(677b) Assessment of the Segregation Potential of Pharmaceutical Direct Compression Blends | AIChE

(677b) Assessment of the Segregation Potential of Pharmaceutical Direct Compression Blends


Kong, A. - Presenter, Pfizer Inc.
Anwar, H. - Presenter, Pfizer Inc.
Narayan, P. J. - Presenter, Johnson & Johnson PRD

Direct compression is the preferred method for the preparation of tablets due to its simplicity compared to wet granulation and dry granulation. However, direct compression blends are more prone to segregation, which can cause the undesirable separation of active pharmaceutical ingredients (API) from excipients leading to variable potency of the final drug product. Fluidization and sifting are the most common segregation mechanisms encountered during direct compression blend handling. The fluidization mechanism describes the vertical separation of particles induced by turbulent airflow, which is experienced during freefall of materials. The sifting mechanism describes the lateral separation of powders which can occur in funnel flow from hoppers for example. In this study ASTM standard testers (Jenike & Johanson) were used to characterize the fluidization and sifting segregation potential of three direct compression blends containing 2%, 4% and 8% API levels by weight. The excipients include direct compression grade lactose and microcrystalline cellulose. The fluidization segregation test was performed by fluidizing and then de-aerating a column of 100 mL powder bed through increasing and decreasing the flow rate of bottom-injected compressed air. After the test, the column was split into three equal fractions: top, middle and bottom. The sifting test was performed by center filling 1000 mL of a blend into a small funnel flow bin and then discharging the material out of the conical hopper. Beginning, middle and end samples were collected during discharge. Samples were then subdivided via a rotary micro-riffler into an appropriate size for API potency and particle size analysis. In parallel, these blends were also tableted at a 50kg pilot scale, and the tablet content uniformity results were compared against blend potency values from segregation tests. In the fluidization test, all three blends exhibited pronounced particle size and potency deviations among top, middle and bottom samples. API potency increased from the bottom to the top fractions, with inverse particle size trending (where coarser size fractions were less potent). This is a typical fluidization segregation phenomenon that is seen when the API particle size is much finer compared to excipient particle size distributions. Compared to fluidization, the segregation tendency by sifting mechanism was relatively low. Potency values slightly increased from beginning to the end samples in all three blends. The segregation indices (defined as maximum potency variation normalized by overall mean potency) were 3%, 5% and 10% for the 2%, 4% and 8% API levels of the blend, respectively. The tablet content uniformity data also showed that tablets collected at the beginning of the compression run tended to have lowest potencies in all three blends. The relative standard deviation (%RSD) of tablet potency was 2.2%, 1.6% and 3.3% for 2%, 4% and 8% API level blend, respectively. Both the sifting segregation test and content uniformity data showed that the 8%API level blend was more prone to segregation compared to the other two blends. The loss of drug-carrying ability of the direct compression excipients with increased drug loading may be contributed to this result. The segregation trend, rank and magnitude seen in the tablet content uniformity data correlated more closely with the results obtained from the sifting segregation test. The high fluidization segregation tendency observed in the experimental test was not reflected in the tablet content uniformity data. This is thought to be due to the fact that the process equipment settings and powder handling in the pilot scale runs minimized fluidization. This would also tend to indicate that the direct compression blends exhibiting high segregation potential could be handled appropriately to minimize content uniformity issues in the compressed tablets.