High risk later or “do it now”?

On a regular basis, Particle Analytical are contacted by customers, who want to use us for their stability studies in relation to crystallinity and particle size. In these cases we always ask  if they expect problems with transitions, i.e. if they know, that their drug is in a relatively stable form.

In more cases, the customer respond that it is “just” for phase I studies – or that they plan is to sell the product, thus it is not required at current time point.

However, in our point of view it is never too early to perform a small screening in order to prevent unpleasant surprises! If such a screening is not performed, there is a high risk that a sudden change in crystal form, for instance after phase I, will require a repetition of the full development program! A repetition is needed, as the new crystal form will have different properties with regard to stability as well as bioavailability. Thus performing a small screening up-front might save a lot of money at a later stage.

The whole idea of performing polymorph screening is to induce different crystallization possibilities for the molecules in order to obtain new crystalline structures. At Particle Analytical we have developed a “minor screening package”, where we expose the drug to different conditions in order to induce new forms. This screening can be performed in few weeks.

Only imagination sets the limit for the experimental conditions that could be examined. A short description of why/how different parameters affect crystallization is summarized in the following paragraphs

  • Solvent properties: By changing the solvent, different crystalline structures might form: One conformation might be “preferred” in a very polar solvent compared to a non-polar solvent (polar groups of the molecules might either try to “avoid” or “get close to” the solvent molecules). The table below lists selected solvents with regard to few of their physical physical properties. A rational approach might be to choose solvents with very different properties in the initial screening, as this might lead to very different behavior of the molecules.  Further, some solvents might have properties that allow them to become part of the crystalline lattice, i.e. solvates can be formed. The possibility of forming solvates is dependent on the physical properties of the solvents as well as their size. Usually solvents are not-wanted in development (except from some hydrates) – but they might be a very interesting starting point for further studies.
  •  Concentration: By choosing different solvents the “crystallization concentration” can be varied: If the concentration of molecules in the solvent is high when crystallization begins, other crystalline structures might form than if the solvent concentration is low. Further, by varying the temperature in the solvents, different concentration levels can be obtained – and thereby optimal crystallization conditions for special structures might occur, for instance if supersaturation occur locally.
  • Temperature: The temperature has a high impact on crystallization. Different polymorphic/crystalline structures might be stable at different temperature intervals, e.g. one form is stable at room temperature, but spontaneous transforms into another form when heated. One obvious way to examine thermal transitions is to heat the sample (for instance using DSC) and look for energy changes that reflect transformations. However, one should be aware that the transition temperature observed in the solid state does not correspond to the thermodynamically transition temperature. The transformation temperature should be found from experiments in different solvents – and an efficient way is to use seeding experiments. When using “seeding”, a small amount of a given crystal structure is added to a solution of a different crystal form. According to the laws of thermodynamics, the less stable form will transform into the more stable form.
  • Evaporation rate: Evaporation rate will affect the crystallization: Do the molecules have more time to settle, they might “choose” a different structure than if crystallization occur very fast. Thus, varying the evaporation rate might be an efficient way to provoke new forms. Fast evaporation might be obtained by increasing the evaporation surface – or by using a high nitrogen flow.
  • Mechanical effects: Crystallization is highly dependent  on the mechanical conditions. Local high concentrations might be obtained if a solution is left without stirring compared to when stirred. Depending on the remaining conditions such as the evaporation rate this might also lead to new forms

It should be stated that at a certain temperature there will be only one stable form. The other identified forms will be metastable – and it is just a question of time before “they find out” that there is a better way of connecting to the “neighbors”.

If you want to read more about the subject: For an introduction into the basic theory of thermodynamic stability of polymorphs: Burger & Ramberger: On the polymorphism of pharmaceuticals and other molecular structures, Microchimica Acta, 1979, 259-271. For more information about the role of the solvent in crystallization: Threlfall: Crystallisation of polymorphs: Thermodynamic insight into the role of the solvent. Organic Process Research & Development, 2000, 4, 384-390