Excipient Screening for Pharmaceutical Delivery

COSMO-RS Biotechnology Pharma Excipient Solubility Solvent optimization

Administration of pharmaceutical chemicals requires an appropriate excipient to achieve in vivo delivery. High-throughput screenings for active compounds are consequently hindered by physicochemical characterization bottlenecking formulation. COSMO-RS provides a fast pre-screening tool to aid in formulation discovery by finding high-solubility excipient candidates. This procedure will be illustrated for danazol, a common steroid.

Create a New Compound

As a first step, we will calculate the electrostatic profile of danazol. 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 danazol C#C[C@]1(O)CC[C@@H]2[C@@H]1CC[C@H]1[C@H]2CCC2=Cc3c(C[C@H]12)cno3 and select OK
4. Select Task → COSMO-RS Compound. This will automatically set the required input to match the default COSMO-RS parametrisation
5. Save the job using File → Save as with the name Danazol
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/danazol_a905542d.png

Screening Excipients

Once the danazol 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 Danazol.coskf file that was created in the previous step
3. Select the Danazol compound from the list and click the Generate button to automatically set the Nring parameter
4. Set Melting Point to 433 K
5. Set Δ_fusion H to 9.4 kcal/mol

In order to calculate the solubility of a solid compound inside a liquid, COSMO-RS requires the melting point and enthalpy of fusion to be known. You can use the Estimate buttons to generate values through machine learning. However, for accurate calculations, it is recommended to use experimental values, as was done here.

../_images/amscrs_e4d6856f.png

For the excipients, we will use compounds from the included CRS database. A selection of commonly-used solvents will be considered here.

1. Choose Search compound in list of added compounds or database to access the database
2. Type N-Methyl-2-pyrrolidone 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 benzyl alcohol, benzyl benzoate, N,N-dimethylacetamide, dimethyl sulfoxide, ethanol, glycerol, propylene carbonate, 1,2-propylene glycol, tetraethylene glycol, ethyl oleate, oleic acid and glyceryl triacetate
../_images/database_0c2f4037.png

Once the excipients have been loaded in, we can now perform a solubility screening:

1. Go to Properties → Solubility in Pure Solvents
2. Click the AddButton to bring up the list of compounds. Select each of the excipients and click Add. (You can use CTRL+LMB or CTRL+SHIFT+LMB to select multiple excipients at once.)
3. 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
4. For the Solute, select the Danazol compound. Make sure the phase is set to Solid
5. Press Run to perform the COSMO-RS calculation

Both a graph and table containing the calculated solubility data will be generated.

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Results

The figure below shows a comparison with experimental solubilities. We see that:

  • COSMO-RS reproduces the general trend in solubility, though predictions for individual excipients can be off.

  • There is a tendency to underestimate the solubility. (There are many possible reasons for this, either in the choice of COSMO-RS parameters, DFT settings or the reference state of the compound.)

  • We were able to correctly classify high-solubility excipients, regardless of the individual sample errors. Detailed quantitative comparisons (seen in the medium-solubility regime) are more difficult.

These results highlight the potential of COSMO-RS as a fast pre-screening tool to enable classification of large excipient databases for finding high-solubility candidates. COSMO-RS can evaluate several hundreds of excipients per second, making it a valuable tool to help guide experimental validation and improve resource usage.

../_images/BP86_0f3b76bb.png

Fig. 76 Comparison between experimental solubilities[1] and predicted values obtained from COSMO-RS at 298.15 K

References