Detailed analysis of packing efficiency allows rationalization of solvate

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Detailed analysis of packing efficiency allows rationalization of solvate formation propensity for selected structurally similar organic molecules Agris B#rzi#š, Dace Zvani#a, and Aija Trimdale Cryst. Growth Des., Just Accepted Manuscript • Publication Date (Web): 26 Feb 2018 Downloaded from http://pubs.acs.org on February 26, 2018

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Crystal Growth & Design

Detailed analysis of packing efficiency allows rationalization of solvate formation propensity for selected structurally similar organic molecules Agris Bērziņš*, Dace Zvaniņa, Aija Trimdale Faculty of Chemistry, University of Latvia, Jelgavas iela 1, Riga, LV-1004, Latvia

In structural study of seven bile acids it was identified that their propensity for solvate formation is directly related to the packing efficiency of the unsolvated phases: low packing index, voids and unsatisfied hydrogen bonding lead to extensive solvate formation, whereas efficient packing to the opposite. This was determined to be caused by the presence of OH group attached to carbon C12. Solvate formation was determined to provide noticeable improvement in the packing efficiency for compounds having ansolvates with inefficient packing.

* Telephone: +(371)-67033903. E-mail: [email protected]

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Crystal Growth & Design 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Detailed analysis of packing efficiency allows rationalization of solvate formation propensity for selected structurally similar organic molecules Agris Bērziņš*, Dace Zvaniņa, Aija Trimdale Faculty of Chemistry, University of Latvia, Jelgavas iela 1, Riga, LV-1004, Latvia * Telephone: +(371)-67033903. E-mail: [email protected]

ABSTRACT In structural study of seven bile acids it was identified that their propensity for solvate formation is directly related to the packing efficiency of the unsolvated phases: low packing index, voids and unsatisfied hydrogen bonding lead to extensive solvate formation, whereas efficient packing to the opposite. This was determined to be caused by the presence of OH group attached to carbon C12. Solvate formation was determined to provide noticeable improvement in the packing efficiency for compounds having ansolvates with inefficient packing.

INTRODUCTION Studies of crystal form landscape are particularly important for pharmaceutical compounds1,2, making these well explored model compounds. While some compounds crystallize only in numerous one-component phases (e.g., ROY3 and flufenamic acid4), other are keen to form multi-component phases by crystallizing together with different solvent molecules, by therefore forming dozens5-7 or even more than 100 solvates8. Two main structural driving forces resulting the incorporation of solvent in the structure are ability of solvent to compensate unsatisfied


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potential intermolecular interactions between the host molecules and ability to decrease the void space and/or lead to more efficient packing9-11, with most solvates including contributions from both of these driving forces9. The search for possibilities to predict propensity for solvate, or particularly hydrate12-14, formation is still ongoing15,16. Although several algorithms for prediction of solvate formation based on fluid-phase thermodynamics computations17,18 as well as knowledge based models15 have been proposed, they are still unable to take into account all of the factors contributing in solvate formation, and border between compounds forming solvates and such forming only onecomponent phases still cannot be confidently drawn. Although it has been shown16,19,20 that the prediction of guest-free higher-energy structures in computational structure prediction study indicates on the tendency to form solvates, such approach has not been additionally validated and, moreover, such study is not feasible for all compounds. In this study propensity for solvate formation of several bile acids: Cholic acid CA, methyl cholate MC, chenodeoxycholic acid CDCA, ursodeoxycholic acid UDCA, deoxycholic acid DCA, hyodeoxycholic acid HDCA, and lithocholic acid LCA, see Figure 1, were rationalized using detailed analysis of already available crystal structures of ansolvates and solvates. Propensity for solvate formation for the first four of these compounds were additionally confirmed experimentally. CA, DCA and MC are keen solvate and other multi-component phase formers with 107 and 41 solvates (including all unique multi-component phases with compounds existing as liquid in ambient conditions) reported for CA and DCA, respectively, in the Cambridge Structural Database (CSD) and 27 solvates reported for MC21. In contrary, CDCA, UDCA, HDCA and LCA are not good solvate formers, with few solvates reported for HDCA22, two for CDCA, and none for UDCA and LCA. As molecular structures of the analyzed bile acids are highly similar, the available solvate prediction algorithms15,17,18 are expected to fail in providing such drastic differences in the propensity for solvate formation.



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Figure 1. Molecular structure of CA, MC, CDCA, UDCA, HDCA, DCA, and LCA with the numbering of non-hydrogen atoms and labelling of flexible dihedral angles.

