TY - JOUR

T1 - Amino acids as co-amorphous stabilizers for poorly water-soluble drugs - Part 2

T2 - Molecular interactions

AU - Löbmann, K.

AU - Laitinen, R.

AU - Strachan, C.

AU - Rades, T.

AU - Grohganz, H.

PY - 2013/1/1

Y1 - 2013/1/1

N2 - The formation of co-amorphous drug-drug mixtures has proved to be a powerful approach to stabilize the amorphous form and at the same time increase the dissolution of poorly water-soluble drugs. Molecular interactions in these co-amorphous formulations can play a crucial role in stabilization and dissolution enhancement. In this regard, Fourier-transform infrared spectroscopy (FTIR) is a valuable tool to analyze the molecular near range order of the compounds in the co-amorphous mixtures. In this study, several co-amorphous drugs - low molecular weight excipient blends - have been analyzed with FTIR spectroscopy. Molecular interactions of the drugs carbamazepine and indomethacin with the amino acids arginine, phenylalanine, and tryptophan were investigated. The amino acids were chosen from the biological target site of both drugs and prepared as co-amorphous formulations together with the drugs by vibrational ball milling. A detailed analysis of the FTIR spectra of these formulations revealed specific peak shifts in the vibrational modes of functional groups of drug and amino acid, as long as one amino acid from the biological target site was present in the blends. These peak shifts indicate that the drugs formed specific molecular interactions (hydrogen bonding and π-π interactions) with the amino acids. In the drug-amino acid mixtures that contained amino acids which were not present at the biological target site, no such interactions were identified. This study shows the potential of amino acids as small molecular weight excipients in co-amorphous formulations to stabilize the amorphous form of a poorly water-soluble drug through strong and specific molecular interactions with the drug.

AB - The formation of co-amorphous drug-drug mixtures has proved to be a powerful approach to stabilize the amorphous form and at the same time increase the dissolution of poorly water-soluble drugs. Molecular interactions in these co-amorphous formulations can play a crucial role in stabilization and dissolution enhancement. In this regard, Fourier-transform infrared spectroscopy (FTIR) is a valuable tool to analyze the molecular near range order of the compounds in the co-amorphous mixtures. In this study, several co-amorphous drugs - low molecular weight excipient blends - have been analyzed with FTIR spectroscopy. Molecular interactions of the drugs carbamazepine and indomethacin with the amino acids arginine, phenylalanine, and tryptophan were investigated. The amino acids were chosen from the biological target site of both drugs and prepared as co-amorphous formulations together with the drugs by vibrational ball milling. A detailed analysis of the FTIR spectra of these formulations revealed specific peak shifts in the vibrational modes of functional groups of drug and amino acid, as long as one amino acid from the biological target site was present in the blends. These peak shifts indicate that the drugs formed specific molecular interactions (hydrogen bonding and π-π interactions) with the amino acids. In the drug-amino acid mixtures that contained amino acids which were not present at the biological target site, no such interactions were identified. This study shows the potential of amino acids as small molecular weight excipients in co-amorphous formulations to stabilize the amorphous form of a poorly water-soluble drug through strong and specific molecular interactions with the drug.

UR - http://www.scopus.com/inward/record.url?scp=84876917381&partnerID=8YFLogxK

U2 - 10.1016/j.ejpb.2013.03.026

DO - 10.1016/j.ejpb.2013.03.026

M3 - Journal article

C2 - 23567485

VL - 85

SP - 882

EP - 888

JO - European Journal of Pharmaceutics and Biopharmaceutics

JF - European Journal of Pharmaceutics and Biopharmaceutics

SN - 0939-6411

IS - 3, Part B

ER -