Why Do Chemically Similar Pharmaceutical Molecules Crystallize in

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Why do chemically similar pharmaceutical molecules crystallize in different structures: a case of droperidol and benperidol Agris B#rzi#š, and Andris Acti#š Cryst. Growth Des., Just Accepted Manuscript • Publication Date (Web): 11 Feb 2016 Downloaded from http://pubs.acs.org on February 11, 2016

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Crystal Growth & Design

Why do chemically similar pharmaceutical molecules crystallize in different structures: a case of droperidol and benperidol Agris Bērziņš* and Andris Actiņš Faculty of Chemistry, University of Latvia, Jelgavas iela 1, Riga, LV-1004, Latvia

A detailed study of molecular conformation and intermolecular interactions in the experimental crystal structures and general trends observed in the CSD as well as theoretical calculations were performed to identify the reason for the formation of different crystal structures of two chemically very similar pharmaceutical molecules benperidol and droperidol. The most important difference between both molecules was the weak intermolecular interactions formed by the central ring which therefore was responsible for the formation of different crystal structures. Cross-seeding experiments were performed to check the possibility for the formation of mutually isostructural phases and theoretical calculations were performed to compare the stability of experimentally observed phases and theoretical isostructural phases by therefore rationalizing the results of the cross-seeding experiments. In cross-seeding crystallizations three new droperidol phases – an ethanol monosolvate, a dihydrate and a new polymorph, all three isostructural to already known phases of benperidol – were obtained.

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

1 ACS Paragon Plus Environment


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Why do chemically similar pharmaceutical molecules crystallize in different structures: a case of droperidol and benperidol Agris Bērziņš* and Andris Actiņš Faculty of Chemistry, University of Latvia, Jelgavas iela 1, Riga, LV-1004, Latvia * Telephone: +(371)-67033903. E-mail: [email protected]

Abstract A detailed study of molecular conformation and intermolecular interactions in the experimental crystal structures and general trends observed in the CSD as well as theoretical calculations were performed to identify the reason for the formation of different crystal structures of two chemically very similar pharmaceutical molecules benperidol and droperidol. The most important difference between both molecules was the weak intermolecular interactions formed by the central ring which therefore was responsible for the formation of different crystal structures. Cross-seeding experiments were performed to check the possibility for the formation of mutually isostructural phases and theoretical calculations were performed to compare the stability of experimentally observed phases and theoretical isostructural phases by therefore rationalizing the results of the cross-seeding experiments. In cross-seeding crystallizations three new droperidol phases – an ethanol monosolvate, a dihydrate and a new polymorph, all three isostructural to already known phases of benperidol – were obtained. 2 ACS Paragon Plus Environment

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1

Introduction Molecular packing in the solid state is controlled by the formation of conventional hydrogen

bonds1,2 and also other weak intermolecular interactions, and the role of the latter ones has received particular attention in the last decade. Besides, for flexible molecules also the differences in the molecular conformation provide a way for different molecular packing3 and the lowest energy in vacuo conformer not necessarily will be the most efficient for construction of crystal structures4. Different packing possibilities results in the formation of different crystal structures and it has been shown that organic molecules can form up to 10 polymorphs5,6 or, even more, by packing together with solvent molecules7-9 more than 100 solvates10. Furthermore, polymorphism is of particular interest in the pharmaceutical industry as different molecule packing results in different physiochemical properties of the resulting phases. Contemporary computational structure prediction tools are successful in the prediction of polymorphs and their relative stability11-20 and, although more challenging, prediction of some hydrate14,21-24 and solvate25,26 systems. Still the effect of minor changes in the chemical structure of the compound altering the possible formation of weak intermolecular interactions and therefore the molecular packing are in general unpredictable27. Therefore systematic studies of these effects has become an important part of the crystal engineering. The effect of differences in the molecular structure on the formation of crystal structures have been investigated, by usually studying the effect of systematic replacement of functional groups at some particular sites, the effect of systematic change of the position of a particular functional group in the studied compounds, or the effect of exchange of the counter ion28,29. Also the effect of the molecular structure and presence of chloride counter-ions on the molecular aggregation and solid state properties of morphinane hydrates has been investigated30. Detailed analysis of the crystal structures formed by different isomers or compounds with similar molecular structures can 3 ACS Paragon Plus Environment


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provide insights into the driving forces determining the resulting molecular arrangement

31

,

although still in some cases it is concluded that the variation of structure and bonding do not yield any kind of detailed predictive possibilities27. The analysis of crystal structures recently have been complemented by the use of various computational techniques. For example, structural similarity for a large set of structurally related compounds can easily be identified, evaluated and quantified using XPac program32,33, used to study structural similarity of carbamazepine and its analogues34, barbiturates35, substituted benzenesulfonamides and their derivatives36-38, sulfonylhydrazones39 and substituted mandelic acids40. Energetic contributions in crystal structures can be compared using results from interaction

energy

calculation

in

code41,

PIXEL

used

to

compare

structures

of

dichlorobenzaldehyde isomers31 and derivatives of 1,2,4-triazole42 and dihydropyrimidinium hydrochloride43. Comparison of various properties plotted on the Hirshfeld surfaces and the respective 2D-fingerprint plots have been used to analyse the intermolecular interactions and the crystal packing behaviour of different molecules42-44. In our previous studies9,45-47 we have investigated the formation and stability of solvate forms of two active pharmaceutical ingredients (APIs) droperidol, 1-{1-[4-(4-Fluorophenyl)-4oxobutyl]-1,2,3,6-tetrahydro-4-pyridyl}-1,3-dihydro-2H-benzimidazol-2-one (Figure 1 (a)), and benperidol, 1-{1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol2-one (Figure 1 (b)). Molecular structures of both compounds are very similar, and the difference is in the fact that in benperidol C8-C9 bond is saturated and therefore it contains a piperidine moiety, whereas in droperidol C8-C9 is unsaturated and therefore this molecule contains a 1,2,3,6-tetrahydropyridine moiety.


