Upscaling of external lubrication from a compaction simulator to a rotary tablet press.

External lubrication is a highly valuable alternative lubrication method as it minimizes the negative impact on tablet properties encountered when using internal lubrication. In current study, experiments were performed with automated external lubrication systems implemented in a compaction simulator and rotary tablet press using three lubricants (magnesium stearate (MgSt), sodium stearyl fumarate (SSF) and glyceryl dibehenate (DBHG)). The effect of process parameters related to the tableting process (main compaction pressure and tableting speed) and external lubrication systems (spraying time, atomizing pressure, dust extraction system and lubricant feed rate) on the responses was studied for a placebo formulation which is non-processable without lubrication. Low and comparable ejection forces were recorded for all lubricants on both tablet presses. No negative effect on tensile strength was observed for process parameters of both external lubrication systems, irrespective of lubricant type. Disintegration times were slightly higher for SSF compared to MgSt and DBHG for the tablets produced on the rotary tablet press, linked to higher lubricant concentrations on the tablets for SSF, while disintegration times were similar for all lubricant types on the compaction simulator. The potential of external lubrication for implementation on production scale tableting equipment and during scale-up was demonstrated for multiple lubricants.

Screening of lubricants towards their applicability for external lubrication.

Internal lubrication is associated with decreasing tensile strength and prolonged disintegration. These effects can be minimized using external lubrication. In current study, six lubricants (magnesium stearate, sodium stearyl fumarate, stearic acid, glyceryl dibehenate, poloxamer 188 and sucrose monopalmitate) were processed with an external lubrication system implemented in a compaction simulator. The effect of process parameters related to the tableting process (main compaction pressure and tableting speed) and external lubrication system (spraying time, atomizing pressure and dust extraction system) on the responses was studied for a placebo formulation (80% mannitol - 20% microcrystalline cellulose). Internally lubricated blends (0.75 - 4%) were processed as reference. All lubricants proved successful in reducing ejection forces through external lubrication while yielding substantially lower lubricant concentrations compared to internal lubrication. No negative effect of external lubrication on tensile strength and disintegration time was observed, irrespective of lubricant type. Similar tensile strengths and disintegration times were measured for the different lubricants. This was in contrast to internal lubrication where a decrease in tensile strength and prolonged disintegration was generally observed. Additionally, the lubricant types affected tensile strength and disintegration differently. This study demonstrates the versatility of external lubrication as an alternative lubrication method for production of pharmaceutical tablets.

Impact of alternative lubricants on process and tablet quality for direct compression.

Internal lubrication with magnesium stearate (MgSt) is associated with a reduced tensile strength and prolonged disintegration and dissolution times. In the current study, alternative lubricants to MgSt were compared with regard to lubrication efficacy and their impact on tablet properties. The lubricants were combined in different concentrations (0.5-5% w/w) with three fillers (lactose, mannitol and microcrystalline cellulose (MCC)). The high lubrication efficiency of MgSt was associated with the highest reduction of tensile strength. The micronized stearic acid (SA) grades proved good alternatives as they showed a good lubrication efficiency in combination with a limited negative effect on tensile strength. The hydrophobic lubricants (e.g., MgSt and SA) did not prolong disintegration. In contrast, delayed disintegration was observed for sucrose monopalmitate combined with all three fillers and for several other hydrophilic lubricants (sodium lauryl sulfate, poloxamers 188 and P407) combined with MCC. These unexpected findings were explained by the competition-for-water hypothesis. The potential of alternative lubricants to MgSt was demonstrated in this study. Nevertheless, the impact of lubricant addition on process and tablet quality depended on lubricant (type and concentration) and formulation (lubrication need, deformation mechanism and disintegration behavior) properties. Therefore, lubricant selection should be carefully considered in formulation development.

Effect of feed frame on lubricant sensitivity during upscaling from a compaction simulator to a rotary tablet press.

