Predicting the crystalline nature of APIs with a novel in-line X-ray technique: InsituX

During drug manufacturing, active pharmaceutical ingredients (APIs) are exposed to variable environmental conditions and encounter multiple stresses, which may lead to phase transformations. Similarly, during storage, solid-state changes can occur and possibly involve a polymorphic transition, solvate formation or desolvation, or interconversion to an amorphous form (Morris, Griesser, et al. 2001).

The consequences of these changes can affect the performance of an API, and as a result, the quality, stability, and therapeutic effects of the final product may differ from what was expected. It is therefore essential to discover possible phase changes during pharmaceutical development processes, and if possible, take precautions to control them.

Predicting the crystalline nature of an active pharmaceutical ingredient in its solid state remains a trying task for pharmaceutical manufacturers. The formation of hydrates and dehydration are mandatory data for the development of APIs, and ex-situ spectroscopic studies are not satisfactory.

In this on-demand webinar, Prof. Gérard Coquerel, head of the Separative Sciences and Methods Laboratory at the University of Rouen Normandy, illustrates how the precise identification of solid phases and their crystallinity is important for the design of drying, the storage conditions, and the repeatability of the solid transformations regarding APIs, as well as the identification of non-stoichiometric solids and the possible presence of polymorphs of hydrates and anhydrates.

Read on for highlights from the live Q&A session or register to watch the webinar at a time that suits you.

Could you use InsituX for solvates different from hydrates?

GC: Yes, as long as the solvent is volatile enough. It is possible to use a mixture of solvents to crystallize a mix of solvates. This phase allows the possibility to purify an individual solvate, or to access a particular crystalline form after dissolution, as demonstrated with our micro-fin.

Did you ever observe a swap from a solvate to a hydrate by flushing dinitrogen above a threshold in relative humidity?

GC: Dissolution is difficult, and the chemical stability of the compound is jeopardized. This is a problem that we had with Di-isopropyl ether solvate. However, solid-state NMR gave evidence of a very strong bond with an amine group. Therefore, we could swap the solvate by flushing nitrogen with relative humidity and we could also flush out the Di-isopropyl ether molecules.

Is it possible to use other relative humidity ramps rather than those used in dynamic vapor sorption?

GC: Yes, it is beneficial for kinetics studies and to start metastable phases. For instance, fast and slow dissolutions can deliver different sub-hydrates. If you take esomeprazole magnesium hydrates, here you have one hexahydrate, one tetrahydrate, one trihydrate, four different dihydrate, and two monohydrates. You have a family link of hydrates and depending on the kinetics that you use, you could see some of them transferring from one to another.

At the beginning of your talk, you mentioned different phenomena such as deliquescence, efflorescence, caking, retraction, and swelling. How can InsituX help to diagnose those phenomena with certainty?

GC: Deliquescence means that the powder uptakes moisture up to partial or total dissolution of the API. But the intensity of the peaks drops as the deliquescence proceeds — when you have complete dissolution, of course, you have no more peaks.
Under a certain threshold of humidity, the solvate cannot survive. It releases the water molecules, leaving sub-solvate or non-solvated phases, which is called efflorescence. Most of the time you have swelling of the powder that I mentioned already.
Now you could have refraction, caking, or other phenomena that could be optically monitored. The philosophy of my institute is to use other compatible technologies such as a camera. Therefore, you have all the necessary information to give a good interpretation.

When a temperature or transition changes by different relative humidity, you said that there is a solid solution of water in the compound. Is this always true?

GC: It is always true. Let us propose there is a polymorphic transition, transition fluctuates with temperature change. During this fluctuation, this means at least one of the two polymorphs provides a solid solution with another component. For example, if we consider the effect of water with dimethyl-thiourea that I showed in the presentation. The hundreds of PPM level could be enough to decrease the temperature of transition by 25 degrees. Some other authors have shown similar phenomena with ammonium nitrate and water. I insist if you have a temperature of transition between two polymorphs which can fluctuate, it means that at least one of the two forms, maybe both of them, give a solid solution within water.

Learn more about the importance of precisely identifying active pharmaceutical ingredients solid phases in this on-demand webinar>>

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