RESULTS AND DISCUSSION Simple solvate screening using 11 common solvents confirmed that CA and MC are keen solvate formers with solvates obtained from 9 solvents for CA and MC each, see Table 1. CDCA was confirmed to be able to form few solvates, whereas no solvates were obtained for UDCA. Thus, even simple solvate screening is enough to test the solvate formation propensity of

these compounds, and the obtained results are fully consistent with conclusion from the available literature. Table 1. Outcome of the performed crystallization experiments of the selected bile acids. Solvent

CA

MC

CDCA

UDCA

H2 O

Sa

S

N

N

Methanol

S

S

N

N

Ethanol

S

S

N

N

Acetonitrile

S

S

N

N

Nitromethane

S

S

N

N

Ethyl acetate

S

N

S

N

3-pentanone

S

S

N

N

DMF

N

S

N

N

N/A

S

S

N

Toluene

S

S

N

N

Acetone

S

N

N

N

Dichloromethane


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a

- S = solvate, N = unsolvated phase, N/A – solubility was too low. See more details in Table S1, Supporting Information. Further the available crystal structures of ansolvates and solvates of CA, MC, CDCA, UDCA, HDCA, DCA, and LCA were analyzed. This was, however, slightly complicated by the absence

of crystal structure information for unsolvated DCA. The analysis of hydrogen bonding in crystal structures of unsolvated CA, MC, CDCA, UDCA, HDCA, and LCA shows that despite all compounds except for the MC has a potential

to employ all hydrogen bond donors and acceptors in formation of hydrogen bond network, this is fulfilled only in CA, UDCA, and LCA, see Table 2. Meanwhile, hydrogen bond network in CDCA is formed without involving O5 of molecule B as an acceptor and O1 of molecule A as a

donor, while in HDCA instead of employing O4 as an acceptor O1 is an acceptor for two hydrogen bonds. In crystal structure of unsolvated MC there are even more unsatisfied hydrogen bond donors and acceptors. However, it can clearly be seen that the satisfaction of hydrogen bonding capability in unsolvated phase is not the driving force of solvate formation in the analyzed bile acids, as propensity of CA to form solvates as well as poor propensity of CDCA and HDCA to form solvates is not explained. Table 2. Packing characteristic of crystal structures of unsolvated bile acids

Solvate former

HDon/ HAcc Elattice / balancea kJ mol–1

Packing indexb

Void space / %b

CA

+

+

–210.6

0.651

9.5

MC

+

–

–191.1

0.667

3.6

CDCA –

–

–176.6

0.693

2.8

UDCA –

+

–196.6

0.701

0

HDCA –

–

–194.7

0.683

1.3

–

+

–154.9

0.662

0

LCA a

- “+” indicates that all hydrogen bond donors (HDon) and acceptors (HAcc, not counting O4 as acceptor) are involved in the formation of hydrogen bonds, “–“ indicates the opposite. b – all structures are determined at 295 K except for that of UDCA (FEBHUP02) determined at 123 K. However, similar results (packing index 0.717 and void space of 0.7%) are obtained for FEBHUP determined at 295 K after automatic addition of hydrogen atoms in Mercury. ACS Paragon Plus5 Environment


Calculation of lattice energy, packing index and void space was used to characterize molecular packing in unsolvated bile acids, see Table 2, where lattice energy calculated in PIXEL23 and void space calculated in PLATON24 are given, with results obtained using alternative methods given in the Supporting Information. Difference in the molecule size allows using the lattice energy for direct comparison of packing efficiency only for CDCA, UDCA, and HDCA, clearly representing the more efficient packing in UDCA and HDCA. This is expected for UDCA because of the efficient hydrogen bonding along with the highest packing index among the analyzed bile acids. Apparently, the packing in HDCA is also efficient, as three unique conventional hydrogen bonds are present, and employing O1 as an acceptor for two hydrogen bonds and O4 for none in this case can be sterically more efficient (as lower repulsion energy compensates the less negative Coulombic and dispersion energy), resulting in very similar lattice energy despite the lower packing index and some voids in the structure. Meanwhile, hydrogen bonding in CDCA cannot lead to as low lattice energy values as for the rest of the two isomers. Interestingly, despite having void space of 2.8%, structure of CDCA has the second highest packing index among all analyzed bile acids. It should, however, be noted that for calculation of void space standard approach implemented in PLATON24 was chosen (using approximately 0.2 Å grid spacing with probe radius of 1.2 Å, with alternative results obtained in Mercury using similar approach and calculation settings) for detection of larger cavities and channels, instead of detailed calculation of all empty space using, e.g., Crystal Explorer25 or very small probe radius in Mercury. Thus in the presented results void space identify larger cavities and channels in the structure, while packing index characterize total efficiency and compactness of the packing. As expected, introduction of an additional hydroxyl group in CA leading to possibility to form four unique hydrogen bonds results in lower lattice energy, although in comparison with UDCA and HDCA, lowering is only by 15 kJ mol–1. Moreover, the packing index of CA is only 0.651 and structure contains voids with volume of 9.5%.


