(M1530-04-23) Effect of Coacervation Processing Parameters on In Vitro Drug Release from PLGA Microspheres

Purpose: Commonly used manufacturing methods for poly (lactic-co-glycolic acid) (PLGA) microsphere drug products include solvent evaporation, coacervation (phase separation), and spray drying. Minor changes in the manufacturing process have been shown to affect the physicochemical properties (such as drug loading, particle size, and morphology) and drug release behavior of microspheres ^[1]. The objectives of this work were to investigate the effect of coacervation processing parameters on PLGA microsphere physicochemical properties and in vitro release characteristics.

Methods: Minocycline hydrochloride was selected as the model drug. Properties of PLGA used in the commercial product Arestin^® (including molecular weight, lactic acid to glycolic acid ratio, and end groups) were determined through reverse engineering. PLGA with similar properties as in the commercial product was used for the formulation preparation. Eight compositionally equivalent microsphere formulations were prepared via a coacervation method using a well-designed glass vessel assembly. Briefly, the micronized minocycline hydrochloride powder was suspended in PLGA solution and then transferred into a vessel equipped with an overhead stirrer. Coacervation was induced by the addition of silicone oil with different viscosities while stirring. The coacervate dispersion was then transferred into a beaker containing a hardening agent for solidification, followed by washing and vacuum drying prior to final microsphere collection. Parameters such as stirring rate, silicone oil viscosity and polymer solvent were changed to prepare different microspheres. The physicochemical properties (including drug loading, particle size, and morphology) of the prepared microspheres were characterized. The internal microstructure was characterized using the Focused Ion Beam Scanning Electron Microscopy (FIB-SEM). In addition, in vitro release testing of the microspheres was conducted using a sample-and-separate method.

Results: Using the coacervation method described above, eight compositionally equivalent formulations of minocycline hydrochloride microspheres were successfully prepared. The drug loading of all eight formulations was around 27% (Table 1). As shown in Fig. 1, Formulations A to D were spherical with relatively smooth surfaces. The surface of Formulations E to H were not smooth and were covered with “buds”, which were confirmed to be polymer coacervates by FIB-SEM. For both the DCM and EA groups, the formulations using 1000 cSt silicone oil (Formulations B, D, F, and H) showed smaller particle size. The main reason for this is that the high viscosity supports smaller droplets during the coacervation step and prevents these small droplets from merging to form large droplets. In vitro drug release characteristics of the prepared formulations were also different (Fig. 2). Formulations A and C with larger particle size had a medium level initial burst release. Formulations B and D had higher initial burst release, which is considered to be due to their smaller particle size and the resulting higher surface area with more surface associated drug. Formulations E to H had very low initial burst release (less than 7% at 1 hour), which is considered may be due to their low glass transition temperature, leading to pore closure.

Conclusion: The physicochemical properties (e.g., particle size and morphology) as well as in vitro release characteristics of the microspheres were determined to be sensitive to minor changes in the coacervation processing (e.g., stirring rate and viscosity of silicone oil). Understanding the effect of processing parameters on the quality and drug release characteristics of the microsphere is of great value to facilitate the development and quality assessment of polymeric long-acting microsphere products.

References: [1] Andhariya, Janki V., et al. Journal of controlled release, 255 (2017): 27-35.

Acknowledgements: Funding for this project was made possible, by the U.S. Food and Drug Administration through Contract # 75F40119C10157. The views expressed in this abstract do not reflect the official policies of the U.S. Food and Drug Administration or the U.S. Department of Health and Human Services.


Table 1. Drug loading and particle size of the prepared microsphere formulations. All data are presented as mean ± SD (n=3).


Fig. 1. SEM images of Formulations A to H.


Fig. 2. In vitro release profiles of the prepared microspheres using the sample-and-separate method at 37℃ in 10 mM PBS (pH 7.4) containing 0.02% (v/v) Tween 20. All of the experiments were performed in triplicate (n=3) and the data are presented as mean ± SD.