(533e) Effect of Lubricant Mixing Time and Concentration, Compaction Speed and Compression Force On the Dissolution Profile of a Control Release Formulation

Sarang Oka, Pallavi Pawar, Fani Boukouvala, Fernando Muzzio

Rutgers University

Segregation or de-mixing of granular matter has been studied in great depth and in the pharmaceutical industry continues to be a routine nuisance. In the current project, significant variability was observed in the dissolution profile between tablets made from a multiparticulate formulation. The formulation in discussion is a typical formulation consisting of an API in the form of granulated pellets, filler, Magnesium Stearate and a rapid disintegrant.  The particle size of the pellets is 600 μm. Tablet dissolution is performed in a standard USP dissolution apparatus-2. The dissolution profile demands no more than 20% of the drug to be dissolved in 60 minutes, no more than 35% in 120 minutes, between 20-45% in 480 minutes and no less than 80% in 1440 minutes.

The standard deviation in the value of the amount of drug dissolved in one hour was found to be unacceptably high by regulatory standards. The observation was attributed to segregation since the final formulation exhibits a significant tendency to demix.  

In order to enable a QbD approach for solving this problem, preliminary studies were conducted to examine the effect of several variables on the dissolution profile of the tablets. It was hypothesized that the amount of lubricant and the amount of shear in lubricated mixture could have a significant impact on the observed response. Compression speed and compression force were also considered to be potentially important.

The work focused on conducting a preliminary set of designed experiments to test the relative importance of multiple variables on a lab scale, perform statistical analysis to determine significant parameters affecting dissolution and consequently develop a more concise Design of Experiment to determine the design space at the manufacturing scale. The original formulation contains 0.2% MgSt. The study was a full factorial DOE with 0.2%, 0.4% and 0.6% MgSt mixed for 50, 100 and 150 revolutions that result in 10 blends (the 10^th blend employs 0.2% MgSt mixed for 300 revs). Mixing was performed in a conical twin-axial mixer at 30 rpm. The blend was sampled to test mixing homogeneity. Mixing homogeneity was quantified by performing offline NIR measurements on extracted samples. The blend is finally compacted in a tablet simulator at 3 speeds and 3 punch depths (compaction force) resulting in 9 compaction conditions per batch leading to 90 tested conditions in all.

Analysis of variance tests are performed on the ensuing data set. Statistical significance of compaction force, compaction speed, concentration of lubricant and mixing time of lubricant on percent drug dissolved in 60 minutes is tested. The compaction speed, lubricant concentration and lubricant mixing time are all found to be statistically significant parameters which affect the amount of drug dissolved in 60 minutes.  Coupled interactions of the above parameters are found to be significant while three way interactions were found to be insignificant.

The dominant effects were the compression speed and the amount of lubricant (Magnesium Stearate in this case) in the formulation., leading to a large interactive effect with the compression force. At low levels of Magnesium stearate, an increase in compression force increased the dissolution rate, perhaps due to increased pellet breakage. On the other hand, at higher levels of Magnesium stearate, the rate of dissolution decreased with an increase in force, due to increased tablet consolidation.