TY - JOUR

T1 - The use of molecular descriptors in the development of co-amorphous formulations

AU - Meng-Lund, Helena Marie Lindholm

AU - Korgaard, Georgia Kasten

AU - Jensen, Katrine Birgitte Tarp

AU - Poso, Antti

AU - Pantsar, Tatu

AU - Rades, Thomas

AU - Rantanen, Jukka

AU - Grohganz, Holger

PY - 2018/7/1

Y1 - 2018/7/1

N2 - Co-amorphous systems consisting of a drug and an amino acid have been investigated extensively for the enhancement of drug solubility and amorphous stability. The purpose of this study is to investigate which molecular descriptors are important for predicting the likelihood of a successful co-amorphisation between amino acid and drug. The predictions are thought to be used in an early screening phase to identify potential drug-amino acid combinations for further studies. A large variety of molecular descriptors was calculated for six drugs (carvedilol, mebendazole, carbamazepine, furosemide, indomethacin and simvastatin) and the twenty naturally occurring amino acids. The descriptor differences for all drug-amino acid combinations were calculated and used as input in the X-matrix of a Partial Least Square Discriminant Analysis (PLS-DA). The Y-matrix of the PLS-DA consisted of the X-ray powder diffraction response (“co-amorphous” or “not co-amorphous”) obtained by ball milling all combinations for 60 min. The PLS-DA model showed a clear separation of the not co-amorphous and the co-amorphous samples and was successfully predicting the class membership of 19 out of the 20 completely left out drug-amino acid combinations of mebendazole. The approach seems to be promising for predicting the ability of new drug-amino acids combinations to become co-amorphous.

AB - Co-amorphous systems consisting of a drug and an amino acid have been investigated extensively for the enhancement of drug solubility and amorphous stability. The purpose of this study is to investigate which molecular descriptors are important for predicting the likelihood of a successful co-amorphisation between amino acid and drug. The predictions are thought to be used in an early screening phase to identify potential drug-amino acid combinations for further studies. A large variety of molecular descriptors was calculated for six drugs (carvedilol, mebendazole, carbamazepine, furosemide, indomethacin and simvastatin) and the twenty naturally occurring amino acids. The descriptor differences for all drug-amino acid combinations were calculated and used as input in the X-matrix of a Partial Least Square Discriminant Analysis (PLS-DA). The Y-matrix of the PLS-DA consisted of the X-ray powder diffraction response (“co-amorphous” or “not co-amorphous”) obtained by ball milling all combinations for 60 min. The PLS-DA model showed a clear separation of the not co-amorphous and the co-amorphous samples and was successfully predicting the class membership of 19 out of the 20 completely left out drug-amino acid combinations of mebendazole. The approach seems to be promising for predicting the ability of new drug-amino acids combinations to become co-amorphous.

U2 - 10.1016/j.ejps.2018.04.014

DO - 10.1016/j.ejps.2018.04.014

M3 - Tidsskriftartikel

C2 - 29649569

VL - 119

SP - 31

JO - Norvegica Pharmaceutica Acta

JF - Norvegica Pharmaceutica Acta

SN - 0928-0987

ER -