Application of Ultra-Centrifugation and Bench-Top 19F NMR for Measuring Drug Phase Partitioning for the Ophthalmic Oil-in-Water Emulsion Products

Abstract

Generic drug products are expected to have the same active pharmaceutical ingredient (API) (Q1) with the same content (Q2) and microstructure arrangement (Q3) as the innovator product. In complex oil-in-water emulsion drugs, the hydrophobic API is mainly formulated in oil droplets stabilized by surfactant and micelles composed of extra surfactant molecules. The API phase partition in oil and water (mainly micelle) is a critical quality attribute (CQA) of emulsion product in demonstrating physicochemical equivalence using difluprednate (DFPN) emulsion product Durezol® as a model, we developed a novel low-field benchtop NMR method to demonstrate its applicability in measuring DFPN phase partition for ophthalmic oil-in-water emulsion products. Low-field F spectra were collected for DFPN in formulation, in water phase and oil phase after separation from ultra-centrifugation. The NMR data showed the mass balance of DFPN before and after phase separation. The average water phase content of different Durezol® lots was 32 ± 3% with 1% variation from method reproducibility test. The partition results were 52 ± 2% for the in-house control products prepared in Q1/Q2 equivalence to Durezol® but by a different process. The significant difference in DFPN-phase partition between Durezol® and the in-house formulation demonstrated manufacture difference readily changed the API partition. The newly developed ultra-centrifugation andF NMR by benchtop instrument is a simple, robust, and sensitive analytical method for ophthalmic emulsion drug product development and control.

Multiphase Drug Distribution and Exchange in Oil-in-Water Nanoemulsion Revealed by High-Resolution 19F qNMR

“…8 This is due to the unique challenge of the o/w soft matter nanocore, which is thermodynamically unstable 1,6 and subject to structural changes upon invasive separation. 9,12 Solution NMR spectroscopy was applied to study the solute transfer rate across the o/w interphase in an emulsion 13 and the drug release rate from the emulsion, which was in good agreement with in vivo results. 14 Both studies identified phasedependent chemical shift changes of solute molecules, 13,14 which supported NMR as an ideal noninvasive method for the drug phase distribution study in NE formulations.…”

“…In the 19 F NMR spectrum of the DP sample DP-95%, that is, 95% (v/v) of DP mixed with 5% D 2 O, F28 peaks were observed in the range of −164.5−−167.0 ppm and F29 peaks in the range of −186.2−−187.4 ppm (Figure 1A), consistent with the previous 19 F chemical shift assignments. 12,15 In comparison with the F29 nucleus which had a chemical shift distribution of 1.2 ppm, the F28 nucleus was more sensitive to the chemical environment and had a broader chemical shift distribution of 2.5 ppm. Therefore, the peak of F28 was used as the reporter for the DFPN phase distribution throughout the study.…”

“…The distribution of 35% of the drug in the (s) phase has not been reported before in any o/w ophthalmic NE formulation but is consistent with the previous UC result which showed 32% of DFPN in the aqueous phase after phase separation. 12 The other filtration and dialysis studies on phospholipid-based o/w emulsion suggested a distribution of about 50% of the drug in the interface layer between the oil and water phases. 7,8 The interface layer is the (s) phase of the NE oil globules in this study.…”

“…9 Studies on the manufacturing process, characterization, and delivery of emulsion products have been abundant. 2,9,10 However, the drug distribution in different phases of o/w emulsions has not been explicitly measured noninvasively 11 despite the distribution studies using separation methods such as ultra-centrifugation (UC), 12 ultrafiltration, 7 or dialysis. 8 This is due to the unique challenge of the o/w soft matter nanocore, which is thermodynamically unstable 1,6 and subject to structural changes upon invasive separation.…”

A Simple and Noninvasive DOSY NMR Method for Droplet Size Measurement of Intact Oil-In-Water Emulsion Drug Products

“…Complex drug products can have molecular, compositional, or drug distribution heterogeneity, pertaining to differences in higher order structure, particle size distribution (PSD), 1,2 chemical composition, 3,4 or multiphase dosage forms. 5 These quality attributes can affect drug bioavailability, efficacy, safety, immunogenicity, and PK/PD properties, and present challenges for drug manufacturers and regulatory agencies to define robust and sensitive methods for measuring these critical quality attributes.…”