Influence of the cooling rate and the blend ratio on the physical stability of co-amorphous naproxen/indomethacin

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• 作者：Andreas Beyer^a ; ^{andreas.beyer@chemie.uni-hamburg.de} ; Holger Grohganz^b ; ^{holger.grohganz@sund.ku.dk} ; Korbinian Lö ; bmann^b ; ^{korbinian.loebmann@sund.ku.dk} ; Thomas Rades^b ; ^{thomas.rades@sund.ku.dk} ; Claudia S. Leopold^a ; ^{claudia.leopold@pharmaceutical-technology.de}
• 关键词：cNAP ; crystalline naproxen ; DSC ; differential scanning calorimetry ; Fam ; amorphous fraction ; FC ; fast cooling ; FTIR ; Fourier-transformed infrared spectroscopy ; IBragg ; intensity under the Bragg peaks ; IC ; intermediate cooling ; IHalo ; intensity under the halo baseline ; IND ; indomethacin ; NMF ; naproxen molar fraction ; NAP ; naproxen ; NAP/IND ; naproxen-indomethacin ; P2O5 ; phosphorous pentoxide ; PC ; principal component ; PCA ; principal component analysis ; RIR ; relative intensity ratio ; SC ; slow coolin
• 刊名：European Journal of Pharmaceutics and Biopharmaceutics
• 出版年：2016
• 出版时间：December 2016
• 年：2016
• 卷：109
• 期：Complete
• 页码：140-148
• 全文大小：1172 K
• 卷排序：109

文摘

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 300 d 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.