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
- 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
- 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.