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1

(a)

O 9 18

19

F1

20

17 21

2O τ 16

τ6

10 5

15

14 τ3

τ4

13

τ

O

NH

7

6 2

11

9

5

N 12 1

1

(b)

2

1

8

3

N τ2

1

4

18

3

19

22

F1

20

17 21

2O τ 16

τ6

10 5

14 τ3

15

τ4

13

NH

7

5

N

τ

12 1 11

2

1

8

3

N τ2

1

6 2

4 3

22

Figure 1. Molecular structure of (a) droperidol and (b) benperidol with the numbering of nonhydrogen atoms and labelling of flexible torsion angles. The droperidol forms four polymorphs (DI - DIV) and eleven solvates: a set of isostructural solvates DSMe, DSEt, DSACN, DSNM, DSCLF, DSDCM, and DNSH (methanol, ethanol, acetonitrile, nitromethane, chloroform, and dichloromethane solvates, and nonstoichiometric hydrate), as well as dihydrate DDH, 1,4-dioxane DSDIOX, toluene DSTOL, and carbon tetrachloride DSTCC solvates. The benperidol forms five polymorphs (BI - BV) and eleven solvates: two sets of isostructural solvates (type 1 solvates with methanol

B

SMe and ethanol

B

SEt and type 2 solvates with

acetonitrile BSACN, ethyl acetate BSEtOAc and nitromethane BSNM) as well as dihydrate BDH, hemihydrate BHH, 1,4-dioxane BSDIOX, benzyl alcohol BSBenz, chloroform BSCLF, and carbon tetrachloride BSTCC solvates. The number of reported cases of isostructural solids formed by conformationally flexible molecules is smaller than that formed by conformationally rigid molecules as change in the conformation, shape and/or hydrogen bonding groups can lead to a different packing arrangement and therefore to different phases

39

. Moreover, likelihood of finding isostructural

droperidol and benperidol phases is even more reduced by the fact that these molecules can form both dimeric and catameric synthons. Besides in a recent study of two similar flexible APIs no general explanation why different crystal structures were obtained was provided48.



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Therefore the aims of this study were to 1) compare the crystal structures of both compounds, 2) rationalize the reasons for formation of different crystal structures and 3) investigate the possibilities for formation of isostructural phases. Consequently we compared the crystal structures of benperidol and droperidol by identifying and trying to rationalize the differences and similarities, by theoretically and computationally analysing molecular conformation, intermolecular interactions and molecular packing in the crystal structures of both compounds and comparing the experimental crystal structures with general trends in the CSD. To theoretically investigate the possibility of the formation of isostructural phases, ab initio calculations of benperidol and droperidol crystal structures where benperidol molecules are replaced by droperidol and vice versa were performed to compare the energy of these theoretically possible structures with that of experimentally observed ones. Finally, the possibility to experimentally obtain isostructural phases by cross-seeding was investigated and the obtained results were compared with the predictions from the theoretical calculations.

2

Experimental

2.1

Materials

Benperidol polymorph BI (purity >99%) and droperidol polymorph DII (purity >99%) was obtained from JSC Grindeks (Riga, Latvia). Organic solvents of analytical grade were purchased from commercial sources and used without further purification. 2.2 B

Preparation of crystalline forms I was prepared by recrystallization of benperidol from isopropanol. BII was prepared by

slowly evaporating benperidol solution in isopropanol at 50°C. recrystallization of droperidol from acetone. BDH and

D

D

II was prepared by

DH were obtained when a similar


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volume of water was slowly added to benperidol or droperidol solution in acetone, respectively, and the resulting solution was kept at 5 °C. BSEt, DSEt, BSMe, DSMe, BSACN, and DSACN were prepared by recrystallization of benperidol or droperidol from ethanol, methanol or acetonitrile respectively. More detailed descriptions can be found in the literature 9,45. 2.3

Crystal structure comparison and analysis

Crystal structures were visualized and analysed using Mercury 3.349. Mogul 1.7 and ConQuest 1.17 were used to search the CSD (version 5.36 May 2015 Updates) to perform torsion angle and non-bonded interaction analysis. The Crystal Explorer 3.150 was used for generation and analysis of 2D fingerprint plots of Hirshfeld surfaces summarizing the information about intermolecular interactions51,52. Detailed analysis of the molecular packing was performed using XPac code32,33. 2.4

Theoretical calculations

Relaxed potential energy surface (PES) scans were performed in Gaussian 09 at the B3LYP/6311G(d,p) level by scanning all six flexible torsion angles (see Figure 1) of both molecules with the step size of 10°. Initial geometry of benperidol molecule was taken from the crystal structure of BSACN, while that of droperidol molecule was taken from the DNSH. Calculation of total cell energy and lattice energy of droperidol and benperidol polymorphs and solvates was performed in Quantum ESPRESSO53 after relaxation of positions of all atoms with ultra-soft pseudopotentials from the original pseudopotential library and a 44 Ry planewave cut-off energy using PBE functional with vdW interactions treated according to the D2 method of Grimme54. The parameters of convergence, pseudopotentials and the k-point grid were used as suggested for structure optimizations of APIs55. Energy of isolated molecules for calculation of lattice energy was calculated by extracting a single molecule from the optimised



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crystal structure and placing it inside a periodically repeating orthogonal unit cell with dimensions 40 × 40 × 40 Å. The lattice energy calculations were also performed using semi-empirical PIXEL41 methodology developed by Gavezzotti. Crystal structures were used after geometry optimization in Quantum ESPRESSO. Crystal structures of isostructural phases (in which droperidol molecules are substituted with benperidol and vice versa) were prepared by removing two hydrogens from benperidol and adding two to the respective atoms of droperidol in Mercury 3.3, followed by full relaxation (unit cell parameters and position of all atoms) of the obtained crystal structures in CASTEP56. Calculations were performed with ultra-soft pseudopotentials and a 600 eV plane-wave cut-off energy using PBE57 functional with vdW interactions treated using the Tkatchenko-Scheer method58. Identical geometry relaxation was performed also with the original benperidol and droperidol phases. Calculation of total cell energy and lattice energy was then performed in Quantum ESPRESSO as described above. The interaction energies between selected pairs of molecules were calculated in Gaussian 0959 using the M06-2X60 functional and 6-311G(d,p) basis set to molecular geometries directly extracted from the crystal structures after the geometry optimization in Quantum ESPRESSO. The basis set superposition error was corrected using the counterpoise method. The interaction energy was calculated as the difference between the total energy of the dimer and the corresponding isolated molecules. 2.5

