Solid form chemistry has a major impact on a wide range of disciplines, including chemistry, manufacturing and control (CMC), medicinal chemistry, process chemistry and drug metabolism and pharmacokinetics (DMPK). To understand, modify and control the solid state properties of a molecule can be a major factor in helping to drive forward its development, de-risk its progress from the laboratory to the clinic, and shorten timelines; ensuring that high quality medicines reach the market in the shortest possible time.

Medicinal chemists will typically make compounds as quickly as possible, and often use preparative high-performance liquid chromatography (HPLC) to purify the material, and subsequently lyophilize fractions, to isolate a molecule. This may well yield amorphous material, and when process chemists optimize the chemistry to scale up the synthesis, crystallization of the product material may occur, sometimes unintentionally. This crystallization can have a significant effect on many of the molecule’s attributes, including solubility, stability, hygroscopicity, handling properties and purity. By nominating a robust solid form at the early stages of a development program, high quality material to feed further studies will be consistently delivered.

A material can produce different solid forms, including solvates and hydrates. Solvates have a consistent amount of a solvent molecule within the asymmetric unit cell of a crystalline material, and are relatively easy to recognize during screening activities. Solvated forms of an API, where the solvent in question is an organic molecule (such as ethanol) are rarely used for development.

However, hydrates occur where the solvent molecule is itself water and present a special case. Hydrate formation can influence many properties and is believed to affect up to 75% of all pharmaceutical compounds.¹

There are two main reasons why development programs need to be mindful of hydrates and actively look for them. First, when the solvent is ethanol, for example, desolvation is a one-way process, but when the solvent is water, hydration and dehydration of the drug compound can be a reversible process and occur under ambient conditions, such as storage.

Second, water is often used during the drug substance manufacture and in drug product formulations. This may be as a solution of one or more reagents, in salt formation, wet granulation in drug product manufacture, or as a solvent for lyophilization—and of course, water is the solvent of life itself. For example, dosing in an anhydrous form that converts upon storage or in the body to a lower-solubility hydrated form may affect the observed solubility and dissolution of the API, making the in vitro / in vivo correlation work more difficult to understand. Prior knowledge of the material’s potential to form hydrates, however, would alert the team to this possibility in advance.

As hydrates can pose a risk to the development of an API, there are many ways these can be de-risked at an early stage, including: dynamic vapor sorption (DVS) analysis; early stability at International Council for Harmonisation (ICH)-like conditions, such as 40°C, 75% relative humidity (RH) or 25°C/60% RH; as well as undertaking various water-activity solvent systems during the screening work.

The following case study illustrates how a good understanding of the crystalline forms of a compound can have implications for selecting the most appropriate solid form chemistry going forward, and any potential risks down the development pathway.

Case study: Racemic model compound
Starting from an amorphous input material, a molecule was screened using a wide range of process-relevant solvents across the ICH classification system coupled to a variety of experimental conditions.

Table 1 shows the API exists in 2 forms, and that the form 1 material predominates from the thermal cycling of the amorphous input material as well as the other process-relevant conditions that the material might encounter during manufacture. However, it also shows that the form 2 material may be a hydrate, isolated from water and also the methanol-water mixture (shown in orange in the table). While the X-ray powder diffraction (XRPD) data alone did not confirm this, it raised a question which needed further investigation. This is where a deep understanding of the solid state area is critical to understanding form 2 as a polymorph or a hydrate of form 1.

The freebase form 1 was highly crystalline with good thermal properties, and showed only slight hygroscopicity when analyzed by DVS. There was no evidence of any form change in the DVS data and this was confirmed by XRPD, post DVS analysis. The single-crystal structure confirmed it was a racemate, as opposed to a conglomerate, and the density and packing indicated that this was probably the most stable polymorphic form of the anhydrous material in a racemate form. There were no holes in the crystal structure, there were no channels and it was very dense, which indicated it was probably the most stable polymorphic form.

DVS analysis of the free base form 2 material yielded some interesting data: form 2 was stable until taken below 10% RH, where a 3.2% mass loss was observed. The material it converted into, though, was stable when exposed to excess of 40% RH, and then it regained the mass (Figure 1). This data suggests that the material converts back to form 2. Performing a variable-humidity XRPD experiment by altering the humidity over the sample and acquiring the resulting data in situ offered absolute proof that form 2 converts to a new form 3 that was not observed in the primary screen, but also that it  converted back to form 2 when rehydrated (Figure 2).



This is a good example of a solvate—and in this case, this hydrate is a special case of solvates—that dehydrates to a novel form that was not isolated during the screening experiments. It is not too difficult to imagine a situation where this might be the most suitable form for further development. This would not normally be a recommended route to manufacture a crystalline form, as the desolvation process can be lengthy, rarely goes to completion, and it is not uncommon for the crystals to shatter during the process. However, if these conditions and this form provide seed material, there is the potential to use these seeds as a true crystallization process.

Although the inter-conversion poses a risk for form 2, this could, in theory, be controlled with even deeper understanding of the experimentation. There is a considerably wide humidity range where form 2 is stable (Figure 2), but it should be noted that this experiment took place at 25°C and different temperatures will affect these results. Experiments with variable temperature DVS can therefore de-risk the hydrates even further, if that is the chosen form to move forward with.

Hydrated forms, as opposed to anhydrous forms, can offer a different route to a crystallization process where solubility, metastable zone width, particle morphology and growth rates can all be different, and sometimes used to the advantage of developers. Rapid polarized light microscopy (PLM) analysis of samples from a variety of different water activity systems, for example, can clearly show that mixtures of tipping point or critical water activity between two forms can be obtained (Figure 3). This information can be used to help develop a crystallization process that controls the desired crystal form produced, while controlling and optimizing other factors, such as particle size, yield, morphology and purity.


It is important to note that different crystal morphology is not proof of a new crystal form or polymorph. Different solvent systems can affect the growth rates of different faces of the crystal, which can lead to fine, acicular, high-aspect crystals, or more block-like, lower-aspect crystals; this has implications for filtration, drawing and handling, for example. As shown in Figure 4, by judicious choice of solvent systems, initial experiments which yield irregular, ill-defined particles can be engineered to yield much bigger, more discrete crystals, that are easier to filter, dry and handle.


Conclusion
Undesired hydrates can appear at any stage in research and development, and manufacturing operations and specific steps can be utilized to avoid them. Understanding the science behind the relationship between the anhydrous and hydrated forms is critical. In the case study described above, the formation of potentially disastrous hydrated forms was successfully avoided, and the final morphology returned solids that filtered efficiently and handled well, leading to a robust and reproducible manufacturing process. 

Sources

1. CrystEngComm; 8 (2006) 11-28