Abstract
Purpose :
This study aims at (i) exploring how variations in polymorphic forms, crystallinity, and particle size distribution of dexamethasone (DEX) affects its in vitro release (IVR) performance from ophthalmic ointments, and (ii) to integrate these findings with research on loteprednol etabonate (LTE) and acyclovir (ACY) ointments, to offer a broader perspective on the effect of drug substance characteristics on IVR.
Methods :
DEX was loaded into oleaginous ointments containing White Petrolatum (USP) via high-shear mixing, and subjected to solid-state characterization (polymorphism and crystallinity via X-Ray Powder Diffraction and Differential Scanning Calorimetry) and IVR testing (USP dissolution apparatus I). Particle size distribution was assessed through laser diffraction and light microscopy.
Results :
Ointments with amorphous DEX showed higher release rates than those with crystalline forms across all kinetic models, with a partially-amorphous ointment having a best-fit release rate of 6.8 ± 0.6 µg/cm2/h, compared to 4.5 ± 0.4 µg/cm2/h for the fully crystalline one. The release rate of ointments loading DEX form B were greater than those with DEX form A, albeit the differences were minor when compared to those containing partially-amorphous DEX. In addition, variations in particle size of DEX (5.4 to 21.2 µm) did not significantly affect product performance within the range studied, with similar release rates observed across the different particle sizes tested.
Conclusions :
The solid-state characteristics of DEX significantly influence its IVR from ophthalmic ointments, being more influenced by solid-state form, particularly the amorphous state, than by particle size. This phenomenon is also observed in LTE ointments.1 Both DEX and LTE, being moderately lipophilic compounds (logP = 1.8-2.0), demonstrate a strong affinity for the oleaginous base, and are subject to size reduction and normalization through high-shear mixing with petrolatum. Conversely, for the hydrophilic drug ACY (logP = -1.6), particle size is crucial, with larger particles leading to slower release rates.2 These integrated findings highlight the need to consider the unique physicochemical properties of drugs and their interactions with bases in ophthalmic ointment development.
1Bao, Q., et al., Int J Pharm, 2017. 523(1): p. 310-9.
2Xu, X., et al., Int J Pharm, 2015. 493(1-2): p. 412-25.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.