(T1230-06-31) Transforming Multi-particle Populations with Normal Size Distribution into Mega Beads with Discrete Sizes and Precise Drug Strengths: Surface Area and Rate of Drug Deposition as Critical Parameters

Purpose: This work demonstrates a manufacturing technique that transforms populations of particles, with normal distribution size and drug load to single beads with discrete size and drug content.

Methods: Preparation of Core Beads: Mega Bead cores consisting of Avicel 101®, Methocel E5, Kollidon CL and a water-soluble sympathomimetic drug were manufactured using extrusion/spheronization technique. Optimization of Drug Layering: Sprayed drug mixtures composed of the drug, Methocel E5®, Poloxamer 188 and purified water at suitable drug layering parameters, Drug layering experiments were conducted, using an O’Hara Labcoat M50 equipped with a 19” coating pan. The effects of surface area of initial bead load and rate of accumulation of the solid drug mass onto beads surface on dose uniformity were examined. Testing of Drug Content Uniformity: For each drug load/strength, thirty individual beads were tested. Drug content was determined using reversed phase HPLC-UV system. Uniformity of drug content and assay were calculated.

Results: Core Bead Analysis: Core beads were analyzed for particle size distribution by sieving. The bead sizes were normally distributed with 84% of beads falling between 2.5 and 4.5 mm. Effect of Bead Surface Area on Drug Layer Uniformity: Reducing the surface area of the beads significantly reduced the variability in the drug content between beads at constant solid addition rate. The % relative standard deviation of drug dropped from 19.1% to 5.4% when surface area of the pan load was adjusted from 5.17 to 2.41 m². The positive correlation between total bead surface area and variability was linear (R²=0.941). Effect of Solid Addition Rate on Drug Layer Uniformity: Reducing the solids addition rate significantly reduced the variability in the drug content of beads, at constant surface area. Relative standard deviation of drug content dropped from 22.4% to 8.1% when the addition rate was adjusted from 5.35 to 2.75 g/minute. The positive correlation between solid addition rate and drug variability was strongly linear (R²=0.930).

Conclusion: Adjusting of pan load surface area and rate of solid deposition allow for manufacturing of Mega Beads with highly precise doses, regardless to pan load weight or targeted drug strength. Beads were successfully converted from a freely formed, normally distributed particle population, into discrete units with precise strengths. Many potent drugs can easily be incorporated into this process to provide individualized dosing.

Table 1. Coating parameters for Mega Bead batches, with varying solid addition rate and surface area.



Figure 1. Size distribution of core drug loaded Mega Beads following extrusion spheronization. Size distribution was determined by sieving.



Figure 2. Drug mass uniformity as a function of (a) surface area of the pan load and (b) the solid addition rate during coating.