TY - JOUR

T1 - The Role of Glass Transition Temperatures in Coamorphous Drug-Amino Acid Formulations

AU - Kissi, Eric Ofosu

AU - Kasten, Georgia

AU - Löbmann, Korbinian

AU - Rades, Thomas

AU - Grohganz, Holger

PY - 2018/9/4

Y1 - 2018/9/4

N2 - The improved physical stability associated with coamorphous drug-amino acid (AA) formulations may indicate a decrease in mobility of the amorphous drug molecules, compared to the neat amorphous form of the drug. Since the characteristic glass transition temperatures ( Tgα and Tgβ) represent molecular mobility in amorphous systems, we aimed to characterize Tgα and Tgβ and to determine their role in physical stability as well as their potential usefulness to determine the presence of an excess component (either drug or AA) in coamorphous systems. Indomethacin (IND)-tryptophan (TRP) and carvedilol (CAR)-TRP were used as model coamorphous systems. The analytical techniques used were X-ray powder diffractometry (XRPD) to determine the solid-state form, dynamic mechanical analysis (DMA) to probe Tgα and Tgβ, and differential scanning calorimetry (DSC) to probe thermal behavior of the coamorphous systems. Tgα analysis showed a gradual monotonous increase in Tgα values with increasing AA concentration, and this increase in the Tgα value is not the cause of the improved physical stability. The Tgβ analysis for the IND-TRP sample with 10% drug had a Tgβ of 226.8 K, and samples with 20-90% drug had similar Tgβ values around 212.5 K. For CAR-TRP, samples with 10-40% drug had similar Tgβ values around 230.5 K, and samples with 50-90% drug had similar Tgβ values around 223.3 K. The similar Tgβ values in coamorphous systems at different drug ratios indicate that they in fact are the Tgβ of the component that is in excess to an ideal drug-AA coamorphous mixture. DSC and XRPD analysis showed that for IND-TRP, IND is in excess if the drug concentration is 30% or above and will eventually recrystallize. For CAR-TRP, CAR is in excess and recrystallizes when the drug concentration is 50% or above. We have proposed a means of estimating, on the basis of Tgβ, which drug to AA ratios will lead to optimally physically stable coamorphous systems that can be considered for further development.

AB - The improved physical stability associated with coamorphous drug-amino acid (AA) formulations may indicate a decrease in mobility of the amorphous drug molecules, compared to the neat amorphous form of the drug. Since the characteristic glass transition temperatures ( Tgα and Tgβ) represent molecular mobility in amorphous systems, we aimed to characterize Tgα and Tgβ and to determine their role in physical stability as well as their potential usefulness to determine the presence of an excess component (either drug or AA) in coamorphous systems. Indomethacin (IND)-tryptophan (TRP) and carvedilol (CAR)-TRP were used as model coamorphous systems. The analytical techniques used were X-ray powder diffractometry (XRPD) to determine the solid-state form, dynamic mechanical analysis (DMA) to probe Tgα and Tgβ, and differential scanning calorimetry (DSC) to probe thermal behavior of the coamorphous systems. Tgα analysis showed a gradual monotonous increase in Tgα values with increasing AA concentration, and this increase in the Tgα value is not the cause of the improved physical stability. The Tgβ analysis for the IND-TRP sample with 10% drug had a Tgβ of 226.8 K, and samples with 20-90% drug had similar Tgβ values around 212.5 K. For CAR-TRP, samples with 10-40% drug had similar Tgβ values around 230.5 K, and samples with 50-90% drug had similar Tgβ values around 223.3 K. The similar Tgβ values in coamorphous systems at different drug ratios indicate that they in fact are the Tgβ of the component that is in excess to an ideal drug-AA coamorphous mixture. DSC and XRPD analysis showed that for IND-TRP, IND is in excess if the drug concentration is 30% or above and will eventually recrystallize. For CAR-TRP, CAR is in excess and recrystallizes when the drug concentration is 50% or above. We have proposed a means of estimating, on the basis of Tgβ, which drug to AA ratios will lead to optimally physically stable coamorphous systems that can be considered for further development.

U2 - 10.1021/acs.molpharmaceut.8b00650

DO - 10.1021/acs.molpharmaceut.8b00650

M3 - Journal article

C2 - 30020794

VL - 15

SP - 4247

EP - 4256

JO - Molecular Pharmaceutics

JF - Molecular Pharmaceutics

SN - 1543-8384

IS - 9

ER -