On the role of salt formation and structural similarity of co-formers in co-amorphous drug delivery systems
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On the role of salt formation and structural similarity of co-formers in co-amorphous drug delivery systems. / Wu, Wenqi; Löbmann, Korbinian; Rades, Thomas; Grohganz, Holger.
In: International Journal of Pharmaceutics, Vol. 535, No. 1-2, 15.01.2018, p. 86-94.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - On the role of salt formation and structural similarity of co-formers in co-amorphous drug delivery systems
AU - Wu, Wenqi
AU - Löbmann, Korbinian
AU - Rades, Thomas
AU - Grohganz, Holger
N1 - Copyright © 2017 Elsevier B.V. All rights reserved.
PY - 2018/1/15
Y1 - 2018/1/15
N2 - Co-amorphous drug delivery systems based on amino acids as co-formers have shown promising potential to improve the solubility and bioavailability of poorly water-soluble drugs. Potential salt formation is assumed to be a key molecular interaction responsible for amorphous stability and increased solubility. However, little is known about the importance of the overall structure of the co-former. In this study, the structurally related amino acids arginine (basic) and citrulline (neutral) were chosen together with four model drugs (acidic furosemide and nitrofurantoin; basic cimetidine and mebendazole) to investigate the importance of salt formation versus structural similarity of co-formers. Drug-amino acid mixtures were ball milled at a molar ratio of 1:1. Generally, arginine showed a higher tendency to successfully form co-amorphous systems with the model drugs compared with citrulline, irrespective of assumed salt formation. Salt forming mixtures showed much higher Tgs, faster dissolution rates, higher solubility and physical stability compared to the corresponding non-salt forming mixtures. In conclusion, structural similarity of the co-formers does not lead to similar co-former performance for a given drug. Salt formation is not a prerequisite for the formation of a co-amorphous system, but if a co-amorphous salt system is formed, improved dissolution rate and physical stability are observed.
AB - Co-amorphous drug delivery systems based on amino acids as co-formers have shown promising potential to improve the solubility and bioavailability of poorly water-soluble drugs. Potential salt formation is assumed to be a key molecular interaction responsible for amorphous stability and increased solubility. However, little is known about the importance of the overall structure of the co-former. In this study, the structurally related amino acids arginine (basic) and citrulline (neutral) were chosen together with four model drugs (acidic furosemide and nitrofurantoin; basic cimetidine and mebendazole) to investigate the importance of salt formation versus structural similarity of co-formers. Drug-amino acid mixtures were ball milled at a molar ratio of 1:1. Generally, arginine showed a higher tendency to successfully form co-amorphous systems with the model drugs compared with citrulline, irrespective of assumed salt formation. Salt forming mixtures showed much higher Tgs, faster dissolution rates, higher solubility and physical stability compared to the corresponding non-salt forming mixtures. In conclusion, structural similarity of the co-formers does not lead to similar co-former performance for a given drug. Salt formation is not a prerequisite for the formation of a co-amorphous system, but if a co-amorphous salt system is formed, improved dissolution rate and physical stability are observed.
KW - Journal Article
U2 - 10.1016/j.ijpharm.2017.10.057
DO - 10.1016/j.ijpharm.2017.10.057
M3 - Journal article
C2 - 29102703
VL - 535
SP - 86
EP - 94
JO - International Journal of Pharmaceutics
JF - International Journal of Pharmaceutics
SN - 0378-5173
IS - 1-2
ER -
ID: 185402438