(T1230-07-40) Investigation of the Impact of Manufacturing Parameters on the Mechanism of Formation of Naltrexone-PLGA Microparticles with SSNMR

Purpose: Naltrexone (NTX) has been used to treat alcohol and opioid use disorder for the last few decades. Injectable formulations of NTX have been made with poly(lactide-co-glycolide) (PLGA) polymers. Despite the extensive studies of PLGA microparticles, there is still a limited understanding of the structure and formation of the microparticles. This study uses solid-state nuclear magnetic resonance spectroscopy (SSNMR) to study the impact of manufacturing parameters including lactide:glycolide ratio, oil phase content, mixing time, and particle sizes in the emulsification-extraction process on the state of the NTX and performance of the naltrexone-PLGA microparticles.

Methods: >NTX-PLGA microparticles were made by an emulsification-extraction process. The microparticles were made using different amount of dichloromethane and benzyl alcohol in the oil phase, ratios of NTX:PLGA, lactide:glycolide ratio of PLGA, batch scales and particles sizes. Samples were packed in 7.5 mm zirconia rotors, sealed with Kel-F end-caps. ¹³C SSNMR spectra were acquired with cross-polarization magic angle spinning (CP/MAS) at 4 kHz, using total sideband suppression (TOSS) and SPINAL64 decoupling.

Results: >Different crystalline forms of NTX were identified by unique peaks in the spectra located around 210, 90 and 51 ppm. Spectra of NTX-PLGA microparticles made as described in the methods section were obtained and compared with several spectra of different crystalline forms of NTX. The peaks around 210, 90 and 51 ppm showed different crystallinity of NTX in the microparticles which correlated with manufacturing parameters. For example, both a final ethanol wash and a larger particle size resulted in a higher level of crystallization of the drug

Conclusion: SSNMR can be used to identify and differentiate different forms of NTX, including in NTX-PLGA microparticles.  Manufacturing parameters including particle size, lactide:glycolide ratio and performing an ethanol wash impact the crystallinity of the drug.  Further investigation is needed to determine how the stereosequence of PLGA impacts microparticle performance.

References: Sharifi, F.; Otte, A.; Yoon, G.; Park, K. Continuous in-Line Homogenization Process for Scale-up Production of Naltrexone-Loaded PLGA Microparticles. Journal of Controlled Release 2020, 325, 347–358.

Figure 1. 13C CP-TOSS spectra of four different forms of NTX



Figure 2. 13C CP-TOSS spectra of 9 NTX-PLGA microparticles made with different manufacturing parameters