(748d) Characterising and Optimising the Use of Flow Additives in Powders and Powder Formulations

Many powders have poor basic flow properties; they block in hoppers and die feed frames, exhibit inconsistent or pulsatile discharge rates; adhere to surfaces of equipment or don’t mix readily with other materials.  In such cases it is possible to reduce particle-particle friction and change the powder’s bulk resistance to movement by the addition of a lubricant powder.

Magnesium stearate (MgSt) is used extensively as a lubricant in the manufacture of pharmaceutical oral solid dosage forms.  It is commonly added to formulations immediately prior to tableting and in low concentrations, (typically < 1-3% w/w.).

However, excessive quantities will not only impact manufacturing costs but may show no increased enhancement of flow behaviour and can produce a blend that is unmanageable in process and ultimately compromise critical quality attributes (such as tablet dissolution).  Previous studies [1-3] have indicated that, for a given system, an optimum concentration of lubricant may exist for a specific flow regime, but none of these investigations consider how different grades of MgSt perform relative to each other and with respect to multiple substrates.  Furthermore, these studies provide limited evaluation of the flow properties and it now widely accepted that a wide range of properties, that relate to the conditions a powder will experience during manufacture, need to be measured to fully understand of the ‘processability’ of a formulation [4-6].  Equally, the ideal lubricant concentration is unlikely to be consistent between different primary substrates.

Thus this study seeks to expand the understanding of the effects of adding MgSt to quantify the optimal concentration for a range of lubricants and substrates and to evaluate if the changes in flowability over a wide range of test conditions can be predicted.

This research, which was split into two parts, investigates how different powders are affected by flow additives by using a powder rheometer to measure dynamic as well as bulk and shear properties.  The analysis of the data demonstrates how the optimum levels of flow additive for each powder type in each of these measurement regimes can be identified and reviews the benefits and possible consequences of using flow additives in several applications or processes.  

Three different magnesium stearate (MgSt) formulations (Stear-O-Wet, Monohydrate & Dihydrate – Malinckrodt) were blended separately with five excipients (Avicel PH101 – FMC; InhaLac230 & GranuLac70 – Meggle; C*Mannidex & C*Sorbidex – Cargill).

The blending was undertaken for a fixed period and rotational speed in a Turbula T2A mixer (Willy A Bachofen AG).  The resultant blends were tested using an FT4 Powder Rheometer® (Freeman Technology) to evaluate their dynamic, bulk and shear properties.  The data were compared with the results generated for their respective substrates without lubricant.

For the first part of the study, PH101 was used as the substrate and combined at three concentrations (0.1, 0.3 and 0.5% w/w) with all three types of MgSt.  The results indicated that even small quantities of MgSt (0.1% w/w) significantly improve the dynamic flow properties but that increases in concentration do not further enhance these properties.  It is also observed that small additions of MgSt can reduce flowability with respect to shear properties with the addition of any of the forms of the lubricant.  Other properties show a divergent response with respect to lubricant type – for example the compressibility data shows that the MgSt dihydrate has little influence at any of the concentrations, whereas the other two forms show a slight increase in compressibility at 0.3% w/w but a 10% reduction in compressibility at the higher, 0.5% w/w, concentration.

For the second part of the study, the four additional substrates were combined with all three types of MgSt – but only at 0.3% w/w.  The results demonstrated even more complex responses.  As with PH101, the dynamic flow properties exhibit a universal improvement and a similar reduction in flowability at higher stresses during shear testing is again observed.  The compressibility data show a variation with respect to MgSt type.  InhaLac230 shows a significant decrease in compressibility when combined with the mono- and dihydrate grades but an increase with Stear-O-Wet.

This study quantifies how the addition of a lubricant can dramatically change the flow properties of a range of typical pharmaceutical materials and how the concentration level and type of lubricant is key to optimising processability and cost-efficiency.  It highlights that the mechanisms of the interaction of the substrates and the MgSt variants are complex and that different substrates interact differently with respect to MgSt type.  Incremental increases in MgSt concentration do not generate a linear response in the flow properties of the mixture and that the response profile depends on the physical and chemical attributes of the substrate and the MgSt variant.  Whilst small changes in MgSt and concentration can have a significant effect on powder flow properties, increasing the concentration further can detrimentally affect certain flow properties.

It strongly suggests that the effect of MgSt cannot be predicted mathematically – it must be measured.  The study further demonstrates why a single number characterisation is not sufficient to fully understand performance of a powder or powder formulation.

This emphasises the premise that powder flowability is not an inherent material property but is more about the ability of powder to flow in a desired manner in a specific piece of equipment and that utilising a wide range of test methodologies that subject the powder to a variety of stresses and flow regimes that simulate what may be experienced in process allowing the formulator to make informed choices. 

REFERENCES:

[1]    Pingali, K. et al, International Journal of Pharmaceutics, Volume 409, Issues 1–2, 16 May 2011, Pages 269-277.

[2]    Podczeck, F. & Newton, J.M., European J Pharmaceutics and Biopharmaceutics, Volume 50, Issue 3, November 2000, Pages 373-377.

[3]    Velasco M.V, Munozruiz A, Monedero M.C, Drug Development And Industrial Pharmacy, 21 (20): 2385-2391, 1995.

[4]    Prescott, J. K. & Barnum, R. A., Pharmaceutical Technology, 60-84, 2000

[5]    United States Pharmacopeia 2007, "<1174> Powder Flow," USP 29/NF24 edn, US Pharmacopial Convention, Inc.

[6]    Freeman R., Powder Technology, 25-33, 174, 2007.