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As expected, replacement of the carboxylic OH group with methoxy group in MC structure and thus limitation of the maximum number of unique hydrogen bonds to three per molecule increase the lattice energy with respect to the CA. However, despite the apparent additional freedom in formation of hydrogen bonds if compared to, e.g., UDCA and HDCA, not as low lattice energy is achieved, which can be associated with the presence of hydrogen bonding network not involving even all the hydrogen bond donors (see Supporting Information) and inefficient packing characterized by packing index 0.667 and void space of 3.6%. Again, as expected, LCA containing only one hydroxyl group has the least negative lattice energy. Nevertheless, more detailed analysis of interaction energy suggest that intermolecular interactions should be regarded as efficient, and also packing index of 0.662 may have to be considered as reasonably efficient, see Supporting Information. Further calculation of packing index and void space as well as evaluation of solvent role in the crystal structure was used to characterize molecular packing in solvates and other multicomponent phases of bile acids. The obtained data for selected solvates of CA, MC and DCA (see Experimental Section) are presented in Figure 2, with more details and data given in the Supporting Information. Incomplete crystal structures with missing hydrogen atom coordinates were auto-edited in Mercury26 before calculation of the presented packing index and void space, while those with absent coordinates for all atoms of solvent molecules were excluded from this representation. Again, in Figure 2 void space obtained using PLATON are given, while the values obtained in Mercury with both used settings (see Experimental Section for details and Table S3 – Table S6 for results) gave essentially identical conclusions. The data presented in Figure 2 (and Supporting Information) clearly show that in nearly all CA and MC solvates the packing index has increased if compared to that of unsolvated phase, with only slightly lower or unchanged packing index observed for the remaining few solvates. Similarly, crystal structures of most solvates do not contain voids, and for the remaining solvates void space has decreased if compared to that in the unsolvated phase. Although no clearly



outlying results were obtained for any of the isostructural solvate groups, G-3 solvates of CA had somewhat larger void space, while G-1 (type 1) solvates of MC had somewhat larger void space and lower packing index than observed for other solvates, see more details in the Supporting Information. The increase in the packing efficiency in MC solvates additionally appears as more efficient hydrogen bond network employing all MC hydrogen bond donors not fulfilled in the unsolvated phase. This occurs also in solvates where solvent is not incorporated in the hydrogen bonding network. Absence of crystal structure information for unsolvated DCA complicated obtaining indisputable conclusions for this compound. However, it is reported that microcrystals of unsolvated DCA give powder pattern closely similar to those of inclusion compound with phenantrene possibly implying that the DCA complexes are primary solid solutions of guest in host

27,28

, which could imply that purely unsolvated stable phase cannot be obtained and

unsolvated DCA is obtained with empty channels, thus expected to have quite inefficient packing (with value of 0.65 marked in Figure 2) and large void space, see more details in Supporting Information. For comparison packing index and void space of unsolvated DCA epimer 3β,12β-dihydroxy-5β-cholan-24-oic acid (DADLEA) having inefficient packing is also presented in Figure 2. Nevertheless, although packing index and void space for DCA solvates with small solvent molecules (two of the hydrates and acetone solvate determined at 295 K) are characteristic for inefficient packing, the packing in DADLEA is even less efficient, whereas packing index and absence of void space classify most of the remaining DCA solvates as efficiently packed.


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Figure 2. Void space (above) and relative packing index (below, except for DCA for which packing index value is shown) in structures of bile acid solvates. See more details and data in Supporting Information. For DCA values of unsolvated epimer 3β,12β-dihydroxy-5β-cholan-24oic acid (DADLEA) are included for comparison. Despite the fact that crystal structures for part of CA and DCA solvates were determined in low temperature measurements (for CA 13/40 at 173 – 228 K and 6/40 ≤123 K and for DCA 6/20 at 103 – 213 K), no obvious correlation between packing efficiency and temperature was observed, thus excluding the possibility that the observed increase of the packing efficiency is because structure determination of solvates is sometimes performed at lower temperatures. Thus, it can clearly be seen that the driving force of extensive solvate formation observed for CA, DCA and MC is the inability of these compounds to form unsolvated phase with efficient

packing, while incorporation of solvent molecules in either structure channels or isolated sites



usually allows significant increase of the packing efficiency. Among the analyzed bile acids particularly CA and MC, and most probably also DCA, see above, clearly have significant problems with packing efficiently in their unsolvated phases (packing index < 0.67 and void space > 3%). Even though MC additionally has imbalance of hydrogen bond donors and acceptors, the increase of the packing efficiency is still the driving force for formation of MC solvates, as this imbalance is not compensated even in solvates where solvent is hydrogen bonded to the MC. CDCA and HDCA can be recognized as the next group among the analyzed bile acids having

slight problems with the packing efficiently in unsolvated phases (with packing index > 0.68, but having some relatively large voids (98%), and MC (purity >98%) was obtained from JSC Grindeks (Riga, Latvia). Organic solvents of analytical grade were purchased from commercial sources and used without further purification. Water was deionized in the laboratory (conductivity

Detailed analysis of packing efficiency allows rationalization of solvate

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