Particle analysis/powder analysis is essential in order to understand and control your drug during development. Lack of control of the particles increases the risk of sudden transformations leading to changes in the stability and properties of the compound. Such changes might have large consequences for the behavior of the compound during manufacturing and -ultimately- in vivo. I.e. the potential risk if these analyses are not performed is that the analytical program and the clinical studies have to be repeated which of course is quite costly.
Figure: Plasma profile of a virtual patient – To obtain the desired effect of a drug, a certain plasma profile should be reached – here illustrated by the red curve. Too low exposure could lead to lack of effect (blue curve) – and too high exposure would lead to toxicological effects (green curve).
- Too low exposure might occur if the particle size is increased or if the crystalline material changes into a more stable form.
- Too high exposure might occur if the particle size decreases or if the crystalline material transforms into a form with higher dissolution rate.
I.e. both particle size and physical form have to be controlled – and specification should be set.
Bioavailablity and particle analysis
Only the dissolved form of a compound, i.e. separate molecules surrounded by water molecules, will be absorbed in the human body. Thus, as long as the compound exist in particles, it is unavailable for the blood stream, and will not reach the “site of action”. When the compound enters the gastrointestinal tract it is most commonly present as particles. Dissolution of these particles will begin in the stomach (at a low pH value).
Depending on the particle size and the solubility of the compound, more or less of the total dose is dissolved here. Following, the compound enters duodenum and continues into jeujenum, where absorption will take place. Depending on the initial dissolution rate in the stomach, and on the further dissolution of the compound in duodenum/jeujenum, more or less compound will be available for absorption. From the initial examination of the particle properties, knowledge about the expected bioavailability can be obtained.
If low bioavailability is expected, following approaches are possible:
- Micronisation of the particles: Larger surface area will increase the dissolution rate – and it might be sufficient to obtain the wanted bioavailability. (Necessary characterisation: PSD and dissolution rate measurements at relevant pH values)
- Change of solid form into, for instance, a salt: Some salts might increase the dissolution rate of the particles – but the overall solubility is not changed! (Necessary characterisation: Generel properties of salt + IDR)
- Change the type of formulation using solubility increasing excipients – either a solid, semi-solid or liquid formulation might be used. (Necessary characterisation: Dissolution, determination of content of particles, solubility etc.)
- What role does particle sizes play in development?
- Why should one try to develop different crystal forms (polymorphic forms)?