Eutectic is basically melting of a physical mixture. If a cocrystal is formed on mixing two pure components, then it is a different compound and not a physical mixture. Hence, XRPD (powder diffraction pattern) and DSC of a physical mixture is expected to be different from a cocrystal.

Thus, the first test could be performing XRPD of the pure components and the sample. If the sample XRPD looks like addition of the pure component XRPDs, then most probably it is a physical mixture. If the XRPD of the sample has characteristic peaks that are different than those in the pure component XRPD, then the sample could be a cocrystal.

A cocrystal has a unique melting point which can be lower or higher than the pure components, while eutectic melting point is always lower than that of the pure components.

The experimental sequence in DSC I would do (assuming I expect a 1:1 cocrystal):

1. Take DSC of the pure components separately.

2. Make a physical mixture of the pure components , for eg.,1:1, 1:2, and 2:1 (The ratios might be selected differently also; the main point is at least three different compositions preferrably on either side of expected stoichiometry of the cocrystal).

(a) Eutectic melting point is always lower than the melting point of each compinent and it is an invariant point,i.e., it does not change with composition (though the enthalpy associated with this endotherm may vary with composition). So, for the the above three samples, identify the invariant endotherm, if any, and that most probably will be the eutectic point of the two components. There could be other endotherms, but look out for the invariant endotherm.

Note: Formation of hte eutectic does not rule out cocrystal formation as the cocrystal may itself form eutectic with one of the components.

(b) If the pure components form physical mixture and not cocrystal, then in addition to the eutectic melting, you would also expect to see another endothem at a lower temp than the melting point of the component that is in excess.

3. Take the DSC of your sample that needs to be tested for cocrystal/eutectic, i.e. physical mixture. Check whether there is a major endotherm at approximately the same temperature as that of the invariant point as described in 2. If there is, then most probably your sample is a physical mixture. However, if the major endotherm is at a different temperature than the invariant point, then the sample could be a cocrystal.

Of course, the interpretations could get complicated if the pure components are polymorphic or there is degradation on heating. The interpretations of DSC could also depend on how the sample was prepared. So, it will be a good idea to check the HPLC of the sample also to ensure that the two pure components are there and without any degradation.

I'm not sure that there is a bench-level lab test that would be definitive. If the low-melting solid looks like a single crystal, is more crystalline, or exhibits a unique habit, it may indicate a cocrystal, though more tests would be required. IR and Raman spectroscopy can be quite helpful here too and often faster than XRD. Depending on the system, you may be able to use density as an indicator as a cocrystal will exhibit a distinct density while a eutectic would be an average of the parts.

This is not so easy, because one first needs to be sure that a stable co-crystal has formed.

In first instance, mixing two components would lead to eutectic phase behavior no matter what their final equilibrium may be (there is no sure-fire way to know whether the system has reached equilibrium, thus quick and dirty methods will certainly not help you in such a case, even X-ray will leave you in the dark of the real equilibrium).

If equilibrium establishes quickly, then again it depends on the information available on the system.

If the system is unknown, I would say that an X-ray powder diffraction pattern would give most useful information. Generally the diffraction patterns of the two pure solids that are mixed are known (or can be measured quite quickly...). A cocrystal must have a different diffraction pattern, because it has a different structure. Thus comparison of the diffraction pattern of the mixture with those of the pure components will quickly show whether there are additional peaks in the pattern that necessarily belong to a cocrystal (and if the diffraction has disappeared altogether, the system most likely has formed an eutectic liquid).

Of course, once the melting point of the cocrystal is known, DSC measurements will be very quick to establish if the cocrystal is present in a mixture, but necessarily a lot of work has to done, before one can rely on this quick measurement. Also the eutectic temperature can be quickly established by DSC

Dsc ?

DSC = Differential Scanning Calorimetry, it's a thermal measurement where a substance is tested against a background measurement. When phase changes or magnetic changes occur they can be identified by endotherms or exotherms on the DSC trace. Also TG (Thermogravimetric Analysis) can also be used to identify these changes.

Correct. Dsc should work, fast, cheap and quite easy

Eutectic is basically melting of a physical mixture. If a cocrystal is formed on mixing two pure components, then it is a different compound and not a physical mixture. Hence, XRPD (powder diffraction pattern) and DSC of a physical mixture is expected to be different from a cocrystal.

Thus, the first test could be performing XRPD of the pure components and the sample. If the sample XRPD looks like addition of the pure component XRPDs, then most probably it is a physical mixture. If the XRPD of the sample has characteristic peaks that are different than those in the pure component XRPD, then the sample could be a cocrystal.

A cocrystal has a unique melting point which can be lower or higher than the pure components, while eutectic melting point is always lower than that of the pure components.

The experimental sequence in DSC I would do (assuming I expect a 1:1 cocrystal):

1. Take DSC of the pure components separately.

2. Make a physical mixture of the pure components , for eg.,1:1, 1:2, and 2:1 (The ratios might be selected differently also; the main point is at least three different compositions preferrably on either side of expected stoichiometry of the cocrystal).

(a) Eutectic melting point is always lower than the melting point of each compinent and it is an invariant point,i.e., it does not change with composition (though the enthalpy associated with this endotherm may vary with composition). So, for the the above three samples, identify the invariant endotherm, if any, and that most probably will be the eutectic point of the two components. There could be other endotherms, but look out for the invariant endotherm.

Note: Formation of hte eutectic does not rule out cocrystal formation as the cocrystal may itself form eutectic with one of the components.

(b) If the pure components form physical mixture and not cocrystal, then in addition to the eutectic melting, you would also expect to see another endothem at a lower temp than the melting point of the component that is in excess.

3. Take the DSC of your sample that needs to be tested for cocrystal/eutectic, i.e. physical mixture. Check whether there is a major endotherm at approximately the same temperature as that of the invariant point as described in 2. If there is, then most probably your sample is a physical mixture. However, if the major endotherm is at a different temperature than the invariant point, then the sample could be a cocrystal.

Of course, the interpretations could get complicated if the pure components are polymorphic or there is degradation on heating. The interpretations of DSC could also depend on how the sample was prepared. So, it will be a good idea to check the HPLC of the sample also to ensure that the two pure components are there and without any degradation.

One cannot produce a real eutectic crystal arrangement from a mixture of powders, but only on cooling the liquid with the eutectic composition. The solid obtained undergoes fusion as a pure compound at the eutectic temperature on re-heating (a single sharp DSC peak). A mechanical mixture of crystals, even if it has the overall eutectic composition, will not undergo simultaneous fusion (broad, or shouldered, or double DSC peak).

I am convinced that the XRD and high resolution microscopy combined with EDS, and PIXE (elemental analysis of compound) are the best. Do you want a dirty method? Try to solve the eutectic and co-crystal in an alkaline or maybe acidic solution and measure the composition of different elements by AA. Based on elemental composition obtained by AA, it is possible to calculate back the structure of the eutectic (from the phase diagram of an eutectic consists of 3-4 compound)

I am convinced that the XRD and high resolution microscopy combined with EDS, and PIXE (elemental analysis of compound) are the best. Do you want a dirty method? Try to solve the eutectic and co-crystal in an alkaline or maybe acidic solution and measure the composition of different elements by AA. Based on elemental composition obtained by AA, it is possible to calculate back the structure of the eutectic (from the phase diagram of an eutectic consists of 3-4 compound)

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Eutectic is a mixture of two phases.

A co-crystal is a single phase.

X-ray diffaction could be usseful to differentiate if the cristal structure of the components are enough different.

The combination with DSC, Raman, IR or microscopy can help.