Investigations on the predictability of the formation of glassy solid solutions of drugs in sugar alcohols.
A prerequisite for the formation of glassy solid solutions prepared by the melting method is the miscibility of the respective drug and the carrier in the molten state. As could be shown experimentally, all investigated drug/sugar alcohol combinations miscible in the molten state form to some extent glassy solid solutions, dependent on their tendency to recrystallize during preparation. Therefore, the present study focuses on the evaluation of factors that govern the miscibility of molten drugs and sugar alcohols as carriers. In this context, solubility parameters are discussed as a means of predicting miscibility in comparison to a new approach, using calculated interaction parameters derived from molecular dynamics (MD) studies. There is evidence that a Coulomb interaction term C(SR), comprising short-range electrostatic interactions and hydrogen bonding energy is essential for the miscibility of drug and carrier in the molten state. To relate C(SR) to the molecular volume, a non-dimensional parameter P(i) is defined. For this parameter, a limiting value for miscibility exists. Contrary, calculated solubility parameter differences between drug and sugar alcohol in the range of 8-15 MPa(1/2) are not suitable for a prediction of miscibility or immiscibility, since the mixtures deviate from regular solution behavior. In irregular mixtures of drugs and sugar alcohols, an excess entropy and the formation of hydrogen bonds between unlike molecules favor miscibility, that cannot be predicted by regular solution theory.
Langer
M
M
Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.
Höltje
M
M
Urbanetz
N A
NA
Brandt
B
B
Höltje
H-D
HD
Lippold
B C
BC
D005898:Glass / Q000032:analysis / Q000737:chemistry*; D019999:Pharmaceutical Solutions / Q000032:analysis / Q000737:chemistry*; D011237:Predictive Value of Tests; D013402:Sugar Alcohols / Q000032:analysis / Q000737:chemistry*
D019999:Pharmaceutical Solutions; D013402:Sugar Alcohols