How to avoid oil precipitation during the crystallization process of small molecular compounds

The phenomenon of oil precipitation is called "oiling", also known as liquid-liquid demixing or liquid-liquid phase separation (LLPS). The solute-enriched phase produced by the oil separation process is called the oil phase, and the solute-rich phase is called the water phase. The frequency of oil separation in the test depends on the specific test conditions and the material system involved. Oil precipitation may be common under certain substances or reaction conditions, including: low melting point, relatively large relative molecular weight, polypeptides, cyclic lipopeptides; molecular species containing flexible structures, such as long carbon chains that are easy to rotate; sugars, etc.

During the test, the phenomenon of oil separation may lead to inaccurate analysis results; the reaction rate slows down, product recovery is difficult, equipment is blocked, and other problems affect the normal operation of the test.In order to avoid or solve the oil precipitation phenomenon,you can control the supersaturation, add seed crystals, remove impurities, remove solvent residues, control the temperature, replace the solvent system, adjust the pH value, control the stirring speed and other operating conditions to reduce the possibility of oil precipitation.

This article has compiled some common questions for everyone, hoping to further help or reduce the worries about oil precipitation/crystallization.

1.What does slurry conversion mean? Is it necessary to keep stirring during the slurry aging process?

Slurry conversion is a maturation process. As the name implies, slurry does not have a clear system and is in a suspended state. The sample is added to a certain solvent to form a suspension. The suspension will look like Like Ostwald's rule, if it is metastable crystalline or amorphous, it may slowly transform into a crystalline form with lower energy. This is maturation.

The slurry needs to be stirred continuously during the maturation process. Stirring can accelerate the disturbance. Otherwise, the seed crystal will remain in one position after being added and it will be difficult to induce it. Stirring is very important for slurry maturation, and both magnetic stirring and mechanical stirring are acceptable.

  2.During the antisolvent crystallization process, when adding the seed crystal, the seed crystal also turns into oil. How to deal with it?

If this situation occurs when adding seed crystals, you can choose to increase the amount of seed crystals, or you need to pay attention to the order of adding materials. For example, if the previous crystallization method is to add the antisolvent to the good solvent, then you can consider adding the seed crystal to the poor solvent to form a suspension, and then slowly add the desired crystallized sample dropwise to the solution with the seed crystal. In the solution, be careful to add the material slowly, as this may induce it.

  3.How to judge crystal purity? How to determine whether it is mixed crystal?

This is the most standard way to judge by simulating powder diagrams based on single crystal data. If it is difficult to prepare single crystals for some compounds, you can conduct multiple batches of experiments, such as using different crystallization methods. It is found that all the XRPD, DSC and TGA data of the samples obtained can be consistent, and the XRPD patterns are consistent. , then at this time you can basically determine that it is a single crystal form.

The XRPD spectrum of the mixture is the superposition of the XRPD spectra of each component, so the most likely case of multi-peak XRPD is that other crystal forms of the compound are mixed in.  Assuming that A and B are mixed crystals, the characteristic peaks of both crystal forms may be present.  Appear.  Because it has fingerprint properties, if you can observe the characteristics of A and B through the XRPD pattern, you can judge that it is a mixed crystal.  If the purity of the crystal form is to be judged, quantitative analysis method development is required.  It is difficult to tell the proportion of crystal forms just by looking at an XRPD chart.

  4.How are structurally similar crystal forms removed from the product?

The amount of seed crystals used for induction is very small. After the foreign matter is added, a batch of samples will be induced. Then the induced products will be used as seed crystals to induce the next batch. Slowly, the added foreign matter will It will be gradually diluted and gradually removed.

  5.What should be done if solids are obviously suspended at -10 degrees and turn into mucus during subsequent filtration?

It looks like a solid, but in fact it is not a real solid (crystal). It is actually a gel. When you suck it up with a disposable straw, you will find that it absorbs moisture immediately and then melts. For solutions, you can refer to the solutions in the live broadcast, or you can try to lower the temperature before investigating, or you can also consider extending the stirring time.