TY - JOUR

T1 - A new method to determine drug-polymer solubility through enthalpy of melting and mixing

AU - Meiland, Peter

AU - Larsen, Bjarke Strøm

AU - Knopp, Matthias Manne

AU - Tho, Ingunn

AU - Rades, Thomas

N1 - Funding Information: The travel expenses for this study were supported by NordForsk for the Nordic University Hub project Nordic POP (No. 85352, Denmark).

PY - 2022

Y1 - 2022

N2 - In this study, a new method to determine the solubility of crystalline drugs in (amorphous) polymers is proposed. The method utilizes annealing of supersaturated amorphous solid dispersions to achieve equilibrium between dissolved and recrystallized drug. By measuring the enthalpy of melting and mixing (Hm+mix) of the recrystallized drug, the equilibrium solubility of the drug in the polymer at the annealing temperature is determined. The equilibrium solubilities at these elevated temperatures were used to extrapolate to room temperature using the Flory-Huggins model. The new Hm+mix method showed solubility predictions in line with the melting point depression (MPD) and recrystallization (RC) methods for indomethacin (IMC) -polyvinylpyrrolidone (PVP). For IMC-hydroxypropyl methylcellulose (HPMC), the MPD method plateaued rapidly, leaving only one usable data point. The RC method showed large variations in the solubility predictions possibly due to a narrow glass transition temperature (Tg) window or inaccurate Tg determination. In contrast, the new Hm+mix method showed robust solubility prediction over the entire annealing temperature range with low variation and narrow error margins after extrapolation for both drug-polymer systems. The new Hm+mix method was able to accurately determine the drug-polymer solubility of IMC-HPMC, showing promise as a new tool to determine the solubility of problematic drug-polymer systems.

AB - In this study, a new method to determine the solubility of crystalline drugs in (amorphous) polymers is proposed. The method utilizes annealing of supersaturated amorphous solid dispersions to achieve equilibrium between dissolved and recrystallized drug. By measuring the enthalpy of melting and mixing (Hm+mix) of the recrystallized drug, the equilibrium solubility of the drug in the polymer at the annealing temperature is determined. The equilibrium solubilities at these elevated temperatures were used to extrapolate to room temperature using the Flory-Huggins model. The new Hm+mix method showed solubility predictions in line with the melting point depression (MPD) and recrystallization (RC) methods for indomethacin (IMC) -polyvinylpyrrolidone (PVP). For IMC-hydroxypropyl methylcellulose (HPMC), the MPD method plateaued rapidly, leaving only one usable data point. The RC method showed large variations in the solubility predictions possibly due to a narrow glass transition temperature (Tg) window or inaccurate Tg determination. In contrast, the new Hm+mix method showed robust solubility prediction over the entire annealing temperature range with low variation and narrow error margins after extrapolation for both drug-polymer systems. The new Hm+mix method was able to accurately determine the drug-polymer solubility of IMC-HPMC, showing promise as a new tool to determine the solubility of problematic drug-polymer systems.

KW - Amorphous solid dispersion (ASD)

KW - Differential scanning calorimetry (DSC)

KW - Hydroxypropyl methylcellulose (HPMC)

KW - Indomethacin (IMC)

KW - Melting point depression (MPD) method

KW - Polyvinylpyrrolidone (PVP)

KW - Recrystallization (RC) method

KW - Solubility

U2 - 10.1016/j.ijpharm.2022.122391

DO - 10.1016/j.ijpharm.2022.122391

M3 - Journal article

C2 - 36379397

AN - SCOPUS:85142871579

VL - 629

JO - International Journal of Pharmaceutics

JF - International Journal of Pharmaceutics

SN - 0378-5173

M1 - 122391

ER -