The ICH guideline Q6A dictates the requirement of a polymorph screening for all pharmaceutical products. This requirement is driven by a focus on patient safety, as conversion of a polymorphic form into another form with different properties potentially poses a risk to patient safety. The example normally used for highlighting the risk is Abbott’s (now AbbVie’s) Ritonavir, where transformation of a polymorph into a much more stable form led to a sudden lack of effect in the product.  Similar transformations have been observed for other products, very rarely leading to critical safety concerns, but nonetheless very costly to pharma companies. Thus, the reason for having your polymorphism under control is obvious.

As stated in the guideline, you must perform a polymorph screening. The question then arises: How? The guideline does not say anything about how to perform the screening — it is up to you to show that the whole  “polymorph issue” is under control. This is where risk assessment comes into play: Your screening has to ensure that the polymorphic form you use in development is sufficiently stable — but depending on your product, it might not be critical and you will have to decide what amount of resources you will invest in it at the given moment.

How To Create New Polymorphic Forms
It is well known that almost all APIs are able to arrange in different crystal lattices. Polymorphic forms/new crystal forms can be formed by changing the surroundings, e.g. using different solvents at different temperatures for crystallization. It is not possible to predict the number of polymorphs from the molecular structure — and neither is it possible to predict which form is the most stable. Thus, the only way to examine this issue is in the laboratory; as there is no official procedure or guideline, the only limitation to the number and the nature of possible experiments is your imagination (and your budget). Who knows if a new crystalline structure will form in, say, a mixture of acetone, water and ethanol at 60° C if you leave it for four hours? You cannot examine all possible crystallization conditions — so how are you to choose among an unlimited number of possibilities?

Risk Mitigation
In early development the risk that your product will fail at some stage is (unfortunately) quite high, and traditionally the budget for polymorph screening is usually limited. However, considering the level of risk mitigation that can be gained by a limited investment, a failure should never be caused by lack of control of the polymorph (i.e. lack of effect in the clinical studies due to, for instance, precipitation). At this early stage in development you might not yet have determined the to-be-marketed dose. However, you probably have an idea from preclinical studies of the dose that makes it possible to determine whether the drug is “highly soluble” or “poorly soluble”. Especially for the poorly soluble drug, control of polymorphism is critical; small changes in solubility will affect the dissolution rate in vivo. For a highly soluble drug this is less likely to be a problem, however you still have to demonstrate that the risk of formation of a polymorph with a much lower solubility is low. Further, you should evaluate the properties of the API in relation to the therapeutic window: If the expected therapeutic window is very narrow (i.e. the effective plasma concentration is close to the toxicological limit), polymorphic control is more important.

Setting Up the Right Number of Experiments
The number of experimental variables in a polymorphic screening has to be carefully defined. As you cannot examine all variables, the best you can do is to make a scientifically well founded selection. A relevant approach is to examine all the conditions that your API could potentially be exposed to during development/manufacturing. These factors include temperature, pressure and humidity. Further, all the solvents that could be used during manufacturing should be examined.

The best possibility of obtaining new polymorphic forms is obtained by drastically changing the crystallization conditions. This is done by completely dissolving the API in different solvents with very different properties (crystallization will depend on, for instance, the polarity of the solvent). It should be noted that crystallization in general is quite unpredictable — and more frustratingly, it’s not always repeatable. However, by selecting solvents with very different properties — and by varying temperature and concentration in the solvent, you increase the chance that the molecules find new ways of arranging themselves in crystal lattices. To demonstrate that the number of experiments does not need to be unlimited in order to get a good representation of the relevant crystal forms, we have tested a “scientifically well-founded” number of experimental conditions on a well-known API: Aciclovir has been reported in literature to have six different polymorphic forms — our screening set-up revealed five of these forms!

Aciclovir Case Study
The polymorph screening was divided in a “wet part” and a “dry part”. In the “wet part”, crystallization was induced in three solvents with very different properties: Hexane, water and acetonitrile. The samples were exposed to different crystallization conditions (different temperatures, evaporation rates, concentrations). In the dry part it was examined whether pressure, temperature or humidity changes induced new polymorphic forms. It should be noted that only 100 mg Aciclovir was used for the full screening. All samples were subsequently analyzed by XRD (Bruker AXS D8 Advance) — the gold standard method for identifying new crystalline forms. Further, new forms were analyzed by TGA (SDTA851e from Mettler Toledo) in order to separate true polymorphs from solvates.  Five crystalline forms were identified in the polymorph screening (Figure 1). Four of these were true polymorphs and one was a solvate (Figure 2).

The example illustrates that you can actually get quite far by using a scientifically well-founded set-up. As this can be performed in a highly cost-effective manner, it might be relevant to perform such a screening on all new APIs in very early development, in order to minimize the risk that you do not have the chosen crystalline form under control. CP

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Karin Liltorp is principal scientist at Particle Analytical ApS. She can be reached at kli@particle.dk. Søren Lund Kristensen is chief executive officer at Particle Analytical ApS. He can be reached at slk@particle.dk. Thomas Andresen is QA manager at Particle Analytical ApS. He can be reached at tan@particle.dk.