Particles in liquid formulation is a concern, critical for injectable but also parenteral and per os.
Also called unexpected, undissolved or undesired particles, they can be of different nature:
– Exogenous as dust, metal particles, joint particles (e.g. silicone/PTFE)
– Also, endogenous to the solution as the API can precipitate/recrystallize.
The starting API, crystalline or amorphous (typical high solubility, lyophilisate), is solubilized.
From the solution, there is a recrystallization (the undesirable).
There are three types of recrystallizations that can appear:
1. A more stable form of the API than the initial API form used for the reconstitution of the liquid formulation (polymorphe/hydrate/solvate);
2.When the free form API is non soluble, a salt can be prepared to improve solubilization. However, salt disproportionation can occur, leading to the free form recrystallization;
3.Rare situation (but still possible!), low solubility co-crystal between an excipient and the API.
Multiple causes and origins are possible, which is why the particle must be chemically identified: is it API? a piece of silicone gasket? something else?
– If it is exogenous, we must find the origin of the pollution to eliminate it.
– If it is API (means endogenous), we will investigate what is the nature of the solid that constitutes the particles? it is necessary to physically characterize the type of crystallization.
Once the nature of the particle has been identified (co-crystal, hydrate, etc.), we want to understand the cause of its appearance, that is to say, describe the balances involved (e.g. solubility curves).
Determining resolution paths will involve assessing compliance/feasibility with pharmaceutical development. Changing the API concentration, adapting the composition of the vehicle, modifying the Ph, changing an excipient are some of the potential solutions.
We must therefore be able to characterize the particles and understand their equilibria.
It is also essential to have a good knowledge of the crystalline forms of the product, also and especially the crystalline forms that we DO NOT want to obtain*, in order to be able to propose solutions from early stage (development) to avoid this problem or in trouble shooting to solve it.
*screenings are the best way to identify crystalline forms.
In conclusion, undesired particle in liquid formulation is a recurring problem.
It can be treated during trouble shooting but also in early stage and thus be avoided.
Holodiag, specialist in solid state and crystallization processes, has the expertise, the equipment to support you with these topics.