Powder X-ray diffraction (PXRD)

The PXRD patterns were measured at ambient temperature on a D8 Advance (Bruker) diffractometer using copper radiation (CuKα) at the wavelength of 1.54180 Å, equipped with a


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LynxEye position sensitive detector. The tube voltage and current were set to 40 kV and 40 mA. The divergence slit was set at 0.6 mm and the antiscatter slit was set at 8.0 mm. The diffraction patterns were recorded using a 0.2s/0.02° scanning speed from 3° to 35° on 2θ scale. For crystal structure determination, PXRD patterns were measured on a D8 Discover (Bruker) diffractometer at transmission geometry using Göbel Mirrors and a capillary sample stage. Other settings and equipment were identical to those used for D8 Advance. Samples were sealed in rotating (60 rpm) borosilicate glass capillaries of 0.5 mm outer diameter (Hilgenberg glass No. 10), and data were collected using 36s/0.01° scanning speed from 2.5° to 70° on 2θ scale. 2.6

Crystal structure determination and refinement

The PXRD pattern was indexed for the first 20 peaks (excluding peaks from impurity) using SVD indexing algorithms61 (implemented in TOPAS v4.2). Structure solution was performed by Monte Carlo/Simulated annealing technique implemented in Expo201462,63, using a rigid model, flexible about the torsion angles τ1–6 by also determining the center of mass location and molecular orientation. The initial geometries of benperidol and ethanol molecules were taken from the results of theoretical calculations. The final refinements were carried out in Expo2014 by the Rietveld method using soft constraints on bond distances and angles. The background was modelled by a 20th-order polynomial function of the Chebyshev type; peak profiles were described by the Pearson VII function and a common (refinable) isotropic thermal factor was attributed to all non-hydrogen atoms, while that of hydrogen atoms was assumed to be 1.2 times higher.



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2.7

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Differential thermal analysis/thermogravimetry (DTA/TG)

The DTA/TG analysis was performed with Exstar6000 TG/DTA6300 (SII). Open aluminum pans were used. Heating of the samples from 30 to 200°C was performed at a 5°·min–1 heating rate. Samples of 5–10 mg mass were used, and the nitrogen flow rate was 100±10 mL·min–1. 2.8

Cross-seeding crystallizations

Cross-seeding is known method for obtaining isostructural phases37,40 if the conventional crystallization experiments produced solid products with different crystal structures. For crystallization of polymorphs and methanol, ethanol, and acetonitrile solvates saturated or almost saturated acetone, isopropanol, methanol, ethanol, or acetonitrile solution of the benperidol or droperidol was prepared, the obtained solution was filtrated and poured in the flasks containing slightly ground seeds of the polymorph or corresponding solvate of the other API. Crystallization was allowed to take place at 25 °C and –10 °C. In other experiments the obtained suspensions were intensively mixed with magnetic stirrer at 25 °C. For crystallization of dihydrates saturated acetone solution of the benperidol or droperidol was prepared. For some crystallizations the obtained solution was filtrated and poured in the flask, then a similar volume of water was slowly added immediately followed by the addition of slightly ground seeds of the dihydrate of the other API. The flask was then thermostated at 5 °C. For other crystallizations seeds of the dihydrate of the other API was added to the water and the suspension was intensively mixed with magnetic stirrer. Then the saturated acetone solution was quickly added. The amount of seeds in all of the experiments was approximately 1-3% from the resulting solid product. Most of the experiments were performed in duplicate. More details are given in the Table S14, Supporting Information.


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3

Results and discussion

3.1

Comparison of benperidol and droperidol crystal structures

As stated, both droperidol and benperidol forms numerous polymorphs and for each compound there are two hydrates as well as seven solvates with identical organic solvents (see Figure S1, Supporting Information). To identify possible structural similarities, crystal structures or PXRD patterns for phases without structural information were compared. Comparison of the space group, strong hydrogen bond motif of API molecules and intermolecular interactions of solvent molecules is given in Table 1. No structural similarities were identified between polymorphs, alcohol solvates, and lower-stoichiometry hydrates as crystal structures were described in different space groups with different hydrogen bonding pattern and other intermolecular interactions. Table 1. Comparison of crystal structures formed by droperidol and benperidol

Phase

Space group

Hydrogen bonding motifa

Intermolecular interactions of solvent moleculesb

P21/c

ܴଶଶ (8) dimers

–

I

R3

ܴ଺଺ (48) rings

–

II

P–1

ܴଶଶ (8) dimers

–

P–1

ܴଶଶ (8)

–

Designation D

II

B

Polymorphs

B B

III

dimers

‫ܥ‬ଶଶ (9) O2…H-O3-H…N3c D

DH

P21/n

‫ܥ‬ଶଶ (10) N3…H-O3…H-N2

–

‫ܥ‬ଶଶ (15) O2…H-O3… H-N2

Dihydrates B

Lowerstoichiometry hydrates Ethanol solvatesd Acetonitrile

‫ܥ‬ଶଶ (10) O1…H-O3-H…N3

DH

P21/n

–

NSH

P–1

ܴଶଶ (8) dimers

C2/c

ܴଶଶ (8) dimers

D

SEt

P–1

ܴଶଶ (8) dimers

B

SEt

P21/c

SACN

P–1

D

B

D

HH

‫ܥ‬ଶଶ (15) O2…H-O4… H-N2 ‫ܦ‬ଷଷ (7) O1…H-O3-H…O3-H…O1 ‫ܦ‬ଶଶ (5) N3

…

H-O3-H… N3

‫(ܦ‬2) O3-H…O1

‫ܥ‬ଶଶ (10) chains N2-H…O3-H…N3 ܴଶଶ (8) dimers

2 weak hydrogen bonds formed



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solvatese

B

SACN

P–1

ܴଶଶ (8) dimers

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by N4 and one by C24-H

a

– Hydrogen bonding motifs of the API molecules are given;

b

– Only the most characteristic interactions are reported here;

c

– Second level graph sets for both hydrates are given;

d

– Identical information is characteristic for isostructural methanol solvates;

e

– Identical information is characteristic for isostructural nitromethane solvates.

