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Solution Behavior of PVP-VA and HPMC-AS-Based Amorphous Solid Dispersions and Their Bioavailability Implications

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ABSTRACT

Purpose

To identify the mechanism behind the unexpected bio-performance of two amorphous solid dispersions: BMS-A/PVP-VA and BMS-A/HPMC-AS.

Methods

Solubility of crystalline BMS-A in PVP-VA and HPMC-AS was measured by DSC. Drug-polymer interaction parameters were obtained by Flory-Huggins model fitting. Drug dissolution kinetics of spray-dried dispersions were studied under sink and non-sink conditions. BMS-A supersaturation was studied in the presence of pre-dissolved PVP-VA and HPMC-AS. Potency and crystallinity of undissolved solid dispersions were determined by HPLC and DSC. Polymer dissolution kinetics were obtained by mass balance calculation. Bioavailability of solid dispersions was assessed in dogs.

Results

In solid state, both polymers are miscible with BMS-A, while PVP-VA solublizes the drug better. BMS-A dissolves similarly from both solid dispersions in vitro regardless of dissolution method, while the HPMC-AS dispersion performed much better in vivo. At the same concentration, HPMC-AS is more effective in prolonging BMS-A supersaturation; this effect was negated by the slow dissolution rate of HPMC-AS. Further study revealed that fast PVP-VA dissolution resulted in elevated drug loading in undissolved dispersions and facilitated drug recrystallization before complete release. In contrast, the hydrophobicity and slower HPMC-AS dissolution prevented BMS-A recrystallization within the HPMC-AS matrix for >24 h.

Conclusions

The lower bioavailability of PVP-VA dispersion was attributed to BMS-A recrystallization within the undissolved dispersion, due to hydrophilicity and fast PVP-VA dissolution rate. Polymer selection for solid dispersion development has significant impact on in vivo performance besides physical stability.

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ACKNOWLEDGMENTS & DISCLOSURES

We thank Dr. Sarah Nicholson and Mrs. Victoria Wright (Drug Product Science and Technology, Bristol-Myers Squibb Company, Moreton, United Kingdom) for helpful discussions regarding BMS-A tablet formulation development and evaluation.

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Authors and Affiliations

  1. Drug Product Science & Technology, Bristol-Myers Squibb Co., New Brunswick, New Jersey, 08903, USA

    Feng Qian, Jennifer Wang, Ruiling Hartley, Jing Tao, Raja Haddadin, Neil Mathias & Munir Hussain

Authors
  1. Feng Qian
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  2. Jennifer Wang
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  3. Ruiling Hartley
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  4. Jing Tao
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  5. Raja Haddadin
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  6. Neil Mathias
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  7. Munir Hussain
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Correspondence to Feng Qian.

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Qian, F., Wang, J., Hartley, R. et al. Solution Behavior of PVP-VA and HPMC-AS-Based Amorphous Solid Dispersions and Their Bioavailability Implications. Pharm Res 29, 2766–2776 (2012). https://doi.org/10.1007/s11095-012-0695-7

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  • DOI: https://doi.org/10.1007/s11095-012-0695-7

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