(M0930-01-04) Integrated Approach to Enhance Formulation Robustness in Multiparticulate Formulations

Purpose: The dissolution of extended release (ER) multiparticulate formulations depends on drug solubility, film permeability, and membrane coating thickness. Film thickness affects drug diffusion through it. Consistent film thickness relies on selecting a substrate with low friability, consistent sphericity, narrow particle size distribution, and batch-to-batch consistency. Choosing the right coating composition and process parameters is crucial. Monitoring particle size growth can help control coating thickness for consistent quality and performance. The study aimed to utilize a laser light source optical measurement system to examine the dynamic monitoring of particle size growth during ER barrier membrane coating processes in a fluid bed coating machine. The final particle size distribution (PSD) data from in-line measurement were compared with PSD data from an off-line particle size measurement tool.

Methods: Manufacturing of Venlafaxine HCl Extended Release Multiparticulate: Venlafaxine hydrochloride was layered onto 710 to 850µm sugar spheres (Suglets 20/25, Colorcon) using a HPMC based Opadry Clear (17% solids in purified water) as a binder in a GPCG 1.1 Wurster process at 100% weight gain (WG). This was followed by a seal coat of a HPMC based Opadry Clear (8% solids in purified water) at 7% WG. The seal-coated multiparticulate were further divided into 2 lots, and each lot was further coated with a functional coat of formulated ethylcellulose coating (Corelease EC 505O, Colorcon) at 12% WG using IPA: water (90:10) at 6% solids. In Lot 1, the coating trial was performed without continuous inline monitoring, and the PSD of the multiparticulate was evaluated employing offline measurement tool, Camsizer. Furthermore, GPCG 1.1 equipment connected with a Parsum probe (SOPAT GmbH) along with an inline disperser D12 for laser light optical measurement (Figure 1), was utilized to measure PSD after completion of functional coating. In both methods (Camsizer and Parsum), the particle size was measured in the direction of feret max (length) of the particle. In Lot 2, the functional coating trial using Corelease EC was conducted in the GPCG 1.1 equipment, connected with an in-line Parsum probe. During the coating trial particle size growth was continuously measured until the PSD was similar to Lot 1. Pellets from Lot 2 trials were also tested for PSD using Camsizer P4 to confirm findings of the in-line measurements. Evaluation of Venlafaxine HCl Multiparticulate: Multiparticulates from both Lot 1 and 2 were evaluated for PSD (D10, D50, and D90) using both Camsizer and Parsum (Table 1). A correlation coefficient (%R²) and intercept equation were established from the PSD data of Camsizer versus Parsum for Lot 1 trial's functional coat. This further assisted in determining the PSD of the Lot 2 trial, which was performed with an in-line Parsum probe. Multiparticulates from both lots were evaluated for % assay of drug, using a UV-Visible spectrophotometer (Lambda 25, PerkinElmer) and dissolution performance (EDT-08LX, Electrolab) in 900mL of purified water, Apparatus I (Basket) at 100 rpm.

Results: Evaluation of Multiparticulate: PSD data from Camsizer and Parsum methods showed a strong correlation (%R2 = 99%) in both lots, confirming their consistent and reliable measurement results. Figure 2 shows a graphical representation of the particle size growth during the entire functional coating process of Lot 2. Notably, as the coating process advanced, the PSD - D50 - displayed a gradual and consistent increase in particle size. This trend suggests a smooth progression of the coating process of Corelease EC. Prior to the functional coating process in the Lot 2 trial, PSD monitoring via the Parsum showed a D50 of which subsequently increased to 1126µm by the end of the coating process, indicating an overall particle size growth of 41µm after functional coat. Similarly, for the Lot 1 trial, PSD analysis with Camsizer exhibited a D50 value of 1033µm for seal-coated multiparticulate, and 1171µm for functional-coated multiparticulate, demonstrating a total growth of 38 µm after functional coat. These findings suggest a comparable particle size growth between both lots. The drug Assay analysis of Lot 1 and 2 multiparticulate yielded values of 99% and 98%, respectively. Moreover, the drug release profiles produced a similarity (f₂) factor of approximately 70. These results highlight consistent % Assay and dissolution performance in the Corelease EC functional coating process, with similar particle size growth observed in both trial lots.

Conclusion: The study demonstrates successful formulation of ER multiparticulate containing venlafaxine hydrochloride. The application of Suglets as consistent substrates, followed by an Opadry seal coat and Corelease EC coating, achieved consistent coating process and drug release. Real-time monitoring with a Parsum enabled in-line process monitoring and control. Both the Camsizer and Parsum methods exhibit high correlation (%R2 = 99%) in Lot 1 and 2, validating particle size growth measured by Parsum.


Figure 1: In-line Monitoring Setup for Coating Trial with GPCG 1.1


Figure 2: A Plot of Particle Size Growth (D50) with Time from Lot 2 Trial


Table 1: PSD of Lot 1 and Lot 2 Corelease EC coated Multiparticulate