(W0930-06-38) Optimized Platform-Based Formulation Strategies Can Accelerate Drug Development for Targeted Delivery: From Process Design to Performance Evaluation

Purpose: A platform-based drug delivery system offers a predefined and optimized framework that can be readily adapted for the development of drug-loaded microparticles, potentially reducing formulation development timeframes. Spray-drying, a well-established and scalable manufacturing technique, enables the precise engineering of particle delivery platforms. Through careful control of spray-drying parameters, critical quality attributes (CQAs) can be effectively tailored for targeted drug delivery. Despite its advantages, however, small changes in processing conditions can lead to large variations in the CQAs of the final product. This potentially extends development, requires significant resources, and poses challenges for rapid formulation development. In the context of nose-to-brain drug delivery, effective targeting of the olfactory region requires engineering microparticles within a specific size range, typically 10–50 µm (1). The goal of the present study was to optimize spray-drying parameters using a design of experiments (DoE) approach for the development of a PVP-based delivery platform. The optimized spray-drying conditions were later adapted for the spray drying of drug-loaded microparticles intended for nose-to-brain delivery.

Methods: A D-optimal design with three-factors (atomization pressure, solids content and inlet temperature), 3 levels, and 18 experiments was developed using JMP® Pro version 15.2.0 (SAS Institute Inc., Cary NC) for a delivery platform comprising PVP K12/maltodextrin (20:80). This design was intended to screen the impact of spray-drying parameters on CQAs and to identify compositions that will help generate solid microparticles having a tunable size suitable for nose-to-brain drug delivery. Median particle size (Dv₅₀), moisture content, span and flow properties were selected as the DoE responses. Atomization pressure (X1) was tested at 0.05, 0.15, and 0.25 MPa; inlet air temperature (X3) at 170°C, 180°C, and 190°C; and solids content (X2) at 15%, 25%, and 35%. Constant exhaust fan speed (0.41 m³/min) and feed flow rate (8.2 mL/min) were maintained across all runs. Feed solutions were prepared by dissolving the components in deionized water, with sonication up to 45 min used to aid dissolution. To assess the impact of drug-loading and variation of composition on CQAs, two batches of L-DOPA loaded microparticles were prepared using one of the optimized spray-drying conditions identified from the DoE. Batch 1 consisted of 20% w/w L-DOPA and 80% w/w PVP K12/maltodextrin (20:80). In Batch 2, the polymer ratio was adjusted to 60:40 while maintaining the same drug-loading. Microparticles were processed using a Yamato ADL 311S mini spray-dryer, equipped with a 0.7 mm spray nozzle. Microparticle size was characterized using an Olympus light microscope to determine the Feret diameter from images obtained at 10x magnification and processed using ImageJ software(ij153-win-java8). Moisture content was determined using thermogravimetric analysis, and flow properties were represented as Carr’s index.

Results: Spray-dried microparticles of PVP K12/maltodextrin had a Dv₅₀ ranging from 16-25µm, residual moisture content between 2.5 – 4.5%, a span ˂1.5, and Carr’s index ranging from 10-22.2. Results were statistically analyzed using JMP 17.1 software (JMP, Version 17.1, SAS Institute Inc, Cary, NC, 2022-2023), with p ˂0.05 set as the minimal significance level. The model {Dv₅₀ = 22.54 -3.09 X₁ + 1.48 X₂ – 2.81(X₂)²} was obtained by regression analysis of Dv₅₀ exhibited a good fit. The actual versus predicted plot in Figure 1A shows that results were significant with RMSE=1.34 R²=0.93 p-value =0.0008 (α). The effect of each parameter on Dv₅₀ is shown in Figure 1B and 1C, demonstrating that particle size decreased with increasing atomization pressure, while increasing solids content resulted in a significant elevation in Dv₅₀. Although the span value, moisture content and Carr’s index were within acceptable ranges, there was no significant impact of the studied parameters on these responses. PVP K12/maltodextrin microparticles having Dv₅₀ ~ 21μm, moisture content of 3.6%, span of 1.16, and Carr’s index of 16.6 was deemed optimal. Microparticles from batch 1 and 2 were similar to the optimal particles, having Dv₅₀ ~ 21μm (Figure 2), moisture content of 3.4- 3.6%, span of 1.0-1.2 and Carr’s index of 17-18.

Conclusion: D-optimal design enabled systematic optimization of spray-drying parameters for the development of a PVP K12/maltodextrin-based microparticle platform suitable for nose-to-brain drug delivery. The Dv₅₀ prediction model obtained from the DoE study guided engineering of spray-dried PVP-based microparticles. The presence of L-DOPA in the delivery platform or the variation of polymer ratios did not affect the CQAs, suggesting that the spray-drying conditions can be optimized using the delivery platform, making this approach more appealing for accelerated drug product development at an early stage.

References: 1. Fransén N. Studies on a novel powder formulation for nasal drug delivery: Acta Universitatis Upsaliensis; 2008.


Figure 1: Actual versus predicted plot (A), and response surface plots for Dv50 against solids content and inlet temperature (B), and Dv50 against atomization pressure and solids content(C).


Figure 2: Particle size distribution (PSD) of samples from the DoE experiment, batch 1 and batch 2. The comparable PSD profiles indicate that drug loading and variation of composition ratio did not affect PSD under optimized spray-drying conditions.