Measuring erosion of biodegradable polymers in brimonidine drug delivery implants by quantitative proton NMR spectroscopy (q-HNMR)

• Published in: Journal of pharmaceutical sciences 2025-01, Vol.114 (1), p.245-255
• Main Authors: Wang, Hongpeng, Roof, Mike, Burgher, Kyle, Pham, Chiem, Samuels, Eric R., He, Yan, Jian, Huahua, Wang, Tao
• Format: Article
• Language: English
• Subjects: Biodegradable polymer(s); Brimonidine Tartrate - administration & dosage; Brimonidine Tartrate - chemistry; Delayed-Action Preparations; Drug Delivery Systems - methods; Drug Implants - chemistry; Drug Liberation; Excipients - chemistry; Lactic Acid - chemistry; Molecular Weight; Nuclear magnetic resonance (NMR) spectroscopy; Ophthalmic drug delivery; Polyesters - chemistry; Polylactic acid (PLA), and polylactic-co-glycolic acid (PLGA); Polylactic Acid-Polyglycolic Acid Copolymer - chemistry; Polymer biodegradation; Polymer chemical degradation; Polymeric drug delivery system(s); Polymers - chemistry; Proton Magnetic Resonance Spectroscopy - methods
• ISSN: 0022-3549; 1520-6017; 1520-6017
• DOI: 10.1016/j.xphs.2024.08.028

•A qNMR method with an internal standard was developed to monitor the following changes in the micro-implants during 84-day drug release (DR) tests: 1. The remaining overall PLA/PLGA mass. 2. The remaining lactic acid (LA), glycolic acid (GA) unit and PLGA ester end group percentage. 3. The trace content of PLA/PLGA oligomers as degradants retained in implants.•Previous efforts to measure remained PLGA weight of dexamethasone micro-implant using qNMR with external calibration have been performed as described in ref,26 however, the measurements do not account for chemical structure change (LA to GA ratio changes from time zero) of PLGA implants during drug release tests.•The qNMR method in this work not only accounts the structure changes of PLGA but also enables to determine percentage of remaining LA, GA and ester end group at each DR time point. Compared to the overall PLA/PLGA remaining mass generally monitored in erosion studies, the percentage of remaining LA, GA and ester end group percentage provides more informative microstructure change of PLA/PLGA.•Additionally, the submitted qNMR method can complement GPC methods by measuring the change of remaining PLA and PLGA oligomer concentrations in brimonidine implants, with tenfold less sample and no MW cutoff (∼ 200 Dalton) for GPC.•The qNMR method in this study is expected to advance excipient PLA/PLGA material characterization and facilitate deeper fundamental understanding of PLA/PLGA erosion effect in correlation with other interacting factors that dominate the drug release mechanisms of biodegradable polymer-based implants. Erosion of biodegradable polymeric excipients, such as polylactic acid (PLA) and polylactic-co-glycolic acid (PLGA), is generally characterized by microbalance for the remaining mass of PLA and/or PLGA and Gel Permeation Chromatography (GPC) for molecular weight (MW) decrease. For polymer erosion studies of intravitreal sustained release brimonidine implants, however, both microbalance and GPC present several challenges. Mass loss measurement by microbalance does not have specificity for excipient polymers and drug substances. Accuracy of the remaining mass by weighing could also be low due to sample mass loss through retrieval-drying steps, especially at later drug release (DR) time points. When measuring the decrease of polymer MW by GPC, trace amounts of polymeric degradants (oligomers and/or monomers) trapped inside the implants during DR tests may not be measurable due to s