Internal lubrication can be associated with reduced tabletability. Deformation mechanism, lubricant type, lubricant blending time and paddle speed (PS) of the forced feeder are known to be influenceable factors. This study investigated the effect of lubricant blending time and PS of forced feeders on the tensile strength of lubricated microcrystalline cellulose (MCC) and lactose tablets. Magnesium stearate (MgSt), sodium stearyl fumarate (SSF) and stearic acid (SA) were used as lubricants. Tablets were produced on a compaction simulator and a rotary tablet press to investigate lubricant sensitivity during upscaling. Lubricant sensitivity was found higher for MCC compared to lactose which was attributed to the higher plasticity of MCC. The reduction in tensile strength upon lubricant addition followed the order: MgSt > SSF > SA; which could be linked to particle size, specific surface area and particle shape of the lubricants. Although differences in tensile strength were observed between the lubricant types, comparable ejection forces were obtained. The impact of PS on tensile strength was higher compared to lubricant blending time for both tableting machines. A good correlation of tensile strength and lubricant sensitivity between the compaction simulator and rotary tablet press was observed based on the calculation of paddle passes (NPP).

Effect of binder type and lubrication method on the binder efficacy for direct compression.

The effect of different binders for direct compression on tablet critical quality attributes was investigated. Dicalcium phosphate, lactose and microcrystalline cellulose were used as fillers and combined with ten binders (10, 20 and 30% w/w). Binder properties were linked to tensile strength via partial least square analysis. Tablets containing VA64F and PH105 exhibited the highest tensile strength which was linked to their compaction properties (specific work of compaction, elasticity, cohesion index) and particle size. In contrast, S1500 and E15 exhibited the lowest tensile strength of all binders. Lubrication method influenced the tensile strength as lubricant sensitivity was observed to some extent for all binders. Tensile strength was significantly higher applying external compared to internal lubrication. Fast disintegration was observed for MCC (PH105 and PH200) and starch (S1500 and NMSt) grades, whereas HPC (KEXF and KEF) and E15 resulted in delayed disintegration. Wettability measurements, via determination of contact angle, correlated well with the disintegration behaviour of the binders and can therefore be used as an indicative measurement for tablet disintegration. This study revealed the effect of binder properties, filler type and lubrication method on tablet critical quality attributes. In addition, the potential of dry binder addition for direct compression was highlighted.

Identifying Critical Binder Attributes to Facilitate Binder Selection for Efficient Formulation Development in a Continuous Twin Screw Wet Granulation Process.

The suitability of pharmaceutical binders for continuous twin-screw wet granulation was investigated as the pharmaceutical industry is undergoing a switch from batch to continuous manufacturing. Binder selection for twin-screw wet granulation should rely on a scientific approach to enable efficient formulation development. Therefore, the current study identified binder attributes affecting the binder effectiveness in a wet granulation process of a highly soluble model excipient (mannitol). For this formulation, higher binder effectiveness was linked to fast activation of the binder properties (i.e., fast binder dissolution kinetics combined with low viscosity attributes and good wetting properties by the binder). As the impact of binder attributes on the granulation process of a poorly soluble formulation (dicalcium phosphate) was previously investigated, this enabled a comprehensive comparison between both formulations in current research focusing on binder selection. This comparison revealed that binder attributes that are important to guide binder selection differ in function of the solubility of the formulation. The identification of critical binder attributes in the current study enables rational and efficient binder selection for twin-screw granulation of well soluble and poorly soluble formulations. Binder addition proved especially valuable for a poorly soluble formulation.

Evaluation of an external lubrication system implemented in a compaction simulator.

The internal blending of magnesium stearate is often associated with decreasing tensile strengths and longer disintegration and dissolution times. Therefore, external lubrication has gained interest in the pharmaceutical industry as these negative effects could be minimized using this method. In this study, an external lubrication system implemented in a compaction simulator was investigated. The influence of 2 process parameters related to the external lubrication system, spraying time and atomizing pressure, on the responses was studied using 4 common fillers and 2 model drugs. While the parameters of the external lubrication system had a significant impact on the ejection forces, no negative effect was observed on the tensile strength and disintegration time as similar values were obtained compared to non-lubricated experiments. Moreover, equal or lower ejection forces were obtained for external lubrication using a lower concentration of magnesium stearate compared to internal lubrication, where a decrease in tensile strength and prolonged disintegration was noticed for most formulations. The observed results could be correlated to the wall friction angle, compaction properties and tablet brittleness index of the raw materials and blends. This study showed the potential of external lubrication as an alternative lubrication method for lubricant-sensitive formulations.