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

Helena Marie Lindholm Meng-Lund; Georgia Kasten Korgaard; Katrine Birgitte Tarp Jensen; Antti Poso; Tatu Pantsar; Thomas Rades; Jukka Rantanen; Holger Grohganz

doi:10.1016/j.ejps.2018.04.014

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

Helena Marie Lindholm Meng-Lund, Georgia Kasten Korgaard, Katrine Birgitte Tarp Jensen, Antti Poso, Tatu Pantsar, Thomas Rades, Jukka Rantanen, Holger Grohganz

17 Citations (Scopus)

Abstract

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.

Original language	Danish
Journal	European Journal of Pharmaceutical Sciences
Volume	119
Pages (from-to)	31
Number of pages	38
ISSN	0928-0987
DOIs	https://doi.org/10.1016/j.ejps.2018.04.014
Publication status	Published - 1 Jul 2018

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10.1016/j.ejps.2018.04.014

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title = "The use of molecular descriptors in the development of co-amorphous formulations",

abstract = "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.",

author = "Meng-Lund, {Helena Marie Lindholm} and Korgaard, {Georgia Kasten} and Jensen, {Katrine Birgitte Tarp} and Antti Poso and Tatu Pantsar and Thomas Rades and Jukka Rantanen and Holger Grohganz",

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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

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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.

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