21
September 2022

Cocrystal - Motivation and Theory - Solid Form Screening

Motivation

Sponsors may require a cocrystal screen for a number of reasons, or a combination of these:

Dissolution rate/solubility
There is strong theoretical basis for cocrystals possessing high dissolution rates in water, this is explained below. Strictly speaking solubility is measured at equilibrium with undissolved solid and is a fixed thermodynamic property. In practice, however formulation often uses non-equilibrium conditions and this gives a useful window of apparently higher solubility.

Crystallinity
Cocrystals give access to a wide range of potentially crystalline forms and are especially favoured where the API is neutral or unstable to acid.

Novelty
A new cocrystal form is patentable if it has some demonstrable advantage over the prior art and the inventor has a proven method of preparation, i.e. reduction to practice. It is therefore prudent to look for optimal solid forms that offer little scope for attack from competitors who may see an opportunity to exploit a flawed profile.

Hydration issues
Where the API has high water affinity, consideration of the H-bond balance (donors v. acceptors) can suggest classes of coformer that satisfy the H-bond potential of the API and hence give stable cocrystals.

Other processability
This can include issues in large scale synthesis such as slow filtration, and further downstream processes such as compressibility etc.

Stability
Compounds that are unstable to acids strong enough to make salts may be suitable candidates for cocrystal formation.

Theory

Cocrystals are defined as multi-component crystalline forms of defined stoichiometry stabilised by non-bonded interactions, usually H-bonding and lipophilic interactions. They are distinguished from salts in that no proton transfer occurs. Hydrates and solvates are closely related to cocrystals in that the interactions are similar. If sufficiently stable, hydrates may be considered viable forms, solvates are not usually developed, toxicity of the solvent and instability to drying are considerable barriers to progression.

Selection of coformers for cocrystal screening

Selection of coformers uses 5 criteria

1. H-bonding balance
In a stable crystalline form no strong H-bond donor will be without an associated acceptor. Examples of typical H-bond acceptors and donors are given below. Since cocrystals are stabilised largely by H-bonding it is important to consider the overall H-bond balance of the product. Combinations that contain excess H-bond donors will tend to hydrate and solvate to attain a better balanced overall structure. In general drugs contain more H-bond acceptors than donors (H-bond donors tend to reduce the ability of drugs to cross lipophilic membranes so are limited in drug design). Therefore drugs tend to contain excess acceptors and require coformers to contain donors to achieve a balanced system.

Here are some examples of typical H-bond synthons:

H-bonding is a key component of drug-receptor interaction so experienced medicinal chemists will have an in-depth knowledge of H-bonding strength and directionality and an awareness of other examples.

The Mercury software can also predict likely H-bond interactions and in-silico methods are likely to become more powerfully predictive and be able to handle more complex structures in future. This software has also begun to tackle the more difficult issues of lipophilic interaction and shape complementarity, notable early work in this area by Tomoslav Friscic has developed some predictive algorithms for cocrystal design.

2. Preferred diacids
Carboxylic acids are popular choices for screening since they are strong H-bond donors and there are many diverse, safe and cheap examples available. Among these, particularly recommended are the diacids which allow a 2:1 stoichiometry creating a larger unit structure which is prone to crystallisation.

An example is the oxalic acid:caffeine 1:2 cocrystal as shown:

For reasons to do with the symmetry groups available, the ‘even’ diacids create higher melting crystalline derivatives than the ‘odd’ numbered chain lengths and should be high on the preferred selection list.

Some common diacids used in cocrystal screening are listed below. This list is not exhaustive, many other diacids with various substituents are available.

Some other examples of commonly used diacid coformers:

3. Prior art
There are classes of cocrystal known for which the H-bond balance design protocol does not hold. These have often been discovered serendipitously. A well-known example is using proline as a coformer with lipophilic compounds possessing limited H-bond capacity where the stabilising interaction is not obvious. Searching for coformers used for close analogues or part structures of the API in the CCDB can reveal unexpected and otherwise unpredictable successful cocrystal coformers.

4. Solubility
The interaction between cocrystal components is not as strong as with salts, so the individual solubility of each component is a useful guide in cocrystal design. In general the solubilities of the coformer should be similar in the chosen solvent to allow cocrystal formation by slow evaporation. The ternary phase diagram explains why.

In this ternary phase diagram L represents the liquid phase, D the solid drug, D.C the cocrystal and C the coformer alone.

Diagram (a) describes the situation where the solubilities of drug and coformer are similar. Slow evaporation is represented by the vertical line down to the 1:1 point of drug and coformer, this line intersects the point where the cocrystal starts to precipitate (D.C +L). This demonstrates the viability of slow evaporation as a method for cocrystal formation from solution where conditions are such that the solubilities of cocrystal former and drug are selected to be similar by a combination of coformer choice and solvent selection.

Diagram (b) describes the situation where the solubilities are different. The same vertical line does not intersect the cocrystal precipitation point, instead the least soluble component precipitates first, (L+D) then a mixture of cocrystal and drug (L+D.C+D).

This diagram also explains the well known alternative methods for cocrystal formation of ball-milling of neat components or cogrinding with a drop of solvent present. Both methods are represented in the diagram by the 1:1 point of drug and coformer which has a small component of viable cocrystal formation.

Diagram (a)
Diagram (b)

5. Safety
There is no requirement for acidic or basic centres in cocrystal formation so in principle any neutral coformer with appropriate H-bonding capacity and solubility can be selected for screening. GRAS (generally regarded as safe) and EAFUS (everything added to food in the US) lists contain hundreds of compounds that are already cleared for human consumption and are considered benign to add to drug formulations.

Cocrystals and polymorphism

As with all crystalline materials, cocrystals may exist as different polymorphs. It has been stated (McCrone) that the number of polymorphs discovered is proportional to the time spent looking for them. Polymorphs of cocrystals appear to be less common than for salts, perhaps because they are more recent and less effort has been expended in exhaustive searches.

Cocrystals aqueous dissolution

As described above cocrystals are stabilised largely by H-bonded interactions. Dissociation of the components is thus expected in strongly H-bonding solvents such as water that can disrupt the H-bonded network. This effect gives rise to the ‘spring and parachute’ effect where initial rapid dissolution under non-equilibrium conditions gives high concentrations of drug in solution which can be maintained by use of crystallisation inhibitors in the formulation.

Note that over time the concentration of the drug in solution may return to the solubility limit due to spontaneous crystallisation of the parent API. This behaviour in aqueous systems is relevant in the design of suitable formulations, awareness of the tendency to dissociate in water is important to ensure adequate stability and consistent pharmaceutical performance.

Cocrystal characterisation

The following methods are useful in confirming cocrystal formation and stoichiometry:

» PXRD to confirm crystallinity
» DSC for melting point and stability
» NMR (1H) for cocrystal stoichiometry
» CHN elemental analysis

In addition the sponsor may be interested in further properties:

» TGA for stability
» DVS Cocrystals are seldom hygroscopic but this is often requested by sponsors. Note that they may dissociate at high RH.
» Dissolution/solubility. As mentioned above the solubility study of cocrystals needs careful design in respect of their tendency to dissociate under aqueous conditions.
» Stability. Cocrystal formation is not a challenge to API structure, stability studies are unlikely to generate any surprises.

Learn more about our Cocrystal Screening Services

 

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Cocrystal Screening - Motivation and Theory PDF

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