The crystal form in a pharmaceutical product should be specified. However, it is not enough to state that the product contains “form A” – you should also be able to quantify the given form. Small amounts of other polymorphic forms/amorphous material will influence the behaviour of the drug and thus affect patient safety. In the “pure API” it is possible to quantify “crystal impurities” down to 1-10% – depending on the material in question and the methods used. In the product the quantification limit depends on the characteristics of the excipient and the drug load.
The first challenge when analysing the final product is to find a method that is sufficiently sensitive to detect the solid form of the API in the product. Depending on the drug load and on the special characteristics of the API, different methods might be suited. In most cases a crystalline API can be identified based on one or two peaks by XRD . A simple approach is to compare XRD diffractograms of the API, the product and the placebo – and identify the peaks separating the placebo and the product in a region where the signals from the excipients are limited.
If the product is a tablet (100 mg) containing 1 mg API it is unlikely than you can detect 1% (or even 10%) of “another form” with any of the known methods. In these cases it is necessary that you have shown by other experiments that the risk of transformation is insignificant. These other experiments might be stability studies, where you detect crystalline purity after long term storage – including at accelerated conditions. Further, if you use the stable crystalline form of the API in your product you might argue that the risk of transformation is very limited – as a spontanous transformation into a metastable form is against the “laws of thermordynamics”. Still, in this case it should be shown experimentally that the API in question is actually the stable form (e.g. results from polymorph screening). Further, you should be able to show that interactions with the excipients cannot induce transformations, for instance based on the results from a compatibility study.
If the product contains a larger drug load, the crystalline purity can be determined directly from measurements on the final product. In this approach the results reflect the interactions in the product – thus, it is taken into account that the interactions in these systems, containing several excipients, might be different than the interactions seen in, for instance, a compatibility study. Since measurements on the final product are not derived from the more indirect examination needed at lower drug loads, it might be considered a more correct way of examining the system. Click here to see an example of a XRD quantification method.
Please do not hesitate to contact us for a quote for examination of your product with regard to crystalline purity.