Scanning Analysis of Sequential Semisolvent Vapor Impact To Study Naltrexone Release from Poly(lactide-co-glycolide) Microparticles

Abstract

Poly(lactide-co-glycolide) (PLGA)-based microparticle formulations have been a mainstay of long-acting injectable drug delivery applications for decades. Despite a long history of use, tools and techniques to analyze and understand these formulations are still under development. Recently, a new characterization method was introduced known as the surface analysis after sequential semisolvent impact using sequential semisolvent vapors. The vapor-based technique is named, for convenience, surface analysis of (semisolvent) vapor impact (SAVI). In the SAVI method, discretely controlled quantities of selected organic semisolvents in the vapor phase were applied to PLGA microparticles to track particle morphological changes by laser scanning confocal microscopy. Subsequently, the morphological images were analyzed to calculate mean peak height (S a ), core height (S k ), kurtosis (S ku ), dale void volume (V vv ), the density of peaks (S pd ), maximum height (H m ), and the shape ratio (R s ). Here, the SAVI method was applied to naltrexone-loaded microparticles manufactured internally and Vivitrol, a commercial formulation. SAVI analysis of these microparticles indicated that the two primary mechanisms controlling the naltrexone release were the formation of discrete, self-crystallized portions of naltrexone within the PLGA structure and the degradation of PLGA chains through nucleophilic substitution. The relatively higher amounts of naltrexone crystals resulted in prolonged release than lower amounts of crystals. Data from gel permeation chromatography, differential scanning calorimetry, and in vitro release measurements all point to the importance of naltrexone crystal formation. This study highlights the utility of SAVI for gaining further insights into the microstructure of PLGA formulations and using SAVI data to support research, product development, and quality control applications for microparticle formulations of pharmaceuticals.

Microstructure Formation and Characterization of Long-Acting Injectable Microspheres: The Gateway to Fully Controlled Drug Release Pattern

“…Hence, CLSM offers a powerful support for a more comprehensive study of the drug distribution and release mechanism of microspheres. Garner et al 18,19 used CLSM to track the three-dimensional structural changes of naltrexone microspheres after sequential semi-solvent vapor impact (SAVI) and further elucidated the factors that were critical to the microsphere microstructure (nucleophilic attack capacity and self-crystallizing capacity) and their effects on release behavior.…”

“…Garner et al characterized the microstructure of naltrexone microspheres (Vivitrol ® ) and the microstructure changes during release by SAVI and observed drug-containing core and cubic crystals of self-crystalized naltrexone. 18 Wang et al characterized the surface drug distribution of octreotide acetate microspheres (Sandostatin LAR ® ) by CLSM. 121 It has been recognized that microstructure is related to product performance closely.…”

“…14,15 The significant impact of microstructure on LAI microsphere product release behavior has been emphasized in numerous studies. 8,[16][17][18][19] The FDA also recommended Q3, the similarity of microstructure, as part of the bioequivalence assessment. Many studies have also suggested that Q1/Q2/Q3 is necessary for bioequivalence.…”

“…29 Currently, more and more studies are emerging to focus on the characterization of the microstructure of LAI microspheres and to explore the relationship between microstructure and product performance. 9,18,30,31 Significant advances in characterization techniques along with artificial intelligence (AI) based image analytics have been introduced into the microstructure study of LAI microspheres. 29,30 The techniques utilized in the study of the microstructural characterization of LAI microspheres include focused ion beam scanning electron microscopy (FIB-SEM), energy dispersive spectroscopy (EDS), synchrotron radiation X-ray microcomputed tomography (SR-μCT), X-ray microscopy (XRM), confocal laser scanning microscopy (CLSM), confocal Raman microscopy (CRM), transition temperature microscopy (TTM) and time-of-flight secondary ion mass spectrometry (ToF-SIMS).…”

Bohemian Rhapsody of Future Drug Delivery Systems: Rational Changes Necessary for the Next Revolution

“…Introducing more LAI formulations requires a better understanding of the mechanisms of drug loading and release from LAI formulations. Recent studies on PLGA formulations initiated by the FDA have produced a wealth of information on the nature of PLGA polymers, the impact of PLGA polymer types on the drug releaser properties, the impact of processing parameters on the drug release kinetics, and reverse engineering. − …”