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Influence of Low-Molecular-Weight Excipients on the Phase Behavior of PVPVA64 Amorphous Solid Dispersions

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Abstract

Purpose

The oral bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs) can be improved by the preparation of amorphous solid dispersions (ASDs) where the API is dissolved in polymeric excipients. Desired properties of such ASDs like storage stability, dissolution behavior, and processability can be optimized by additional excipients. In this work, the influence of so-called low-molecular-weight excipients (LMWEs) on the phase behavior of ASDs was investigated.

Method

Binary ASDs of an amorphous API, naproxen (NAP) or acetaminophen (APAP), embedded in poly-(vinylpyrrolidone-co-vinyl acetate) (PVPVA64) were chosen as reference systems. Polyethylene glycol 1500 (PEG1500), D-α-tocopherol polyethylene glycol 1000 succinate (TPGS1000), propylene glycol monocaprylate type II (Capryol™ 90), and propylene glycol monolaurate type I (Lauroglycol™ FCC) were used as LMWEs. The API solubility in the excipients and the glass-transition temperature of the ASDs were modeled using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) and the Kwei equation, respectively, and compared to corresponding experimental data.

Results

The API solubility curves in ternary systems with 90/10 wt%/wt% PVPVA64/LMWE ratios were very close to those in pure PVPVA64. However, the glass-transition temperatures of API/PVPVA64/LMWE ASDs were much lower than those of API/PVPVA64 ASDs. These effects were determined experimentally and agreed with the predictions using the PC-SAFT and Kwei models.

Conclusion

The impact of the LMWEs on the thermodynamic stability of the ASDs is quite small while the kinetic stability is significantly decreased even by small LMWE amounts. PC-SAFT and the Kwei equation are suitable tools for predicting the influence of LMWEs on the ASD phase behavior.

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Abbreviations

APAP:

Acetaminophen

API:

Active pharmaceutical ingredient

ARD:

Average relative deviation

ASD:

Amorphous solid dispersion

DSC:

Differential scanning calorimetry

HPMC:

Hydroxypropyl methylcellulose

HPMCAS:

Hydroxypropyl methylcellulose acetate succinate

LMWE:

Low-molecular-weight excipient

NAP:

Naproxen

PC-SAFT:

Perturbed-Chain Statistical Associating Fluid Theory

PEG1500:

Polyethylene glycol 1500

PVP:

Poly(vinylpyrrolidone)

PVPVA64:

Poly(vinylpyrrolidone-co-vinyl acetate) (VA64)

SLE:

Solid-liquid equilibrium

TPGS1000:

D-α-tocopherol polyethylene glycol 1000 succinate

\( \varDelta {\mathrm{c}}_{\mathrm{p},0,\mathrm{API}}^{\mathrm{SL}} \) :

Difference in the solid and liquid heat capacities of the pure API (J/(molK))

\( \varDelta {\mathrm{h}}_{0,\mathrm{API}}^{\mathrm{SL}} \) :

Enthalpy of fusion of the pure API (J/mol)

\( {\mathrm{T}}_{0,\mathrm{API}}^{\mathrm{SL}} \) :

Melting temperature of the pure API (K)

a :

Helmholtz energy (J)

K :

Gordon-Taylor binary parameter

kB :

Boltzmann constant

kij :

PC-SAFT binary interaction parameter

M :

Molar mass (g/mol)

mseg :

Segment number

Nassoc :

Number of association sites

qij :

Kwei binary interaction parameter

R :

Universal gas constant (8.1345 J/(molK))

T :

Temperature (K)

Tg :

Glass-transition temperature (K)

u/kB :

Dispersion-energy parameter (K)

w :

Content (wt%)

x :

Mole fraction

γ :

Activity coefficient

εAiBi/kB :

Association-energy parameter (K)

κAiBi :

Association-volume parameter

ρ :

Density (g/cm3)

σ :

Segment diameter (Å)

0 :

Pure component

API :

Active pharmaceutical ingredient

calcd :

Calculated

exptl :

Experimental

hc :

Hard chain

L :

Liquid phase

LMWE :

Low-molecular-weight excipient

Ai, Bi :

Association sites A and B of molecule i

assoc.:

Association

disp:

Dispersion

i, j:

Component indices

res:

Residual

seg:

Segment

SL:

Solid-liquid

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ACKNOWLEDGMENTS AND DISCLOSURES

This study was funded by AbbVie. AbbVie participated in the study design, research, data collection, analysis and interpretation of data, as well as writing, reviewing, and approving the publication. S.K., M.D., and K.L. are AbbVie employees and may own AbbVie stock/options. G.S. is an employee at the Department for Biochemical and Chemical Engineering of the TU Dortmund University and has no conflict of interest to report.

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Authors and Affiliations

  1. Global Pharmaceutical R&D, AbbVie Deutschland GmbH & Co. KG, Knollstraße, D-67061, Ludwigshafen am Rhein, Germany

    Kristin Lehmkemper, Samuel O. Kyeremateng & Matthias Degenhardt

  2. Department of Biochemical and Chemical Engineering, Laboratory of Thermodynamics, TU Dortmund, Emil-Figge-Str. 70, D-44227, Dortmund, Germany

    Kristin Lehmkemper & Gabriele Sadowski

Authors
  1. Kristin Lehmkemper
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  2. Samuel O. Kyeremateng
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  4. Gabriele Sadowski
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Correspondence to Samuel O. Kyeremateng or Gabriele Sadowski.

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Lehmkemper, K., Kyeremateng, S.O., Degenhardt, M. et al. Influence of Low-Molecular-Weight Excipients on the Phase Behavior of PVPVA64 Amorphous Solid Dispersions. Pharm Res 35, 25 (2018). https://doi.org/10.1007/s11095-017-2316-y

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