Preformulation is a multidisciplinary development of a drug candidate. Material characterization techniques play a key role in a QbD approach during preformulation activities by determining the physical and mechanical properties of APIs, excipients, and blends. This helps to ensure stability, bioavailability, and lot-to-lot consistency of materials while beginning to define your design space and overall control strategy.
During this phase, research is directed to APIs and excipients, both as individual components and blends. Identification and evaluation through physical measurements include: particle size, particle shape, porosity, bulk powder flow, BET surface area, water vapor sorption, surface energy, and density. All can be utilized during this stage of development.
|Particle Size||Solubility, Bioavailability, Powder Flow, Compaction, Compression, Dissolution, Downstream Manufacturing Efficiencies||Magnesium stearate as a lubricant in tablet production and its effective lubricity can be correlated to tablet ejection forces. Magnesium stearate batches with a smaller particle size distribution and larger surface area produces increased lubricity when compared with batches of larger particle size and smaller surface area.|
|Particle Shape||Bioavailability, Compaction, Powder Flow, Dissolution||The principle used by Laser Diffraction assumes all particles arespheres. In practice, when irregularly-shaped particles are present in greater degrees, the DLS particle size may be erroneous and this could prevent a proper assessment of bioavailability/dissolution downstream, as well as compaction and flow.|
|Surface Area||Dissolution, Solubility Compaction||Increasing surface area may improve solubility and dissolution, hence a control parameter for proper dosage/bioavailability. Surface area also plays a significant role in material flow and bonding properties.|
|Density||True Density, Roller Compaction-Lubrication Tableting Setting, Segregation, Compaction, Crystallinity||Knowing the density distributions in the ribbons is very important in improving the effectiveness of the roller compaction process and the granules produced for milling. Other applications include tablet void volume and predicting material segregation. Blends with varying particle densities may require special handling.|
|Porosity||Roller Compaction, Tablet Strength (physical), Fragmentation, Compaction, Content Uniformity/Dissolution||Porosity measurement can evaluate the ability of liquids to penetrate the tablet for dissolution assessment. Can assist in parameter setting for material flow in coating operations. Predictive evaluation for pellet deformation during compression. Total pore volume and percent porosity for roller compacts.|
|DVS-Dynamic Vapor Sorption||Stability, Shelf Life, Appearance, Excipient- API Chemical Stability, Cohesion-Adhesion||
Loss/formation of water content from API can lead to conversion to amorphous form. FDFs are exposed to a variety of environmental conditions from manufacturing to packaging to transportation to storage. Must know the behavior of active material under a variety of humidities to design proper packaging. If a drug forms a hydrate at elevated humidities, the hydrated form of the drug may require further testing as a new chemical entity. If the hydrated form is not desired, then special material handling during manufacturing and packaging may be required.