Coformer Screening for Cocrystal Formation

COSMO-RS Biotechnology Pharma Cocrystal

Cocrystallization is a commonly-used method employed in pharmaceutical design to improve the solubility or stability of active ingredients. Experimental determination of suitable cocrystallization conditions is typically quite time-consuming as different synthesis routes are evaluated. The use of virtual pre-screening is therefore quite appealing to narrow down suitable coformer candidates.

In this tutorial, we will showcase such a coformer screening for itraconazole, a prominent antimycotic.

Create a New Compound

As a first step, we will calculate the electrostatic profile of itraconazole. This will provide the required parameters for the COSMO-RS calculation.

1. Start AMSinput: SCM → New Input
2. Choose File → Import Coordinates (System) → From SMILES
3. Enter the SMILES code for itraconazole O=C1N(/N=C\N1c2ccc(cc2)N7CCN(c6ccc(OC[C@@H]3O[C@](OC3)(c4ccc(Cl)cc4Cl)Cn5ncnc5)cc6)CC7)C(C)CC and select OK
4. Select Task → COSMO-RS Compound. This will automatically set the required input to match the default COSMO-RS parametrization
5. Save the job using File → Save as with the name Itraconazole
6. Start the simulation using File → Run

The COSMO-RS compound task will perform a geometry optimization of the molecule. A COSKF file will then be produced for the optimized geometry, which contains the required COSMO-RS parameters.

../_images/itraconazole_28fc4425.png

Screening Coformers

Once the itraconazole calculation has finished, we can add the new compound to our COSMO-RS workspace.

1. Start AMScrs: SCM → COSMO-RS
2. Choose Compounds → Add compound and select the Itraconazole.coskf file that was created in the previous step

For the coformers, we will use compounds from the included CRS database. On account of the basic nature of the itraconazole, a series of acidic partner molecules was considered here.

1. Choose Search compound in list of added compounds or database to access the database
2. Type Tartaric acid in the search bar. Select the compound from the list and click the OK button to add it to the workspace
3. Repeat this step for fumaric acid, succinic acid, malic acid, glutaric acid and adipic acid
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../_images/input_1112ea2f.png

For each coformer, we can predict the stability of the binary mixture with itraconazole. A trimeric molecular crystal will be considered here, where 2 itraconazole molecules coordinate to each coformer. (This is the expected ratio based on the hydrogen bonding structure of the acid-base pairs, and has been verified experimentally.[1])

1. Go to Properties → Vapor Pressure Mixture
2. In the Solvent section, set the first component to Tartaric acid by selecting the compound from the drop-down menu
3. Set the second component to Itraconazole
4. Set the Mole fraction of tartaric acid to 0.33
5. Set the Mole fraction of itraconazole to 0.67 (to match our trimeric cocrystal state)
6. Set the temperature to 298.15 K. We will focus on a single temperature here, so both from and to fields should be the same
7. Press Run to perform the COSMO-RS calculation

Both a graph and table containing the mixture properties will be generated.

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We can repeat this calculation for each of the coformers in order to compare the cocrystal affinities. COSMO-RS predicts the excess free energy and enthalpy for the coformer mixture. This excess energy quantifies the stability of the coformer blend relative to the pure compounds. Large excess energies indicate favorable interactions between the itraconazole and the acid, thereby increasing the likelihood for the compounds to coprecipitate.

Results

An overview of the excess mixture energies for each of the coformers is given in the figure below.

../_images/cocrystal_5d176dde.png

Fig. 56 Comparison of excess free energy and enthalpy for 2:1 itraconazole:coformer mixtures predicted by COSMO-RS at 298.15K. Cocrystals were experimentally observed for the lowest 4 coformers

The 4 coformers with the highest excess energy have been experimentally reported to form cocrystals. The excess energy (either the enthalpy or free energy) can therefore be considered as a candidate indicator for cocrystallization.

  • The energies can be used to rank coformer candidates, preferring large excess energies. Because COSMO-RS calculations take into account both electrostatic interactions and geometric factors, these predictions are considerably more reliable than using simple metrics such as the pH/pKa[1]

  • A cocrystallization boundary could be defined in the figure, situated around a free energy of 0.85 kcal/mol. Coformers with excess free energies above this threshold would then be expected to deposit as pure compounds. Deviations from a strict boundary are expected to occur as our predictions focus only on the thermodynamics: process kinetics may affect cocrystallization depending on the chosen synthesis route

  • The cocrystallization threshold cannot be predicted a priori as crystallization kinetics are omitted

These results indicate that COSMO-RS is preferably used to screen candidate coformers with strong tendencies to affiliate with the active pharmaceutical compound. These candidates are expected to be located well within the cocrystallization regime. Different experimental cocrystallization methods can then be tested to evaluate kinetically viable routes for cocrystal synthesis.

References