Both acetonitrile (and nitromethane) solvates crystallize in P–1 structures where droperidol and benperidol molecules forms hydrogen bonded dimers and solvent molecules are arranged in structure channels without any strong hydrogen bonds. However, solvent stoichiometry, cell dimensions and arrangement of API molecule pairs (see Figure S2, Supporting Information) are different. The only crystal structures in which the space group and the number of hydrogen bonds formed are identical, and the lattice parameters are similar are both dihydrates. However, detailed analysis of the hydrogen bonding network revealed that the water molecules are linking different atoms of the API molecules, see Figure 2, which therefore leads to different packing of the API molecules, despite that in two of the projections both structures appeared to be almost identical, see Figure 2. XPac analysis confirmed that there is no common substructure between both dihydrates.


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Figure 2. Representation of strong hydrogen bonds (1B and 1D) and molecular packing (2B – 3D) in crystal structures of benperidol and droperidol dihydrates. The PXRD patterns of both dioxane solvates and tetrachlorocarbon solvates, as well as those of polymorphs with unknown crystal structures also indicated that the crystal structures of these phases are different (see Figure S4, Supporting Information). Therefore despite the similar molecular structure of benperidol and droperidol as well as the existence of numerous polymorphs and solvates with the same solvent, direct comparison of the crystal structures and structural information from the PXRD patterns showed that none of the phases are mutually isostructural. 3.2

Comparison of molecular conformation

As stated above, the only structural difference between benperidol and droperidol is the order of the C8–C9 bond in the central ring of the molecule. The piperidine ring of benperidol in all its crystal structures takes the chair conformation, whereas the 1,2,3,6−tetrahydropyridine ring of droperidol in all its crystal structures takes the half-chair or skew conformation. Nevertheless, the overall conformation difference between benperidol and droperidol molecules caused by the 13 ACS Paragon Plus Environment


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presence of different rings is not significant. By comparing the values of flexible torsion angles from crystal structures of both compounds it was concluded the conformation of benperidol and droperidol in all of the structures except for two (BII and DII) is very similar (see Supporting Information). Nevertheless, more detailed comparison (see Table S1, Supporting Information) showed that the average value (calculated by excluding the significantly different values and structures determined from PXRD data) of the torsion angles τ1, τ3, and τ5 in benperidol and droperidol crystal structures differs by 11 – 13°, while the respective standard deviation is only 2 – 6° (1 – 4° if one most different value is excluded). If the observed difference in the values of τ1 is apparently caused by the adjacent structural differences, the values of τ3 and τ5 should not be affected by it. As a result the overlay of the whole molecules does not provide ideal overlap due to accumulation of differences in the torsion angles, particularly in the 4-oxobutyl side chain (see Figure 3). An exception is droperidol molecule in DDH, conformation of which is more similar to that observed in the benperidol crystal structures.

Figure 3. Overlay of droperidol and benperidol molecules from benperidol BSEt (in dark green) and BSACN (in dark blue) and droperidol DNSH (in cyan) and DDH (in red). The most different conformation is that in DNSH and the main differences accumulates in the torsion angles of 4oxobutyl side chain. Besides the comparison of the experimental molecular conformations, PES scans with respect to each flexible torsion angle ߬ଵ – ߬଺ were performed in Gaussian 09. The PES scans for 4phenyl-4-oxobutyl side chain (scans with respect to torsion angles τ2 to τ6, see Figure S5,


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Supporting Information) were nearly identical for both molecules and in most of the cases very similar experimental molecular conformations corresponding to the energy minima were observed. The only exceptions were observed for BII structure: appearance of different τ4 value for one of the molecules as well as a deviation from the energy minimum for τ6. Therefore the differences observed in the experimental values of τ3 and τ5 were not caused by differences in the location of the energy minima. Logically, the PES scans for τ1 differed quite significantly (see Figure 4) due to the different hybridization of carbon C8 and the associated structural differences right next to it. However, almost all of the experimental crystal structures corresponded to the global energy minima, which are located at similar τ1 values for both compounds.

Figure 4. Potential energy surface scans of torsion angle ߬ଵ in benperidol and droperidol molecules. Values observed in benperidol and droperidol experimental crystal structures are represented with red and black circles respectively.

D

NSH, BSEt and BSACN represents one

structure from the respective group of isostructural solvates. Therefore the chemical structure difference was not able to change the molecular conformation energy in a way that would explain crystallization in different crystal structures. This conclusion



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was directly supported by very similar molecular conformations in all droperidol and all benperidol solvates as well as in BI and BIII. As expected, the conformation of τ1 – τ6 observed in the experimental crystal structures matched to that typically observed in the CSD. The same was true also for the conformation of the piperidine and 1,2,3,6-tetrahydropyridine rings. More details are given in the Supporting Information. 3.3

Comparison of intermolecular interactions

Both in benperidol and droperidol there is one strong hydrogen bond donor (N2-H) and three hydrogen bond acceptors (carbamide O1, phenone O2 and tertiary amine N3). Moreover, carbamide moiety consisting of N2-H and O1 can form either dimeric or catameric motifs. Dominant hydrogen bonding motif in benperidol crystal structures was hydrogen bonded homodimers with graph set ܴଶଶ (8) (present in BII, BIII, BHH, and type 2 solvates, see Table 1 and Table S3, Supporting Information), employing hydrogen bond N2-H…O1. Formation of chains, however, was observed in crystal structures of BI via hydrogen bond N2-H…N3 (although the resulting hydrogen bonding motif is ܴ଺଺ (48) ring formed from 6 benperidol molecules) and two different structures of alcohol solvates (type 1 solvates and

