Over 90% of NCEs in the pipelines of pharmaceutical companies for oral delivery have poor solubility and/or permeability leading to poor bioavailability in humans. These compounds in crystalline form show negligible aqueous solubility which is a prerequisite for oral absorption. Without screening techniques to enhance poor solubility, many of these potentially lifesaving drugs would be eliminated from development path and never become a drug product.
Solution Engine 2.0
BioDuro-Sundia has developed Solution Engine 2.0 to screen technologies to enhance solubility of lead APIs at discovery stage when limited API is available. Our expert scientists screen formulations with amorphous solid dispersion (ASD) technologies. In-vitro discriminating analysis is coupled with animal PK data to ensure best composition is selected for further scale up and accelerated stability studies. Alternative arms are added as needed to formulation screening and animal PK study arms if required by clients which includes but is not limited to lipid-based solutions/suspensions, self-micro emulsifying drug delivery systems (SMEDDS), nanosuspensions and micronization technologies.
Amorphous Solid Dispersions (ASD) Screening Studies
ASDs are formed by breaking the lattice of crystalline API and dispersing it at the molecular level within a polymer matrix. We are able to screen ASD polymers with only 100 mg of API. Rather than empirically mixing and matching polymer: drug combinations, BioDuro-Sundia utilizes a systematic approach to select pairs that have highest chance of miscibility based on estimated solubility parameters and potential for polar, dipole and ionic interactions between groups available on polymer backbone and drug structure. We utilize Flory-Huggins equation of Gibbs energy of mixing to identify concentration of drug (solute) in a polymer matrix (solvent) where Gibbs free energy (i.e. saturation solubility limit) is minimized.
Solutions of polymers at drug concentrations predicted from this in-silico model are combined in small micro-evaporation tubes. The combinations of polymer: drug ASD are then tested in rodents for PK profile. The combinations with best absolute oral bioavailability in animal studies are selected for scale up and stability studies.
ASD Stability Studies (Spray drying and Hot Melt Extrusion)
The best combinations of drug: polymer ASD candidates (highest absorption based on PK data) are selected for spray drying dispersion (SDD) and/or Hot Melt Extrusion (HME) using Buchi B290 and Haake extruder respectively. These experiments require 1 to 2 grams of API use in up to 5 gram batch sizes. The ASDs are fully characterized at BioDuro-Sundia for amorphous content determination (XRPD), thermal properties (mDSC and TGA), assay/related substance and in-vitro non-sink dissolution before being staged in ICH accelerated stability chambers. The stable ASDs are then selected and tested in PK studies to further confirm identify the best combination for process scale up and clinical trial material (CTM) manufacturing.
ASD Process Scale Up and Clinical Trial Material (CTM) Manufacturing
BioDuro-Sundia has process development and cGMP manufacturing capabilities for SDD and HME from gram to 100s of Kg of batch sizes of intermediate ASDs, downstream process and finished tablets and capsules.
Spray drying process is scaled up to Anhydro MS35 (up to 500 g/h aqueous and 2 Kg/h of solvent spray rates) and Anhydro MS150 (up to 2Kg/h aqueous and 10 Kg/h of solvent spray rates) for engineering process development experimental design based on availability of API followed by CTM cGMP manufacturing, packaging, labeling (open or blinded) and clinical site distribution. The next level scale up in spray-drying will be performed in BioDuro-Sundia’s commercial site starting 4th quarter 2023 upon installation and qualification of GEA PSD4 unit purchased in 2022.