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Prediction and Construction of Drug-Polymer Binary System Thermodynamic Phase Diagram in Amorphous Solid Dispersions (ASDs)

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  • Advancements in Amorphous Solid Dispersions to Improve Bioavailability
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Abstract

Amorphous solid dispersion (ASD) has been well known as a potential strategy to improve the bioavailability and dissolution performance of poorly water-soluble drugs. The primary concern of this approach is the long-term stability of the amorphous drug in the solid dispersion. Accurate prediction and detection of the solubility and miscibility of drug in polymeric binary system will be a milestone to the development of ASDs. In this investigation, a method based on Flory–Huggins (F–H) theory was proposed to predict and calculate the solubility and miscibility of the drug in polymeric matrix and construct the phase diagram to identify the relevance between drug loading and temperature for ASDs development. Indomethacin (Indo) was chosen as the model drug, and polyvinyl pyrrolidone vinyl acetate (Kollidon® VA 64) was used as a polymeric carrier for the ASD systems. Physical mixtures were prepared with different drug loadings (10 to 90%) and analyzed by differential scanning calorimetry (DSC). The interaction parameter χ was calculated for physical mixtures by the melting point depression and solubility parameter contribution methods. The phase diagram was constructed to investigate the impact of other parameters like drug loading, processing temperature, and Gibbs free energy of mixing (ΔGmix). For further validation, formulations were developed using HME to verify the accuracy of the phase diagram and to guide in the hot-melt extrusion (HME) process design space and optimization.

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Abbreviations

ASD:

Amorphous solid dispersion

HME:

Hot melt extrusion

Indo:

Indomethacin

PVP VA 64:

Polyvinyl pyrrolidone vinyl acetate

Kollidon® VA 64:

Polyvinyl pyrrolidone vinyl acetate

F–H theory:

Flory-Huggins theory

G-T equation:

Gordon-Taylor equation

BCS:

Biopharmaceutical classification system

DSC:

Differential scanning calorimetry

TGA:

Thermogravimetric analysis

Eq:

Equation

χ :

Interaction parameter

T g :

Glass transition temperature

T g mix :

ASDs glass transition temperature

T g 1 :

Drug glass transition temperature

T g 2 :

Polymer glass transition temperature

w 1 :

Drug weight fraction

w 2 :

Polymer weight fraction

φ :

Drug volume fraction

φ polymer :

Polymer volume fraction

1-φ :

Polymer volume fraction

ρ 1 :

Drug density

ρ 2 :

Polymer density

K :

Adjustable fitting parameter

T m :

Melting point temperature

ΔG mix :

Gibbs free energy of mixing

ΔH mix :

The change in enthalpy

ΔS mix :

The change in entropy

δ t :

Solubility parameter

δ d :

Components of disperse forces

δ p :

Components of polar group forces

δ h :

Components of hydrogen bond energy

F di :

Group contribution to the disperse forces,

E hi :

Group contribution to hydrogen bonding energy

F pi :

Plane symmetry factor of polar groups

V 0 :

Group contributions to the molar volume

R 2 :

R-Squared

GFA:

Glass forming abilities

MPD:

Melting point depression

UCST:

Upper critical solution temperature

T min :

Minimum processing temperature

GI fluids:

Gastrointestinal fluids

PM:

Physical mixture

T deg :

Degradation temperature

XRD:

X-ray diffraction

PXRD:

Powder X-ray diffraction

θ :

Theta

RH :

Relative humidity

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Acknowledgements

Authors gratefully acknowledge Rasha El-Kanayati and Joshua Daniel Theus, who kindly reviewed the earlier version of this manuscript and provided valuable suggestions.

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Authors and Affiliations

  1. Department of Pharmaceutics and Drug Delivery, School of Pharmacy, The University of Mississippi, University, MS, 38677, USA

    Zhiqing Hu, Pengchong Xu, Eman A. Ashour & Michael A. Repka

  2. Pii Center for Pharmaceutical Technology, University of Mississippi, University, MS, 38677, USA

    Michael A. Repka

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Hu, Z., Xu, P., Ashour, E.A. et al. Prediction and Construction of Drug-Polymer Binary System Thermodynamic Phase Diagram in Amorphous Solid Dispersions (ASDs). AAPS PharmSciTech 23, 169 (2022). https://doi.org/10.1208/s12249-022-02319-4

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