chaussade et al., 1986; Felder et al., 1984). In pharmaceutical technology, thermal techniques of granulation, extrusion, and the like, polymers and active pharmaceutical ingredients (APIs)
are known for achieving better solubility of low soluble substances or for achieving slow release of highly soluble substances from solid preparations (Obradović et al., 2016) Several different formulations were tested in which they were varied: the presence of different polymers Eudragit® RS PO and/or PMMA, wet granulation and direct compression procedure, different granulation of filler calcium hydrogen phosphate dihydrate, and the time of sintering in a pair of organic solvents of acetone or IPA at different time intervals. The results of the tensile
strength of the tablets that are important for the further sintering process and the degradability of sintered tablets were monitored as the output parameter. In the final
manufacturing process - tablet sintering, only formulations in which the tensile strength of the tablet was ≥20 MPa were used. For this reason, direct
compression tablets, as well as wet granulation formulations with PMMA, are not sintered. The tensile strength of the tablet before and after sintering indicates that the "wet" granulation is more efficient with IPA
because it produces better compacted granules (higher tensile strengths), while acetone is more efficient in the sintering process at 35oC , which is expected due to the higher vapor pressure at that temperature compared to the IPA.
Materials and Methods The tablets are made by the wet granulation process, and the direct compression process, and the pharmaceutical and technological characteristics of the tablets have been compared. The API Barium sulphate (Merck, Germany) was used. The essence of the formulation is based on the use of two polymers: polymethyl methacrylate (PMMA DP 300 U) and copolymers of ammonium methacrylic acid (Eudragit® RS PO).The role of PMMA DP 300 U is to with Eudragit® RS PO synergistically form in physiological
media an insoluble, completely impermeable and non-
swelling martix regardless of the pH value of the media.
Calcium hydrogen phosphate dihydrate, an insoluble excipient, was selected as the filler. Two types of this filler were selected, powder and fine granular (Emcompress®) intended for direct compression due to improved flowing and compressible properties. Magnesium stearate was used in order to achieve adequate lubrication and to eject the tablets from the matrix. Acetone and/or IPA were chosen as solvents in combination with concentrated ethanol and water. Wet granulation In laboratory tests, mixing and wet granulation were
carried out in a high shear mixer and dried at 50 °C in a fluidization oven. A vacuum processor was used for the pilot test. In the vacuum processor homogeneous mixing of the previously measured barium sulphate, calcium hydrogen phosphate dihydrate, Eudragit RS PO, and PMMA DP 300 U. The granulation solution is a mixture
of acetone or isopropanol, concentrated ethanol, and purified water, i.e. isopropanol and purified water and purified water. The wet agglomerated mass is dried in a vacuum processor by heating to a temperature of 50 °C.,
and the vacuum is included with occasional stirring until is achieved loss on drying of not more than 1% (at 105
oC). Magnesium stearate was added to the diluted granulate and further stirred. Tableting Compression of laboratory trials was performed on an eccentric tablet press EKO type, and pilot trials were performed on a Kilian rotary tablet press Synthesis 500.
For the 80 mg dose, the characteristics of the tablets were:
mass: 0.268 g, diameter: 8.8 - 9.2 mm, and hardness: at
least 20.0 MPa. Sintering Tablets were sintered in a sealed chamber saturated with either acetone vapor or isopropanol vapor at 35ºC (± 2 ºC) for 8h, 16h, 24h, 32h, and 40h. Drying After sintering, the tablets were dried or residual
acetone or isopropanol is removed to a maximum of 2.5 mg/tablet. The sintered tablets were dried according to the scheme: 1) Temperatures 22 ºC for 16 h, 2) 40ºC for 24 h, 3) 50 ºC for 8 h and 4) 55ºC for 8 h.
Results and discussion In the case of tablets made by direct compression, it
was not possible to achieve the corresponding mechanical characteristics of the tablets: the strength and friability, which were necessary for the further process and manipulation, or consolidation, by sintering in an organic solvent vapor. Formulation made with PMMA DP 300 U, without the addition of the Eudragit® RS PO polymer, could not be compressed due to the spherical shape of PMMA DP 300 U which is extremely unfavorable for compression. The results of tablet tensile strengths before
and after sintering indicate, for IPA and acetone solvents, that IPA solvent is more effective for wet granulation because it produces better compacting granules (higher tensile strengths are obtained), while acetone is in the sintering process at 35 °C a more efficient solvent, as expected given the higher vapor pressure at that temperature compared to IPA. The time interval during
which the disintegration was tested was up to 7 days because it is the interval during which the transit of the tablet through the column in subjects with slow passage is examined in vivo. When it comes to the efficiency of the
organic solvent in the process of polymer matrix consolidation by sintering, the slightly lower efficiency of isopropanol compared to acetone is observed. The
sintering time has a significantly greater effect on matrix consolidation. The criteria for intact barium sulphate tablets within a 7-day time interval was fulfilled only by formulations with a mixture of Eudragit® RS PO and PMMA DP 300 U polymers obtained by granulation with acetone or isopropanol using a sintered process during 35h. Conclusion Tests of various formulations and technological parameters in the production process have shown that in order to obtain a contrast agent for testing the functional radiology of the colon, rectum and anal canal, i.e. measuring the transit time through the colon, which meets the defined criteria, optimal formulation is with calcium hydrogen phosphate dihydrate powder, an equivalent amount of Eudragit RS PO and PMMA DP 300 U
polymers, isopropanol as solvent in addition to ethanol
and water in the process of wet granulation, and sintering process in an organic acetone solvent vapor at 35°C.",
publisher = "Macedonian Pharmaceutical Association, Faculty of Pharmacy, Ss Cyril and Methodius University in Skopje",
journal = "Macedonian Pharmaceutical Bulletin",
title = "Pharmaceutical and technological characteristics of barium sulphate tablets -the screening of various formulation factors",
volume = "68",
number = "Suppl 1",
pages = "243-244",
doi = "10.33320/maced.pharm.bull.2022.68.03.116"
}
