Salts or Co-crystals

For co-crystal design strategies based on strong hydrogen bonds (as the vast majority are), there is a possibility that the proton involved in the 

To provide one practical example of the complexity of the situation, proton transfer in the carboxylic acid-pyridine synthon has been investigated systematically by Tocher and co-workers through co-crystallisation of pyridine or 4-dimethylaminopyridine (DMAP) with five different carboxylic acids (Table 2.1) Since the pATa value for the conjugate acid of DMAP (pATa = 9.70) is considerably larger than that of any of the carboxylic acids, salts should be expected for all crystals containing DMAP and this was indeed found to be the case. However, two different crystal forms were established for the fumarate salt, both of which also contained neutral fumaric add molecules. 

For pyridine (p a = 5.14), the expectation on the basis of pA a values is much less clear and the resulting multi-component crystals were characterised as three co-crystals, one salt and one structure including disordered H atoms. Thus, even this limited grid demonstrates the difficulties associated with predicting salt or co-crystal formation. 

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Computational methods could, therefore, potentially impact on polymorph screening, salt or co-crystal selection, as well as the avoidance of solvates. The outline of such a possibility should not be viewed as an over-optimistic assessment of current capabilities, but rather a goal towards which developments should aim. Given that progress is being made on flexible molecules and multi-component crystal structures, the methods that are necessary for such in silico screens are attainable, although it is difficult to predict the rate of progress and, therefore, when such calculations will be practical for the typical pharmaceutical molecule. Moreover, results will always need to be interpreted with care and a realistic view of the approximations and limitations of the methods. This is where continued assessment of methods on well-characterized systems is needed, to inform our level of confidence in the calculations. 

Celecoxib Low solubility, incomplete oral bioavailability, slow onset of action Celecoxib sodium and celecoxib nicotinamide salt or co-crystal plus formulation with improved dissolution profiles... 

Form diversity Carbamazepine Polymorph/solvate formation leading to low solubility form Pharmaceutical salts or co-crystals that are less prone to form conversion... 

Another approach that is fast gaining popularity is the formation of cocrystals to alter the pharmacokinetics of a drug. The tendency of the system to salt or co-crystal formation is governed by the pA a difference, steric and electrostatic properties of the molecules involved. The rule of thumb widely accepted is that there is salt formation if ApA a > 2, while ApATg < 0, results in co-crystal formation. For 0 < Ap.Ka < 2, the system could swing either way resulting in the formation of a salt or co-crystal or a complex with partial proton transfer. Other approaches include formation of solvates, hydrates or variation in the crystal lattice through the formation of polymorphs. 

The characterization of melting behavior is particularly important when selecting a salt or co-crystal for a drug product, since processing steps, such as milling or micronization, can generate considerable heat which not all salt and... 

Melting point analysis and binary phase diagrams are well suited for the characterization of neat salt and co-crystal forms however, neat forms comprise only part of the solid form landscape of a given salt or co-crystal. 

HETeronuclear CORrelation spectroscopy), can definitively prove molecular association between the different components in a salt or co-crystal. The ability of CP-HETCOR NMR spectroscopy to confirm co-crystal formation was recently demonstrated for a palmitic acid nicotinamide 1 1 co-crystal." ... 

While Aakeroy et al. have noted dramatically different structural behavior between carboxylic acid co-crystals and carboxylate salts, what effect, if any, the location of the proton specifically has on the physical properties relevant to delivering a drug in a controlled manner is unclear. Indeed for all intents and purposes, whether the form is unionized, a salt or co-crystal should not matter as long as its physicochemical properties are suitable for the drug product. That said, from a regulatory perspective, the jury is still out. Today, the... 

To design a robust solution crystallization process that will consistently deliver the preferred salt or co-crystal form in high yield, equilibrium solubility... 

Although choosing logical combinations to start with, both in terms of molecular recognition and crystal packing, it is almost impossible to know in advance whether a salt or co-crystal will effectively form. As we have seen in this book, methods for prediction of the structure and its properties are still under development and it is common practice to resort to extensive screening to discover co-crystals. 

In summary, at room temperature malonic and glutaric adducts are salts adipic is ambiguous succinic, pimelic, suberic and azelaic adducts are co-crystals. Diffraction data and solid-state NMR data are in agreement except in the case of compound 1C6, which shows proton motion on the NMR time scale. Salt or co-crystals - does it matter The melting points of compounds 1C3-1C9 do not correlate with the saltlike or co-crystal nature of the adducts, but rather with the even-odd carbon chain length in spite of the substantial differences in supramolecular arrangements in the crystals of the adducts with respect to those of the parent diacids. 

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