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Improving Solubility

Many drugs, both currently marketed and in development, are poorly water soluble and this represents a major issue in the generation of effective therapeutics. The bioavailability of a drug is inextricably linked to its solubility. Hence if a drug has low solubility it manifests with poor performance in-vivo in most cases, leading to a requirement for high drug doses and often greater inter-patient variability.

Crystec mSAS® particle engineering technology can be applied to overcome solubility challenges, resulting in a desirable rate of dissolution and stimulating an appropriate pharmacological response in the body. A variety of mSAS® approaches can be taken to address this problem, including the following, and summarised in the video below.

  • Particle size reduction
  • Particle morphology control (targeting a shape with a large surface area, e.g. plates)
  • Modification of the crystal form, including isolation of ‘stable’ metastable polymorphic forms
  • Crystalline composite formation (including scalable co-crystals and lipid-based composites)
  • Salt formation
  • Generation of amorphous dispersions
  • Cyclodextrin complexation

Crystec mSAS® Case Study

The aim of this study was to formulate particles of a poorly soluble drug to enable enhanced oral bioavailability. The target product profile (TPP) was to form particles comprised of an amorphous dispersion of the drug within a polymer matrix. The crystalline drug alone was insoluble in water, so this approach was necessary to enhance dissolution and provide sufficient in-vivo bioavailability.

Product Development

Developing the product involved:
  • A feasibility study to determine if the active pharmaceutical ingredient (API) was compatible with the mSAS® process.
  • Testing the solubility of the API in supercritical carbon dioxide.
  • A compatibility study of the API with the polymer at different API loadings.
  • Investigation of the effects of thermodynamic and kinetic variables on the API/polymer product within the mSAS® environment.
  • Assessment of the critical control parameters.
  • Technology transfer of the process to a commercial scale pilot plant.
  • Analysis of the product by Powder X-Ray Diffraction and Thermal Analysis to determine that the mSAS® product was completely amorphous.
  • Accelerated stability studies.
  • HPLC assay of the API content.
  • In-vitro dissolution testing to determine whether the properties of the material meet the TPP.
  • An in-vivo pharmacokinetic study to ensure that the optimised material has oral bioavailability which meets the TPP.

Product Analysis and Performance

mSAS® produced a stable amorphous formulation containing the correct ratio of API, reproducibly. The dissolution profile of the amorphous mSAS® material was significantly enhanced when compared to the crystalline drug starting material. In-vivo bioavailability studies showed that mSAS® formulation met the target product profile. In addition, the process conditions identified were thermodynamically stable and scaled from laboratory (200ml) to pilot plant (2L) with ease. The parameters were then optimised to ensure that a high yield was obtained per batch.
  • A feasibility study to determine if the active pharmaceutical ingredient (API) was compatible with the mSAS® process.
  • Testing the solubility of the API in supercritical carbon dioxide.
  • A compatibility study of the API with the polymer at different API loadings.
  • Investigation of the effects of thermodynamic and kinetic variables on the API/polymer product within the mSAS® environment.
  • Assessment of the critical control parameters.
  • Technology transfer of the process to a commercial scale pilot plant.
  • Analysis of the product by Powder X-Ray Diffraction and Thermal Analysis to determine that the mSAS® product was completely amorphous.
  • Accelerated stability studies.
  • HPLC assay of the API content.
  • In-vitro dissolution testing to determine whether the properties of the material meet the TPP.
  • An in-vivo pharmacokinetic study to ensure that the optimised material has oral bioavailability which meets the TPP.
Dissolution data in pH 1.0 dissolution media for the mSAS® powder in gelatine capsules demonstrating that powders go rapidly into solution. When a physical mixture of the crystalline API and polymer were used, HPLC analysis showed that no API went into solution during the dissolution experiment.
Plot of mean plasma concentration versus time for the mSAS® powder in-vivo in dogs after oral administration of particle capsules (n=3).
Powder X-Ray Diffraction data of the mSAS® product indicating that it is in the amorphous state (amorphous halo observed).
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