(T1530-01-03) Influence of Polymer Miscibility on Drug Release from Microparticles Prepared Using a 3-Fluid Spray Drying Process

Purpose: Pharmaceutical solid dosage forms can be coated with polymers to modify drug release for various reasons including taste masking, enteric protection, and sustained release. While conventional processes are useful for coating tablets and granules/beads, pediatric patients often have difficulty swallowing and thus there is a need for coated micron-sized particles that could be sprinkled on food or suspended in liquids. Spray drying is an established technique to form micron-sized particles (1). Matrices are created with conventional 2-fluid spray drying (2) whereas two separate liquid feeds are used in 3-fluid spray drying and the outer feed can form a ‘seal’ or coating around the inner matrix (3) (see Figure 1). The objective of this study was to investigate the influence of the miscibility of polymers spray dried from separate liquid feeds using a 3-fluid nozzle configuration on the release of a model water-soluble drug.

Methods: The inner feed consisted of acetaminophen (APAP, 0.8% w/w) and either Eudragit L dissolved in 50:50 ethanol:water or HPMC (Methocel E6) dissolved in water. The concentration of the polymer in the inner feed was either 0.8 or 1.6% w/w. The outer liquid feed contained either Eudragit E or Eudragit L dissolved in 50:50 ethanol:water at a concentration of 2.0 or 2.8% w/w. For comparison, APAP (0.8% w/w) was dissolved in either Eudragit L or Eudragit E (3.6% w/w) in 50:50 ethanol:water or in HPMC (3.6% w/w) in water and spray dried using a 2-fluid nozzle. Solutions were spray dried using a Buchi B-290 at a flow rate of 4 ml/min and the inlet temperature was adjusted to achieve an outlet temperature of about 55°C. Process yields, potency (expressed as the percent of theoretical drug loading), and drug release in pH 6.8 or pH 2 (depending on polymer solubility) was determined. Drug concentration was quantified using HPLC to determine potency and drug release. A second set of microparticles was prepared using fluorescent markers rhodamine B (inner feed) and fluorescein isothiocyanate (FITC, outer feed). These microparticles were analyzed using confocal microscopy to investigate particle structure and potential mixing of the inner and outer polymers during spray drying.

Results: Process yields ranged from about 50 to about 75%, depending on polymers used and nozzle configuration. Yields were lower when Eudragit E was used, irrespective of nozzle configuration. Potency for all microparticles ranged from 95 – 104%. Drug release from the 3-fluid nozzle Eudragit L/Eudragit L formulation was the same as that prepared with the 2-fluid nozzle, suggesting mixing of the polymers rather than the formation of a coating around the microparticle. Compared to powders prepared with the 2-fluid nozzle, drug release was slower when different polymers were used in the inner and outer feeds (Figure 2), suggesting coated microparticles were formed. Drug released more slowly from the HPMC/Eudragit E formulation compared to the Eudragit L/Eudragit E formulation. Moreover, when more polymer was shifted to the outer feed (while maintaining total drug loading), drug release decreased for the HPMC-containing powders whereas no effect was noted for the Eudragit L-containing powders. Colocalization of the fluorescent markers (Figure 3A) indicated that the Eudragit L and Eudragit E mixed during spray drying. These results may be attributed to polymer miscibility, as the solubility parameters of the Eudragit L and Eudragit E polymers are similar (22.5-22.9 and 19.6 (J/cm³)^1/2, respectively) (4). In contrast, colocalization of the fluorescent markers was absent in the HPMC/Eudragit E microparticles (Figure 3B). The solubility parameter of HPMC (28.7 (J/cm³)^1/2) (5) is much higher than that of the Eudragit E, suggesting these polymers are immiscible. Interestingly, the HPMC/Eudragit E microparticles appear hollow.

Conclusion: Microparticles formed using a 3-fluid nozzle slowed drug release of the water soluble drug when different polymers were used in the inner and outer feeds. Our findings suggest that immiscible polymers (based on differences in solubility parameters) should be selected when using a 3-fluid spray drying process to achieve a more robust encapsulation for modified drug release.

References: 1. Ҫelik et al, Spray Drying and Pharmaceutical Applications, from Handbook of Pharmaceutical Granulation Technology, 4th ed., CRC Press, 2021.
2. Price, Stromberg, Kunda, and Muttil, Molecul Pharm, 2017.
3. Kondo, Niwa, and Danjo, Eur J Pharm Sci, 2014.
4. Sarode et al, Eur J Pharm Sci, 2013.
5. Dow Wolff Cellulosics “Solubility Parameters” technical bulletin

Acknowledgements: This work was supported in part by an NIH grant (R21HD095100) and the UNM Comprehensive Cancer Center Support Grant NCI P30CA118100. We would like to thank Evonik and Dupont for donating the polymers used in this study.

Figure 1. Schematic of the two nozzle configurations. (A) 2-fluid; (B) 3-fluid

Figure 2. Dissolution of APAP from spray dried powders. Single polymer systems were spray dried through a 2-fluid nozzle. Concentration of the polymers in the microparticles are shown in parenthesis as % w/w. Drug loading (18% w/w) was held constant for all formulations.

Figure 3. Confocal fluorescent microscopy of the spray dried powders; Rhodamine B (red) was in the inner liquid feed and FITC (green) was in the outer liquid feed. Areas of yellow indicate colocalization of the two fluorescent markers.