title: Influence of the cooling rate and the blend ratio on the physical stability of co-amorphous naproxen/indomethacin.
abstract: Co-amorphization represents a promising approach to increase the physical stability and dissolution rate of amorphous active pharmaceutical ingredients (APIs) as an alternative to polymer glass solutions. For amorphous and co-amorphous systems, it is reported that the preparation method and the blend ratio play major roles with regard to the resulting physical stability. Therefore, in the present study, co-amorphous naproxen-indomethacin (NAP/IND) was prepared by melt-quenching at three different cooling rates and at ten different NAP/IND blend ratios. The samples were analyzed using XRPD and FTIR, both directly after preparation and during storage to investigate their physical stabilities. All cooling methods led to fully amorphous samples, but with significantly different physical stabilities. Samples prepared by fast cooling had a higher degree of crystallinity after 300d of storage than samples prepared by intermediate cooling and slow cooling. Intermediate cooling was subsequently used to prepare co-amorphous NAP/IND at different blend ratios. In a previous study, it was postulated that the equimolar (0.5:0.5) co-amorphous blend of NAP/IND is most stable. However, in the present study the physically most stable blend was found for a NAP/IND ratio of 0.6:0.4, which also represents the eutectic composition of the crystalline NAP/γ-IND system. This indicates that the eutectic point may be of major importance for the stability of binary co-amorphous systems. Slight deviations from the optimal naproxen molar fraction led to significant recrystallization during storage. Either naproxen or γ-indomethacin recrystallized until a naproxen molar fraction of about 0.6 in the residual co-amorphous phase was reached again. In conclusion, the physical stability of co-amorphous NAP/IND may be significantly improved, if suitable preparation conditions and the optimal phase composition are chosen.
authors.affiliation: Division of Pharmaceutical Technology, University of Hamburg, Bundesstraβe 45, 20146 Hamburg, Germany. Electronic address: andreas.beyer@chemie.uni-hamburg.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Beyer
authors.affiliation: Department of Pharmacy, University of Copenhagen, Universitetsparken 2, DK-2100, Denmark. Electronic address: holger.grohganz@sund.ku.dk.
authors.forename: Holger
authors.initials: H
authors.lastname: Grohganz
authors.affiliation: Department of Pharmacy, University of Copenhagen, Universitetsparken 2, DK-2100, Denmark. Electronic address: korbinian.loebmann@sund.ku.dk.
authors.forename: Korbinian
authors.initials: K
authors.lastname: Löbmann
authors.affiliation: Department of Pharmacy, University of Copenhagen, Universitetsparken 2, DK-2100, Denmark. Electronic address: thomas.rades@sund.ku.dk.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rades
authors.affiliation: Division of Pharmaceutical Technology, University of Hamburg, Bundesstraβe 45, 20146 Hamburg, Germany. Electronic address: claudia.leopold@pharmaceutical-technology.de.
authors.forename: Claudia S
authors.initials: CS
authors.lastname: Leopold
mesh_terms: D003460:Crystallization; D004339:Drug Compounding; D015195:Drug Design; D004355:Drug Stability; D005898:Glass; D007213:Indomethacin / Q000737:chemistry*; D009288:Naproxen / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry; D033362:Powder Diffraction; D025341:Principal Component Analysis; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared; D013696:Temperature; D014961:X-Ray Diffraction
chemical_list: D011108:Polymers; D009288:Naproxen; D007213:Indomethacin
keywords: Binary; Co-amorphous; Composition; Cooling; Equimolar; Eutectic; Physical stability