(M1330-09-58) Impact of Alternative Lubricants on Tablet Parameters Approaching the Over-Lubrication Problems in Continuous Direct Compression Processes

Purpose: Lubricants are used in downstream processes to reduce wall friction and powder sticking to metal surfaces during roller compaction and tablet compression. Optimizing powder lubrication is essential to produce solid dosage forms. Lubricants can impact the quality and performance attributes (powder flow, hardness, friability, disintegration, and dissolution) of the drug product, therefore, under-lubricated or over-lubricated blends must be avoided. The use of the right type/quantity of lubricant is key to have a robust process. The extended runs that are expected with continuous direct compression (CDC) processes make this aspect especially critical. This work explores over-lubrication problems by comparison magnesium stearate (Parteck® LUB MST) with alternative lubricants, sodium stearyl fumarate (PRUV® and LUBRIPHARM) and Glycerol dibehenate (Compritol 888). The lubricants were evaluated for their impact in the production of solid dosage forms with the objective to categorise the best lubricant for CDC processes that reduces the risk of over-lubrication, minimizes ejection force and improves flowability.

Methods: The different lubricants were benchmarked for processability, performance and tablet attributes. All the lubricants were added to the same formulation (2:1 MCC:Lactose) in different concentrations (1-3%w/w) and submitted to different mixing conditions (32-67rpm and 7.5-30mins). A total of 32 blends with different lubricant and process conditions were prepared using a Turbula or a 15L bin blender. Powder flow properties were evaluated using a ring Shear Tester RST-XS.s, running yield locus and wall yield locus. Compressibility, tabletability and compactability (CTC) profiles were generated using a benchtop R&D press Styl’one nano from Medelpharm simulating a rotary tablet press at 72 RPM with compaction pressures from 220 to 50MPa. The tablets attributes were evaluated using a hardness tester ERWEKA TBH325, an analytical scale SARTORIUS, and thickness using a digital caliper - Manutan. Friability and disintegration tests were also analyzed using a ERWEKA TBH125 and SOTAX DT50.

Results: CTC’s profiles were obtained by producing 300mg tablets at mixing conditions of 32 rpm (7.5, 15 and 30 mins) and 67rpm (30 mins) corresponding to a range from 240 to 2010 revolutions. TS and ejection forces at fixed solid fraction (SF) were used to compare the impact of the different lubricants on the produced tablets (Fig.1,2). MgSt was the lubricant with the highest impact on the produced tablets. Tablets lubricated with MgSt presented a decrease of 60 and 77% on their TS value at 0.95 SF, for 1 and 3%w/w concentrations, respectively. The results represented in Fig.1, had, also, shown that the highest reduction on TS caused by the MgSt was not associated to the highest lubrication efficacy given that the highest reduction in ejection force, during compression, came from the use of PRUV for 1% w/w concentration and from the use of LUBRIPHARM for 3% w/w concentration, as it is shown in figure 2. Once again analyzing Fig.2 and Fig.1, respectively, PRUV is the one that stands out as the greatest ejection force reducer, while Compritol 888 presented the lowest reduction in TS. Regarding friability, all tablets were tested, but only the ones lubricated with MgSt had a friability percentage equal or above 1.0%. For the other 3 lubricants, in all concentrations and mixing conditions, the tablets had passed the test with the best performance being showed by the tablets lubricated with Compritol 888 where the average friability percentage was always below 0.1%. Disintegration tests were done and had shown that none of the lubricants had a considerable effect on the disintegration time of the produced tablets, as they maintained their disintegration time around 30 seconds for the compaction pressures in study during this test (~100 MPa). The yield locus test, show a FFC (flowability indicator) maximum value (around 20) for powders mixed with MgSt. For powders lubricated with LUBRIPHARM and PRUV, the maximum value decreases to approximately 10-11, although LUBRIPHARM presents slightly higher values. Finally, Compritol 888 presents the lowest values, around 9.

Conclusion: Comparing TS effects with ejection force reduction the most efficient lubricant, was PRUV, as it had low impact on tablets TS while had the highest ejection force reduction percentage. Compritol 888 was the lubricant that less impacted tablet attributes, and despite not being the best performer decreasing the ejection force, the ejection values were acceptable. None of the lubricants tested provided significant changes in disintegration times. Finally, flowability tests had shown that MgSt is the one that has a higher positive impact in the blend flowability. All the blends tested had a free flowing behavior. All in all, this study demonstrated the potential of the different lubricants available in the market. Showing that despite the dominance of MgSt as lubricant the challenges expected in CDC processes (loss in weight feeding, linear blending, etc) could be overcome using other available lubricants as SSF and Compritol 888.

Tensile strength at 0.95 SF vs. blending revolutions

Ejection Force at 0.95 SF vs. blending revolutions