B

SBenz, although in these

structures hydrogen bonded chains ‫ܥ‬ଶଶ (10) were formed together with the solvent molecules). Smaller structural variation of droperidol, however, prevented drawing convincing conclusions about the preferred hydrogen bonding motif, and in this case only hydrogen bonded homodimers based on N2-H…O1 hydrogen bond were observed (in DII and isostructural solvates). However, as the molecular structure difference from the benperidol is very small, there is no direct explanation why only hydrogen bonded homodimers were observed in the crystal structures of droperidol. 16 ACS Paragon Plus Environment

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Comparison of the weak intermolecular interactions formed between the API molecules (see Table S4, Supporting Information) showed that the most typical of these were the weak hydrogen bonds. Statistically the most common of these were CH…O1 (particularly in structures without carbamide homodimers) and CH…O2 (particularly in structures containing carbamide homodimers), followed by less common interactions CH…F and CH…N3 (the latter observed only in droperidol isostructural solvates). In part of the structures a noticeable role was played also by other weak interactions (mainly CH…π). Nevertheless, the observed weak intermolecular interactions in droperidol and benperidol crystal structures appeared to be similar, and the observed differences partially could be explained by smaller number of different structures formed by the droperidol. The incidence of both strong and weak hydrogen bonds observed in the experiment benperidol and droperidol crystal structures agreed to that observed in the CSD, as also in the CSD nonbonded interaction search the most incident interactions were hydrogen bonded homodimers of carbamides and weak hydrogen bonds with carboxyl group, see Supporting Information. More detailed investigation of the intermolecular interactions was performed by comparing relative contributions of different interactions to the Hirshfeld surface area in all droperidol and benperidol crystal structures. The obtained results are shown in Tables S7 and S8, Supporting Information. Only relatively small variation for total contributions of different atom types in Hirshfeld surfaces of benperidol and droperidol molecules were observed (see Figure 5). Comparison of these contributions for droperidol and benperidol revealed that generally only slightly higher contribution of interactions formed by hydrogen and slightly lower contribution of those formed by C and N was observed for benperidol. First two of these observations are due to larger number of hydrogen atoms and lower number of carbon atoms acting as donors of π



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electrons in the benperidol. The observed similarity is in fact expected as both molecules have almost identical element composition and very similar shape. Differences were, however, observed for the total contributions of different atom types to the Hirshfeld surface area of the same solvent molecules in the structures of both APIs, as the environment of the solvent molecules and therefore also the intermolecular interactions in the respective crystal structures were different. Comparison of the contributions of particular interactions (see Figure S7, Supporting Information) showed more pronounced variation between different crystal structures because of the presence of different intermolecular interactions. However, due to much wider structural variance of benperidol, contribution range for any particular interaction observed in benperidol structures included that observed in any of three different droperidol structures. Therefore this analysis confirmed that in general the structural difference between both APIs did not introduce significant change in the formed intermolecular interactions.

Figure 5. Relative contributions of different intermolecular interactions to the Hirshfeld surface areas of benperidol and droperidol in their crystal structures. DIsostruct. solv. represents average value from the crystal structures of droperidol isostructural solvates. Analysis of the weak intermolecular interactions formed particularly by atoms chemically and location-wise affected by the structural difference (C8, C9, C12 and the associated hydrogen 18 ACS Paragon Plus Environment

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atoms, see Table S5, Supporting Information) showed that in benperidol crystal structures the respective hydrogen atoms were donors of weak hydrogen bonds or electron acceptors in CH…ߨ interactions. For droperidol, however, the possibility for such interactions is lower due to the smaller number of these hydrogen atoms, which therefore reduced the frequency of such interactions in the experimental crystal structures. A potential of the double bond to be an electron donor in CH…ߨ interactions was employed instead. Therefore these appeared to be the most important differences between the both molecules resulting the formation of different crystal structures due to slight change in the possibility to form weak intermolecular interactions. However, this observation cannot be considered as completely conclusive as droperidol forms only three different crystal structures and the double bond of the central ring acted as electron donor in CH…ߨ interactions only in the crystal structures of isostructural solvates. 3.4

Quantitative comparison of observed and theoretical crystal structures

The packing of crystal structures with identical composition can be compared quantitatively using the lattice energy (if changes associated with the conformation differences are taken into account or can be neglected). It was assumed that the changes associated with the different number of hydrogen atoms in the central ring of the benperidol and droperidol can be neglected as only the weak intermolecular interactions were slightly disturbed. However, it was possible to use the lattice energy for comparison of the stability of only polymorphs, dihydrates, and hemihydrates, as the stoichiometry of other benperidol and droperidol solvates with known crystal structure information is different. The lattice energy values calculated with QuantumEspresso and PIXEL differed (see Table 2), with the difference appearing to be linearly dependent on the magnitude of lattice energy, which could be associated with completely different methodology used for the calculations. However, identical conclusions were obtained



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from both methods and both results are presented as the results from PIXEL are showed to be correct and reliable64, while energy values for structures with Z´ > 2 could only be calculated using QuantumEspresso. Table 2. Lattice energy of benperidol and droperidol polymorphs, dihydrates and hemihydrates.

