TY - JOUR

T1 - Predictive identification of co-formers in co-amorphous systems

AU - Chambers, Luke I.

AU - Grohganz, Holger

AU - Palmelund, Henrik

AU - Lobmann, Korbinian

AU - Rades, Thomas

AU - Musa, Osama M.

AU - Steed, Jonathan W.

PY - 2021

Y1 - 2021

N2 - This work aims to understand the properties of co-formers that form co-amorphous pharmaceutical materials and to predict co-amorphous system formation. A partial least square - discriminant analysis (PLS-DA) was performed using known co-amorphous systems described by 36 variables based on the properties of the co-former and the binding energy of the system. The PLS-DA investigated the propensity to form co-amorphous material of the active pharmaceutical ingredients: mebendazole, carvedilol, indomethacin, simvastatin, carbamazepine and furosemide in combination with 20 amino acid co-formers. The variables that were found to favour the propensity to form co-amorphous systems appear to be a relatively large value for average molecular weight and the sum of the difference between hydrogen bond donors and hydrogen bond acceptors for both components, and a relatively small or negative value for excess enthalpy of mixing, excess enthalpy of hydrogen bonding and the difference in the Hansen parameter for hydrogen bonding of the coformer and the active pharmaceutical ingredient (API). To test the predictive power of this model, 29 potential co-formers were used to form either co-amorphous or crystalline two-component materials with mebendazole. Of these 29 two-component systems, the co-amorphous nature of a total of 26 materials was correctly predicted by the model, giving a predictive hit rate of 90 %.

AB - This work aims to understand the properties of co-formers that form co-amorphous pharmaceutical materials and to predict co-amorphous system formation. A partial least square - discriminant analysis (PLS-DA) was performed using known co-amorphous systems described by 36 variables based on the properties of the co-former and the binding energy of the system. The PLS-DA investigated the propensity to form co-amorphous material of the active pharmaceutical ingredients: mebendazole, carvedilol, indomethacin, simvastatin, carbamazepine and furosemide in combination with 20 amino acid co-formers. The variables that were found to favour the propensity to form co-amorphous systems appear to be a relatively large value for average molecular weight and the sum of the difference between hydrogen bond donors and hydrogen bond acceptors for both components, and a relatively small or negative value for excess enthalpy of mixing, excess enthalpy of hydrogen bonding and the difference in the Hansen parameter for hydrogen bonding of the coformer and the active pharmaceutical ingredient (API). To test the predictive power of this model, 29 potential co-formers were used to form either co-amorphous or crystalline two-component materials with mebendazole. Of these 29 two-component systems, the co-amorphous nature of a total of 26 materials was correctly predicted by the model, giving a predictive hit rate of 90 %.

KW - Co-amorphous

KW - Partial least squares discriminant analysis

KW - Amino acids

KW - Multi-variate analysis

KW - Molecular descriptors

KW - SOLID-STATE CHARACTERIZATION

KW - WATER-SOLUBLE DRUGS

KW - PHYSICOCHEMICAL PROPERTIES

KW - PHYSICAL STABILITY

KW - CRYSTAL-GROWTH

KW - AMINO-ACIDS

KW - SOLUBILITY

KW - DISPERSIONS

KW - DISSOLUTION

KW - COCRYSTAL

U2 - 10.1016/j.ejps.2020.105636

DO - 10.1016/j.ejps.2020.105636

M3 - Journal article

C2 - 33160046

VL - 157

JO - Norvegica Pharmaceutica Acta

JF - Norvegica Pharmaceutica Acta

SN - 0928-0987

M1 - 105636

ER -