Structural studies of crystalline forms of triamterene with carboxylic acid, GRAS and API molecules

This work discusses the preparation and characterization of crystalline forms of the drug triamterene with various carboxylic acids including Generally Regarded as Safe and Active Pharmaceutical Ingredients using liquid-assisted grinding and solvent-evaporative crystallization; a method of potential benefit to the pharmaceutical industry. Triamterene is selected as an appropriate model compound because it has poor water solubility which can have an impact on its bioavailability as a drug and it contains numerous hydrogen-bonding sites, thereby allowing a study of the competition between the different potential supramolecular synthons. Cambridge Structural Database studies show good agreement between this and previous studies using similar compounds.

Predictions of the adduct formation reactions considered in this study involving 1 and coformers (a-g) in DMSO are expressed as P obs which is the probability of observing AB (cocrystal) and A -B + (salt) in % terms according to the Cruz-Cabeza (2012) formula. P obs (AB, %) = -17 ΔpK a + 72 for -1 ≤ ΔpK a ≤ 4 P obs (A -B + , %) = 17 ΔpK a + 28 for -1 ≤ ΔpK a ≤ 4 Where P obs is the probability of observing the A-B (cocrystal) and A -B + (salt) in % terms.
Using this method the % probability (P obs ) values for the proposed reactions were calculated and compared with the experimental results and summarized in Table S1.

Table S1
Results of the adduct formation reactions considered in this study. Notes:

Acid
• ΔpKa is the difference in the pKa of the most basic atom on 1 and the most acidic atom on the complementary acid. pKa values of 1 are calculated using the SPARC online calculator, http://sparc.chem.uga.edu/sparc while pKa values of the coformers (a-f) are obtained from data compiled by R. Williams, http://research.chem.psu.edu/brpgroup/pKa_compilation.pdf.
• Predicted and experimental results of the adduct formation reactions refer to the form predicted according to the Cruz-Cabeza formula and the actual form obtained by crystallization.  All asymmetric units are drawn using ORTEP-3 for Windows (Farruga, 2012) and employ a labelling scheme consistent with IUPAC and IUCr recommendations for small molecules (see Table S4).

Table S4
Crystallographic labelling of molecules of 1 and 1a-g and DMSO.
Triamterene (1) Coformer (a-g) Solvent (DMSO) The hydrogen bond tables that follow (Tables S5 -S12) were produced using PLATON (Spek, 2009) and contain details of D-H … A bonds and angles generated for hydrogen bonds satisfying the default criteria of distance ( where D is a potential donor, A is a potential acceptor and R is the radius of the designated atom type. In cases where it is obvious that the directed hydrogen bond contributes to the formation of the hydrogen bonded sheet (but is slightly longer than expected) the default criteria have been relaxed and the resulting contacts are highlighted in red (see Tables S6, S7 and S11).

S5.1. Triamterene (1)
Crystallographic data for 1 is taken from Hughes et al. (2017) and renumbered for the systematic purposes of this study.

Figure S16
Comparison of the PXRD pattern for the adduct 1g·DMSO obtained from (a) LAG with (b) simulated from X-ray structure.

Summary
These results show that the crystals grown for single crystal analysis were representative of the bulk samples 1a-g·DMSO. The differences between the experimental and simulated PXRD pattern for 1d.DMSO are thought to be due to the preferred orientation of the plate-like crystals noted in this sample.