Phase

ElattQE, kJ·mol-1 Droperidol Benperidol

ElattPIXEL, kJ·mol-1 Droperidol Benperidol

I: –237.0 II: –232.9 III: –211.5 –127.8 –172.1

II: –182.8

I: –186.4 II: – III: –168.5

– –

– –127.2

Polymorphs

II: –227.0

Dihydrate Hemihydrate

–125.5 –172.3

The lattice energy of both dihydrates and hemihydrates was practically identical, while that of polymorphs showed that molecule packing in BI and BII is energetically more favorable than that in

D

II, while the energy of

B

III was significantly less negative, as expected from the

experimental observations9. Although the relative stability calculated in this way does not take into account the molecular conformation energy, the conformation and also its relative energy in B

I, BIII, and DII was almost the same, while the energy difference between BII and other

polymorphs calculated from the total cell energy and the lattice energy was practically identical. Therefore in general analysis of the lattice energy of polymorphs and hydrates confirmed that the structural differences between both molecules do not introduce significant change in the sum of energy from all intermolecular interactions. Hence the obtained results did not provide an answer to the question why different crystal structures were obtained for droperidol and benperidol despite the very insignificant differences in the observed molecular properties including intermolecular interactions and their energy. To evaluate the possibility for formation of theoretical isostructural phases where benperidol molecules are replaced by droperidol and vice versa, computational simulations were carried out 20 ACS Paragon Plus Environment

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by adding two hydrogen atoms to the droperidol molecules and deleting them from the benperidol molecules in the respective crystal structures, followed by full geometry optimization of the crystal structures in CASTEP. Then the total cell energy of these theoretical isostructural phases was compared with that of the original phases after full geometry optimization (the introduced change in the lattice parameters are given in Tables S11, Supporting Information). The optimization step, however, was unsuccessful for theoretical droperidol polymorph isostructural to BI due to very large unit cell (Z=18) resulting in too long calculations as apparently the starting point was far from the geometry minimum. The obtained unit cell energy differences are given in Table 3. Table 3. Difference in total unit cell energy (in kJ per mole of droperidol or benperidol) between the crystal structures where benperidol molecules were replaced with the droperidol molecules and vice versa and the original benperidol and droperidol structures. Phase

Benperidola

Dropeidolb

II DH SMe SEt SACN

12.0 11.9 50.3 58.7 30.5

1.4 11.1 –27.8 –39.4 –9.7

a

– E(benperidol structure isostructural to droperidol) – E(original benperidol structure)

b

– E(droperidol structure isostructural to benperidol) – E(original droperidol structure)

Comparison of the unit cell energy for polymorphs and dihydrates was straightforward, and it was concluded that the experimentally observed dihydrates BDH and DDH are favorable over the theoretical isostructural phases B-iso-DDH and D-iso-BDH, and the same was true also for the polymorph B

II. However, the total energy of polymorph DII was almost identical to that of D-iso-BII (droperidol



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polymorph isostructural to BII), so its existence is theoretically possible. Interestingly, in

D-iso-B

II

droperidol conformation did not correspond to the energy minimum (τ1 for each of the molecules was 57.0, 80.9 and 108.7°). This energetically inefficient conformation was compensated by more efficient intermolecular interactions, as the lattice energy of

D-iso-B

II was by 10.2 kJ·mol-1

lower than that of the DII. The comparison of the phases with different solvent stoichiometry, however, was again not possible, and the use of the obtained total energy values in this case led to an overestimation of the stability of monosolvate structures if compared to the hemisolvate structures (see Supporting Information). Therefore, to draw any reasonable conclusions, comparison of intermolecular interaction energy values between the experimentally observed and theoretical monosolvates and hemisolvates was made as it provided information which of the two possible structures with the same solvent stoichiometry prefer which of the two APIs, see Table 4. Table 4. Difference in lattice energy (in kJ·mol–1) between the original phases (benperidol monosolvates and droperidol hemisolvates) and the theoretical isostructural phases (benperidol hemisolvates and droperidol monosolvates).

Phase

Monosolvate ELattice, Benp

ELattice, Drop

–155.3 –155.2 SMe –160.4 –163.3 SEt –140.8 –142.2 SACN a - ELattice, Drop - ELattice, Benp b

Hemisolvate ∆ELatticea

ELattice, Drop

ELattice, Benp

∆ELatticeb

0.2 –2.9 –1.3

–180.7 –184.2 –178.3

–177.0 –179.7 –174.1

3.7 4.6 4.2

- ELattice, Benp - ELattice, Drop

The comparison of the lattice energy of hemisolvates showed that the structures formed by droperidol were energetically more efficient. However, the comparison of lattice energy of monosolvates revealed that droperidol in fact would have energetically more efficient


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interactions than benperidol in structures isostructural to those of BSEt and BSACN. Although such comparison does not in any way prove that D-iso-BSEt and BSACN are energetically more favorable structures than the experimentally observed DSEt and DSACN, it showed that the formation of such structures are energetically possible, as structures having less efficient intermolecular interactions are already observed for benperidol solvates. More detailed analysis of these structures were performed by calculations of the pairwise interaction energy values in Gaussian 09. This approach allowed to split the total interaction energy into components and therefore identify the main interactions responsible for the overall stability of one of the structures. The obtained results are given in Tables S12 and S13, Supporting Information. This analysis showed that no particular one or few interactions made droperidol monosolvates more favorable over the benperidol monosolvates, whereas for hemisolvates 5 of the interactions were ~1 kJ·mol–1 favorable for structures containing droperidol molecules. Interestingly, in droperidol monosolvates the energy of interactions formed by solvent molecules was less efficient than that in the benperidol monosolvates, but this was compensated by more efficient interactions between the droperidol molecules themselves. 3.5

Cross-seeding crystallizations

As the theoretical calculations showed that the formation of droperidol solvates isostructural to the benperidol solvates could in fact be possible, cross-seeding crystallizations were performed to check this experimentally. Besides, the possibility of the formation of both droperidol phases isostructural to those of benperidol as well as benperidol phases isostructural to those of droperidol was examined in this way. For these experiments only polymorphs and solvates which were studied theoretically were selected (with an exceptional inclusion of BI – the most stable



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polymorph of benperidol). The phases obtained in these crystallization experiments are shown in Table 5. Table 5. Phases obtained in the cross seeding experiments. Detailed results for all of the performed experiments are given in Table S14, Supporting Information. Solvent

Seed phase

Resulting phase

Solvent

Seed phase

Droperidol Methanol Ethanol Acetonitrile Acetone Acetone Acetone

B

SMe B SEt B SACN B I B II B DH

Resulting phase

Benperidol D

SMe D-iso-B SEt D SACN D II (+ D-iso-BII)a D II (+ D-iso-BII)a D DH (+D-iso-BDH)b

D

Methanol Ethanol Acetonitrile Acetone Isopropanol Acetone

B

SMe D SEt D SACN D II D II D DH

SMe SEt B SACN B II B I B DH B

a

– a mixture was obtained in only one of the experiments.

b

– in part of the experiments pure DDH was obtained, see Table S14, Supporting Information.

