title: Formulation and process factors influencing product quality and in vitro performance of ophthalmic ointments.
abstract: Owing to its unique anatomical and physiological functions, ocular surface presents special challenges for both design and performance evaluation of the ophthalmic ointment drug products formulated with a variety of bases. The current investigation was carried out to understand and identify the appropriate in vitro methods suitable for quality and performance evaluation of ophthalmic ointment, and to study the effect of formulation and process variables on its critical quality attributes (CQA). The evaluated critical formulation variables include API initial size, drug percentage, and mineral oil percentage while the critical process parameters include mixing rate, temperature, time and cooling rate. The investigated quality and performance attributes include drug assay, content uniformity, API particle size in ointment, rheological characteristics, in vitro drug release and in vitro transcorneal drug permeation. Using design of experiments (DoE) as well as a novel principle component analysis approach, five of the quality and performance attributes (API particle size, storage modulus of ointment, high shear viscosity of ointment, in vitro drug release constant and in vitro transcorneal drug permeation rate constant) were found to be highly influenced by the formulation, in particular the strength of API, and to a lesser degree by processing variables. Correlating the ocular physiology with the physicochemical characteristics of acyclovir ophthalmic ointment suggested that in vitro quality metrics could be a valuable predictor of its in vivo performance.
authors.affiliation: Food and Drug Administration, CDER/OPQ/OTR/DPQR, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Xu
authors.affiliation: Food and Drug Administration, CDER/OPQ/OTR/DPQR, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA.
authors.forename: Manar
authors.initials: M
authors.lastname: Al-Ghabeish
authors.affiliation: Food and Drug Administration, CDER/OPQ/OTR/DPQR, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA.
authors.forename: Ziyaur
authors.initials: Z
authors.lastname: Rahman
authors.affiliation: Food and Drug Administration, CDER/OPQ/OTR/DPQR, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA.
authors.forename: Yellela S R
authors.initials: YS
authors.lastname: Krishnaiah
authors.affiliation: Food and Drug Administration, CDER/OPQ/OTR/DPQR, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA.
authors.forename: Firat
authors.initials: F
authors.lastname: Yerlikaya
authors.affiliation: Food and Drug Administration, CDER/OPQ/OTR/DPQR, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Food and Drug Administration, CDER/OPQ/OTR/DPQR, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA.
authors.forename: Prashanth
authors.initials: P
authors.lastname: Manda
authors.affiliation: Food and Drug Administration, CDER/OPQ/OTR/DPQR, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hunt
authors.affiliation: Food and Drug Administration, CDER/OPQ/OTR/DPQR, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA. Electronic address: Mansoor.Khan@fda.hhs.gov.
authors.forename: Mansoor A
authors.initials: MA
authors.lastname: Khan
mesh_terms: D000212:Acyclovir / Q000008:administration & dosage / Q000737:chemistry*; D060433:Administration, Ophthalmic; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical; D003315:Cornea / Q000378:metabolism; D004339:Drug Compounding; D065546:Drug Liberation; D008297:Male; D009824:Ointments; D010316:Particle Size; D010539:Permeability; D011786:Quality Control; D011817:Rabbits; D012212:Rheology; D014783:Viscosity
chemical_list: D000998:Antiviral Agents; D009824:Ointments; D000212:Acyclovir
keywords: Acyclovir; Corneal drug permeation; Design of experiments (DoE); Equivalence evaluation; In vitro release testing; Multivariate analysis; Ophthalmic ointments; Rheology; Yield stress