September 2012 – polymorph screening

 

Is your drug stable? At Particle Analytical we perform polymorph screenings in order to secure you against highly unpleasant surprises in later development. Almost all drugs can form multiple crystalline forms: Lack of control of the crystalline form corresponds to a risk of sudden transformation – and thereby changes in the stability and properties of the drug. Such changes might have large consequences for the behaviour of the drug during manufacturing and -ultimately- in vivo. I.e. the potential risk if a polymorph screening is not performed is repetition of the analytical program and the clinical studies, which of course is quite costly. Because of the large importance of the  crystal forms, Regulatory Guidelines  specify the need for polymorph screenings in development of all new drugs. We perform scientifically well-founded polymorph screenings in order to minimise the risk of transformations of your drug in later development.

Crystalline forms

In a crystalline material all the molecules are attached to each other in well defined pattern giving the individual forms special properties. The “binding strength” between the molecules in the crystal lattice gives the crystal a well-defined energy, melting point, solubility etc. The molecules might bind to each other in many different ways giving rise to different crystalline forms (polymorphic forms). However, one of the ways of binding to each other is optimal, i.e. is the energetically most favorable. Thus, one of the crystal forms will be more stable than the others as one can easily imagine from the simple illustration below.

tændstikkrystallerny

 

Various “crystal structures” illustrated by matchstick men: Depending on the surroundings, different ways of “attaching” will be observed.

Polymorph Screening

Crystallisation might take place in different solvents – and depending on, for instance, the concentration when the first molecules “meet” . Thus, it is possible to induce different crystal formation by changing the concentration at the nucleation point: It can be done by changing solvent or by changing the temperature at which nucleation takes place. Particle Analytical offers different polymorph screening packages. The basis is a “slim-line” screening using a scientifically well founded approach, giving the customers optimal benefit from the investment.

In a polymorph screening it is attempted to crystalline new forms by using different solvent, temperature grad new forms of the drug is first identified by XRD. Following it is determined whether the new forms are true polymorphic forms or solvates (TGA). Subsequently the new forms are analysed with various methods in order to evaluate the relative stability and the dissolution rate.

Polymorphism and bioavailability 

To obtain the desired effect of a drug, a certain plasma profile should be reached – here illustrated by the red curve. Too low exposure would 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 crystalline material changes into a more stable form. Too high exposure might occur if the crystalline material transforms into a form with higher dissolution rate. Thus, lack of control of your polymorphic form could lead to a change in one of the directions, and both cases could be very harmful to the patient. By performing a polymorph screening you minimise the risk that such a transformation will take place. Please contact us for further info about polymorph screening .

plasma profile final