When the droperidol solution in acetone was seeded with benperidol polymorphs BI and BII usually pure

D

II was obtained, but in two of the experiments its mixture with a phase

isostructural to benperidol polymorph BII was obtained (designated as

D-iso-B

II), see Figure S8,

Supporting Information. Similarly, when droperidol solution in a mixture of acetone and water was seeded with BDH, pure DDH was obtained in some of the experiments, but in part of the experiments its mixture with phase isostructural to BDH was obtained (designated as

D-iso-B

DH),

see Figure S9, Supporting Information. The results of the theoretical calculations (see Table 3) showed that neither of the isostructural phases

D-iso-B

II and

D-iso-B

DH were energetically more

favorable over the original DII and DDH. This explains why in these experiments the original droperidol phases mainly were obtained, and

D-iso-B

II and

D-iso-B

DH were obtained only in some

of the experiments and only in mixture with DII and DDH respectively. However, the energy


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difference apparently was small enough to allow the crystallization of these phases in the presence of the seeds of BII and BDH. Quite high energy difference (11 kJ·mol–1) therefore could explains why only small fraction of

D-iso-B

DH (up to only 20% based on the recorded PXRD

patterns) was obtained in the mixture. In all of the crystallizations where saturated solution of droperidol in ethanol was seeded with B

SEt a new droperidol solvate

D-iso-B

SEt isostructural to benperidol ethanol solvate was obtained,

see Figure 6.

Figure 6. PXRD patterns of D-iso-BSEt (black), DSEt (blue), and BSEt (red). Pure

D-iso-B

SEt was obtained in all of the crystallizations and it was observed that the

crystallization of

D-iso-B

SEt started almost immediately after adding the seeds of BSEt. In the

experiments where the amount of the seeds was reduced to ~0.04 and ~0.13% from the total mass of the resulting solid product, a mixture of D-iso-BSEt and DSEt was obtained, while when the amount of seeds was ~0.2% almost pure D-iso-BSEt was already obtained. Therefore the formation of D-iso-BSEt in the presence of BSEt seeds was easy and fast process. In the absence of BSEt seeds, however, only DSEt could be obtained. Seeding of saturated droperidol solution in methanol and acetonitrile with

B

SMe and

B

SACN, respectively, however, produced only already known

droperidol solvates. Therefore it is even possible that the formation of 25 ACS Paragon Plus Environment

D-iso-B

SEt is energetically


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favorable over the formation of DSEt, while it is the other way around for droperidol methanol and acetonitrile solvates. If this is true, the formation of DSEt in the absence of BSEt seeds occurs due to the kinetic control of the crystallization. The observed formation of

D-iso-B

SEt agrees with

the results from calculations presented in Table 4, showing that the formation of D-iso-BSEt has the most energetic favorability over the BSEt if compared to the other two solvates. Besides, it also agrees with the results presented in Table 3, as the energy characterizing the favorability of D-isoB

SEt over the DSEt was significantly higher than that for the methanol solvate despite the

isostructurality between methanol and ethanol solvates. When saturated solutions of benperidol was seeded with the corresponding droperidol phases, only the know benperidol phases were obtained. Also this observation agrees with the theoretical calculations given in the previous section, as the benperidol structures isostructural to those of droperidol were energetically less favorable than the experimental benperidol structures. Nevertheless, interestingly, when benperidol solution in acetone was seeded with DII, in all of the experiments only BII was obtained, although in identical conditions in the absence of seeds BI is obtained and previously BII was crystallized only in few experiments and only from the isopropanol9. 3.6

Study of the obtained new phases

Crystal structure of

D-iso-B

SEt. As pure

D-iso-B

SEt was obtained in the cross-seeding

crystallizations, it was possible to determine its crystal structure. As the crystallization in the presence of BSEt always initiated very fast, only powdered

D-iso-B

SEt samples were obtained.

Therefore the crystal structure was determined from PXRD pattern recorded from sample in the capillary. Although in the conditions of the PXRD analysis part of the D-iso-BSEt transformed into D

SEt (CSD refcode KAMCIK), the crystal structure determination was successful. The obtained


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crystallographic data are given in Table 6. The correctness of the structure was confirmed by the good agreement between experimental and calculated diffraction patterns (with an exception of the impurity peaks from

D

SEt, see Figure 7), as well as by the geometry optimization in

QuantumEspresso introducing only inessential changes in the crystal structure (see Figure S10, Supporting Information). The monosolvate stoichiometry of

D-iso-B

analysis (experimental weight loss: 11.1%, theoretical: 10.8%).


SEt was confirmed by the TG


Table 6. Crystallographic data for the droperidol phase D-iso-BSEt. Empirical formula Mr Crystal system Space group a (Å) b (Å) c (Å) α (o) β (o) γ (o) V (Å3) Z/Z’ T, K Rwp Rp Rexp

C22H22FN3O2·C2H6O 425.49 monoclinic P21/c 15.262(4) 10.7454(20) 15.3174(30) 90 117.982(8) 90 2218.3(8) 4/1 298(2) 0.0611 0.03919 0.00617

Observed Calculated

Intensity

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Difference

**

*

10

*

*

* * *

20

* *

30

40

50

60

70

2θ, °

Figure 7. Experimental (black), calculated (red), and difference (dark blue) PXRD profiles from the final Rietveld refinement of D-iso-BSEt. With asterisks impurities of DSEt are shown. As expected, the crystal structure of energy for

D-iso-B

D-iso-B

SEt was isostructural to that of BSEt. The lattice

SEt (−127.2 kJ·mol–1) was lower than that of BSEt (−122.1 kJ·mol–1, calculated

using PIXEL from crystal structure data at 298 K, see Supporting Information). This agrees with 28 ACS Paragon Plus Environment

