According to the definitions provided by the World Health Organization and the U.S. Food and Drug Administration FDA, an active pharmaceutical ingredient (API) corresponds to any substance or mixture of substances used in a finished pharmaceutical product intended to furnish pharmacological activity or to otherwise have direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to affect the structure and function of the body. So, the Active Pharmaceutical Ingredient (API) is the part of any drug that produces the intended effects. Production of APIs has traditionally been done by the pharmaceutical companies themselves in their home countries. But in recent years the production of APIs has been transferred from the pharmaceutical companies themselves to external manufacturers to cut costs. This has led to more rigorous guidelines and inspections for the production and characterization of API and their formulations..
In addition to the chemical formula, the solid state of the Active Pharmaceutical Ingredient impacts on every aspect of its formulation, from solubility, stability, performance to processability, flowability and product appearance.
Characterization of the API solid state is key to reduce possible future manufacturing or formulation issues and cut drug product development costs and time.
Solubility and permeability of the solid-state dictate bioavailability and thus dosage form efficacy. Many recent drugs are poorly soluble in water and formulation represents a real challenge to improve solubility: in addition to chemical modification of APIs and excipients, the control of particle size and shape allows to increase specific surface area, leading to enhanced dissolution and improved homogeneity of the bulk material. These parameters are the basics of solid state properties.
Many APIs can exist in multiple crystal forms, or polymorphs that are chemically identical but physically distinct as solids. Moreover, the crystal habit i.e. the characteristic external shape of an individual crystal, confers distinct and possibly desirable properties. The drug polymorphs and crystal habit investigation is key for patent claims, formulation strategies and bioavailability.
Laser diffraction, Microscopy, XRD, differential scanning calorimetry (DSC), Morphologically Directed Raman spectroscopy, etc. are ones of the techniques available in Alfatestlab to study solid form properties.
In addition to polymorphs, solvated or hydrated drug crystal forms can occur, forming spontaneously in the presence of excess moisture. Conversely, hydrates can lose water upon drying, leading to physical form changes. In Alfatestlab we provide measurement of API water uptake/loss over the entire humidity range using Dynamic Vapor sorption analysis as well as DSC, thermogravimetric analysis (TGA), and/or XRD measurements
The use of non-crystalline (amorphous) API forms can improve solubility but they are inherently unstable and formulators have to overcome chemical reactivity and hygroscopicity. The glass transition temperature (Tg), measured by DSC, signifies conversion of amorphous to crystalline state, and is used to predict amorphous form stability. In general, the Tg value of amorphous material should be as high as possible to maintain adequate physical stability. Detection and quantification of crystalline content in an amorphous matrix requires appropriate methods such as XRD, Raman, isothermal microcalorimetry, and DSC.
Alfatestlab offers a complete set of physical characterisation techniques for active pharmaceutical ingredient at the particulate level as well as bulk level:
- Particle Size
- Electron Microscopy (SEM) and EDX for Elemental analysis
- Particle shape and morphology
- Aggregation Studies
- Zeta Potential
- Thermal analysis (DSC, TGA)
- Surface area (BET), porosity, density
- Powder flow properties
- Dynamic vapor sorption, etc.
We can provide investigational characterization testing and method development for pharmaceutical materials to support R&D, formulation, process development, production troubleshooting and quality control. Contact us to discuss your analytical needs!
Engineering Crystallography: From Molecule to Crystal to Functional Form pp 367-393