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Calculation of drug-polymer mixing enthalpy as a new screening method of precipitation inhibitors for supersaturating pharmaceutical formulations.

  • Price DJ Merck KGaA, Darmstadt, Germany; Frankfurt Goethe University, Frankfurt, Germany.
  • Nair A Merck KGaA, Darmstadt, Germany.
  • Kuentz M University of Applied Sciences and Arts Northwestern Switzerland, Institute of Pharma Technology, Muttenz, Switzerland.
  • Dressman J Frankfurt Goethe University, Frankfurt, Germany.
  • Saal C Merck KGaA, Darmstadt, Germany. Electronic address: Christoph.saal@merckgroup.com.
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  • 2019-03-17
Published in:
  • European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences. - 2019
Bioenabling formulations
Enthalpy
Precipitation inhibition
Screening
Supersaturation
in silico tools
Chemical Precipitation
Dipyridamole
Drug Compounding
Drug Stability
Fenofibrate
Glyburide
Models, Chemical
Molecular Structure
Polymers
Silicon Dioxide
Solubility
Solvents
Thermodynamics
English Supersaturating formulations are widely used to improve the oral bioavailability of poorly soluble drugs. However, supersaturated solutions are thermodynamically unstable and such formulations often must include a precipitation inhibitor (PI) to sustain the increased concentrations to ensure that sufficient absorption will take place from the gastrointestinal tract. Recent advances in understanding the importance of drug-polymer interaction for successful precipitation inhibition have been encouraging. However, there still exists a gap in how this newfound understanding can be applied to improve the efficiency of PI screening and selection, which is still largely carried out with trial and error-based approaches. The aim of this study was to demonstrate how drug-polymer mixing enthalpy, calculated with the Conductor like Screening Model for Real Solvents (COSMO-RS), can be used as a parameter to select the most efficient precipitation inhibitors, and thus realize the most successful supersaturating formulations. This approach was tested for three different Biopharmaceutical Classification System (BCS) II compounds: dipyridamole, fenofibrate and glibenclamide, formulated with the supersaturating formulation, mesoporous silica. For all three compounds, precipitation was evident in mesoporous silica formulations without a precipitation inhibitor. Of the nine precipitation inhibitors studied, there was a strong positive correlation between the drug-polymer mixing enthalpy and the overall formulation performance, as measured by the area under the concentration-time curve in in vitro dissolution experiments. The data suggest that a rank-order based approach using calculated drug-polymer mixing enthalpy can be reliably used to select precipitation inhibitors for a more focused screening. Such an approach improves efficiency of precipitation inhibitor selection, whilst also improving the likelihood that the most optimal formulation will be realized.
Language
  • English
Open access status
green
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Persistent URL
https://sonar.ch/global/documents/273700
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