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the results from the reported computational simulations and confirms that the interactions in droperidol ethanol monosolvate are energetically more favorable than those in the isostructural benperidol ethanol monosolvate. Phase transitions of

D-iso-B

SEt,

D-iso-B

DH and

D-iso-B

II. Desolvation of samples containing both

of the obtained new solvates were performed. PXRD analysis showed that the desolvation products of

D-iso-B

SEt are dependent on the sample preparation, and include droperidol

polymorphs DI, DII and DISD (the latter one was obtained only when an unground sample was desolvated). Interestingly, the main (for some samples even the only) desolvation product of a mixture of D

DH and

D-iso-B

DH (where the latter was only up to 20%) was

D-iso-B

II (see Figure S12,

Supporting Information). This could mean that this particular phase was favoured in the conditions of the dehydration if droperidol and a small amount of benperidol (at the level of seeds added) were present in the sample. Interestingly, a repeated recrystallization of pure B

II from isopropanol produced only

D-iso-B

II. Besides,

D-iso-B

D-iso-

II did not completely convert to DII

(thermodynamically stable droperidol polymorph at ambient temperature) even during a 5 days long slurry-bridging experiment of a mixture of D-iso-BII and DII in acetone and isopropanol. This suggests that either a)

D-iso-B

II is rather stable (which is supported by very small energy

difference of 1.4 kJ·mol–1 obtained in the computational simulations) or b) the

D-iso-B

II is

stabilized by the small amount of benperidol present and therefore probably cannot completely transform into pure DII. Thermal analysis of

D-iso-B

II confirmed that it is a non-solvated phase

with melting point of 145 °C (see Figure S13, Supporting Information), which is different from that of other known droperidol and benperidol polymorphs, including that of BII (161 °C) and D

II (134 °C).



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4

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Conclusions Comparison of the crystal structures formed by chemically similar APIs droperidol and

benperidol revealed the absence of mutually isostructural phases. A detailed study of the molecular conformation revealed that despite the similarity of the molecules and nearly identical potential energy surfaces obtained in the theoretical calculations ~10° differences appeared between the average values of torsion angles τ3 and τ5 in benperidol and droperidol crystal structures. In the same time the expected difference between potential energy surfaces of torsion angle τ1 was not associated with the different crystal structures obtained. Analysis of the intermolecular interactions, although complicated by the limited number of different structures formed by the droperidol, revealed that no significant differences can be identified between structures formed by both APIs. Nevertheless, the chemical differences slightly altered the possibility of the central ring (differing part of the molecule) to form weak intermolecular interactions which therefore was identified as the most important difference between the both molecules and could result the crystallization into different crystal structures. Quantitative comparison of the total cell energy between experimentally observed and theoretical mutually isostructural phases confirmed that the experimentally observed polymorphs and dihydrates are energetically favorable. However, such comparison was not possible for solvates with different solvent stoichiometry. Alternatively, for these phases a comparison of lattice energy between experimentally observed and theoretical isostructural solvates containing the same solvent was performed by comparing benperidol and droperidol monosolvates as well as hemisolvates. It was found that the packing in the droperidol hemisolvates was favorable over that in the theoretical benperidol hemisolvates. However, the total intermolecular interaction energy in the theoretical droperidol monosolvates was identical or even favorable (particularly for ethanol solvate) over that in the benperidol monosolvates. This result justified the observation 30 ACS Paragon Plus Environment

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that in the cross-seeding experiments a new droperidol solvate

D-iso-B

SEt isostructural to the

benperidol solvate was obtained in all of the respective crystallizations. Interestingly, formation of energetically unfavorable

D-iso-B

DH and

D-iso-B

II was also observed, but only in some of the

experiments and only in a mixture with DDH or DII respectively. Besides, the obtained data provided a possible explanation to the observation that most of the droperidol solvates are isostructural channel solvates, while benperidol forms structurally different stoichiometric solvates instead. Formation of solvates usually starts with a nucleation step, and in case of efficient intermolecular interactions in the initially formed cluster, solvate structure with channels can be obtained65, which can then experience further transformations depending on the relative energy with respect to alternative structures65-67. As already observed, intermolecular interactions in droperidol isostructural solvates are very efficient and therefore solvates with solvents of appropriate size providing sufficiently effective intermolecular interactions are obtained45. As intermolecular interactions in similar benperidol channel solvates are energetically less favorable by at least 4 kJ·mol–1, the absence of identical structures for benperidol is therefore explained. Furthermore, as formation of the nuclei of such structure is the first step of the crystallization and the interactions are so efficient, channel solvate DSEt could be obtained even if the D-iso-BSEt is slightly energetically more favorable due to this kinetic control of the crystallization.

Associated content Supporting Information. Additional data from the comparison of crystal structures, analysis of molecular conformation, intermolecular interactions and their energy, as well as from crossseeding experiments and studies of the new phases obtained in these experiments are presented



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in the Supporting Information, along with X-ray crystallographic information ﬁle (CIF). This information is available free of charge via the internet at http://pubs.acs.org/. Crystallographic information file is also available from the Cambridge Crystallographic Data Center (CCDC) upon request (http://www.ccdc.cam.ac.uk, CCDC deposition number 1440783).

Acknowledgements This work was supported by the European Social Fund within the project “Support for Doctoral Studies at the University of Latvia” and 2014 Ludo Frevel Crystallography Scholarship Award (ICDD).

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FOR TABLE OF CONTENTS USE ONLY Why do chemically similar pharmaceutical molecules crystallize in different structures: a case of droperidol and benperidol Agris Bērziņš and Andris Actiņš

How different are structures?

Similar pharmaceuticals O NH N O N

F

? O NH N O N

F

In a detailed structural and computational study it was identified that the main reason for the formation of different crystal structures by two chemically very similar pharmaceuticals benperidol and droperidol was different weak intermolecular interactions formation possibility of the central ring. Theoretical calculations were used to rationalize why some mutually isostructural phases were obtained in the cross-seeding crystallization experiments.


Why Do Chemically Similar Pharmaceutical Molecules Crystallize in

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