As the demand for small molecule drugs with high bioavailability continues to grow, development on hydrophobic new chemical entities that have very low water solubility also increasing. Recent statistics indicates that approximately 70% small molecules under development belong to Biopharmaceutics Classification System (BCS) II or IV poorly water-soluble drugs.
Low solubility causes great challenges for the formulation development for these compounds, including:
● Low Bioavailability
● Long pharmacokinetic onset time
● High inter- and intro-patient variability of plasma concentration
● Food Effect
● Dose Disproportionality
● Complicated formulations and processes
Crystal Pharmatech utilizes the advanced amorphous solid dispersion (ASD) technology to help our clients solve this low solubility issue. Our two platforms include spray drying and hot melt extrusion.
The scientists at CFS apply the first principle of M3 (Molecule-Material-Medicine) during formulation development. The drug substance is evaluated first for its physicochemical and material properties during preformulation study, the formulation is then scientifically designed based on the properties of both drug substance and excipients, a reliable process including amorphous solid dispersion and downstream processes is developed in parallel with formulation design with expertise knowledge on engineering, thermodynamic and mathematic models. The amorphous solid dispersion solid oral dosage forms are characterized for potential phase separation and recrystallization, and drug product performance during stability study with appropriate packaging design. The formulation and process are optimized and finalized to achieve acceptable stability and human exposure.
ADS Development Process
For spray drying, drug substance and polymer carrier(s) are dissolved in organic solvent(s), the organic solution is atomized into droplets and quickly dried with hot gas to form micron-size particles. Since this process involves heat, mass and momentum transfer, and cross disciplinary principles from thermodynamics, fluid dynamics, and rheology should be applied, the spray drying process and its control are therefore very complicated. The fluid dynamics for lab, pilot and commercial scale spray drying equipment are quite different, leading to significant challenges for scaling up and technology transfer. Our core technical team have solid knowledge and expertise in the fundamentals and scaling up principles for spray drying process, and commercialized several amorphous solid dispersion solid dosage form drug products. With our expertise and world-class manufacturing and analytical equipment, we are confident that we can support amorphous solid dispersion formulation development world widely at high speed and with high quality.
Hot Melt Extrusion
Hot melt extrusion uses twin screw extruder to fully mix API and polymer carrier in a molten state under heat and mechanical stress and form a solid dispersion after extrusion and cooling. Unlike spray drying, HME does not involve organic solvent(s) but adds a factor of mechanical stress, especially high shear stress. The process utilizes the principles of thermodynamics, rheology, and material science. Due to the viscoelasticity of polymer materials and the thermal stability of API and carriers, the design and control of the hot melt extrusion process is very complicated, including feeder design, screw size, configuration and combination, residence time distribution (RTD), and mold type etc. In addition, extrudate cooling and milling, and tablet formulation and process also have significant impact on the bioavailability of the drug product. Finally, HME is a continuous manufacturing process, the on-line PAT detection and analysis can also be a challenge.
The core team of Crystal Pharmatech has a strong background in polymer materials, chemical industry, and machinery, adhering to the guidance of rheology and engineering principles, and has deep attainments in the field of HME. We have developed formulations and technology platforms including immediate release and sustained release and have a successful experience in process scale-up and commercial production. Like spray drying, we have world-class bench-to-production process equipment and analytical instruments. We hope to help innovative drug customers overcome the barriers of insoluble drugs with HME's method.