Journal
MOLECULAR PHARMACEUTICS
Volume 14, Issue 12, Pages 4374-4386Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.7b00492
Keywords
amorphous solid dispersion; polymer; thermodynamic model; phase behavior; physical stability; excipient
Funding
- AbbVie
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The purpose of this work is to compare the long-term physical stability of amorphous solid dispersion (ASD) formulations based on three different commercially used excipients, namely, poly(vinylpyrrolidone) K25 (PVP), poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA64), and hydroxypropyl methylcellulose acetate succinate 126G (HPMCAS), at standardized ICH storage conditions, 25 degrees C/0% relative humidity (RH), 25 degrees C/60% RH, and 40 degrees C/75% RH. Acetaminophen (APAP) and naproxen (NAP) were used as active pharmaceutical ingredients (APIs). 18 month long stability studies of these formulations were analyzed and compared with the API/polymer phase diagrams, which were modeled and predicted by applying the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) and the Gordon-Taylor or Kwei equation. The study showed that, at dry storage, the solubility of the APIs in the polymers and the kinetic stabilizing ability of the polymers increase in the following order: HPMCAS < PVPVA64 < PVP. RH significantly reduces the kinetic stabilization as well as NAP solubility in the polymers, while the impact on APAP solubility is small. The impact of RH on the stability increases with increasing hydrophilicity of the pure polymers (HPMCAS < PVPVA64 < PVP). The experimental stability results were in very good agreement with predictions confirming that PC-SAFT and the Kwei equation are suitable predictive tools for determining appropriate ASD compositions and storage conditions to ensure long-term physical stability.
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