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Role of functionalities in structural analogues, Urocanic acid and LHistidine, towards the formation of anhydrous and hydrated molecular salts Ramesh Ganduri, Diptikanta Swain, Suryanarayan Cherukuvada, and Tayur N. Guru Row Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.8b01822 • Publication Date (Web): 12 Feb 2019 Downloaded from http://pubs.acs.org on February 13, 2019
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Crystal Growth & Design
Role of functionalities in structural analogues,Urocanic acid and L-Histidine, towards the formation of anhydrous and hydrated molecular salts Ramesh Ganduri, Diptikanta Swain, Suryanarayan Cherukuvada and Tayur N. Guru Row* Solid State and Structural Chemistry Unit, Indian Institute of Science, Bengaluru 560012, India. *E-mail:
[email protected]; Fax: +91-080-23601310; Tel: +91-080-22932796
ABSTRACT Cocrystallization of structural analogues, Urocanic acid and L-Histidine with mono–, di–,tri– substituted hydroxy benzoic acids, have been carried out to gain insights into the formation of anhydrous and hydrated molecular salts. Urocanic acid generated anhydrous molecular salts with 2-hydroxy, 3,5-Dihydroxy and 2,4,6-Trihydroxybenzoic acids whereas 2,3-Dihydroxy, 3,4Dihydroxy and 3,4,5-Trihydroxybenzoic acids resulted in hydrated salts. Cocrystallization experiments of anhydrous L-histidine with 2,3-Dihydroxy, 3,4-Dihydroxy, 3,5-Dihydroxy, 3,4,5Trihydroxy and 2,4,6-Trihydroxybenzoic acids resulted in hydrated molecular salts. However, Lhistidine 2-hydroxybenzoic acid formed an anhydrous molecular salt. In this context, the hitherto elusive structure of native urocanic acid(anhydrous form) has been determined. The rationale for the formation of hydrated and anhydrous salts is evaluated in terms of the hydroxyl substituents on benzoic acids and the presence of additional amino group in L-histidine. Differential Scanning Calorimetry(DSC) and Thermal gravimetric analysis (TGA) proved the presence or absence of hydration, whereas Fourier-transform Infrared (FT-IR) experiments confirmed proton transfer suggesting the formation of molecular salts for those combinations which did not produce good quality single crystals for diffraction. INTRODUCTION Effective screening of a potential solid form is a crucial step in developing a drug and for tuning the properties to generate the desired solid form.1 Cocrystallization is a powerful technique practiced in pharmaceutical industry to produce a multi-component crystalline solids such as cocrystals, (molecular) salts, salt-cocrystals, solid solutions, (organic) eutectics, solvates, hydrates etc.,2,3 to establish a desired form with altered physicochemical properties.4−6 It has been estimated that over half of the drugs/APIs marketed are administered as molecular salts, as they are found to be most suited for drug therapy with altered solubility, dissolution rate,
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bioavailability and efficacy.7 Molecular salts exist in both hydrated and anhydrated forms, the presence of the water molecule basically dictates varied packing modes, improved stability, crystallinity, and hygroscopicity while influencing the solubility and bioavailability. Based on a systematic study of Cambridge Structural Database (CSD) analysis, it has been shown that among the NH+ containing salts only a few molecular salts with carboxylate anions are hydrated.8,9 There are reports stating that water plays a crucial role in structure-stability relationships of host-guest systems in multi-component adducts.10,11 The calculated enthalpy values, strengths of H-bonds in varied kinds of amines in different systems show that cyclic and primary amines have more propensity to form hydrates as compared to secondary and tertiary amines.12 Recently, Aitipamula et al. reported that a salt hydrate, a stable polymorph of neuroleptic drug haloperidol, with carboxylic acids and sweeteners show a higher solubility and intrinsic dissolution rate compared to haloperidol.13 In this study, two structural analogues, Urocanic acid (abbreviated as UA; Figure 1), and LHistidine (abbreviated as LH; Figure 1), are subjected to cocrystallization and the propensity of salt formation is explored in terms of hydration and hydrogen bonding features. UA was first isolated in 1874 and is an intermediate in the catabolism of L-Histidine.14 It is usually produced in upper layers of mammalian skin and acts as an absorber of ultraviolet radiation.15 Indeed, UA acts as a natural sunscreen and is a photoprotectant against UV induced DNA damage. It is also involved in photoisomerization, and photo-dimerization through radicaladdition/elimination.16 LH is an important amino acid which plays a significant role in protein synthesis, plant growth, and development. It is also a precursor for histamine, which regulates inflammation.17,18 Cocrystallization studies were conducted on UA and LH with mono–, di–, and tri–hydroxy substituted benzoic acids, which are categorized as GRAS/ EAFUS (Generally Recognized As Safe/ Everything Added to Food in the United States) molecules that contain carboxylic acid, and hydroxyl functionalities.19 Interestingly, based on an analysis of the CSD (Version 5.39, 2018) it was found that UA exists as hydrated zwitterion in the crystalline state with no other multi-component adducts,20,21 whereas LH exists in an anhydrous zwitter-ionic form with very few multi-crystalline solids.22 We report here the crystal structure of a guest free (anhydrous form) of native UA crystallized for the first time. Both UA and LH contain a common imidazole ring, however, the presence of amino group in LH makes it more basic. All combinations of UA, and LH with hydroxy benzoic acids resulted in the formation of molecular salts. Cocrystallization of anhydrous UA with 2hydroxy, 3,5-dihydroxy and 2,4,6-trihydroxybenzoic acids resulted in anhydrous molecular salts
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Crystal Growth & Design
whereas hydrated molecular salts are formed with 2,3-dihydroxy, 3,4-dihydroxy and 3,4,5trihydroxybenzoic acids.23 It is noteworthy that these salts are the first multi-component adducts of UA to be reported. Anhydrous L-Histidine with 3,4-dihydroxy, 3,5-dihydroxy, 2,3-dihydroxy, 3,4,5-trihydroxy and 2,4,6-trihydroxybenzoic acids resulted in hydrated molecular salts except for 2-hydroxybenzoic acid. Figure 1 lists the molecular components together with the abbreviations used in this cocrystallization study.
Figure 1. Molecular structureswith their corresponding acronyms of the componentsused in this study. A variety of methodologies are known in literature for the identification of coformers to obtain cocrystals and salts. The strategies hover around the possibility of predicting different hydrogen bonding propensity based on the approach developed at Cambridge Crystallographic Data Center (CCDC).24,25An equally successful approach uses the molecular shape and polarity descriptors.26 In a recent study of the drug triamterene,27 diversity created by variations in hydrogen bond donors and acceptors in two classes of coformers, mono and dicarboxylic acids have been analysed to arrive at several useful insights into the propensity of salt formation. In the present study, the role of additional amino group on LH unlike that of UA, the proximity and number of hydroxyl groups on the benzoic acid moiety organize the supramolecular assembly to accommodate hydration levels.28
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RESULTS AND DISCUSSIONS Single crystals of anhydrous UA were grown by slow evaporation from a solution of Acetonitrile kept in an oven at 50-60 °C. All cocrystallization products of UA and LH were obtained using the popular liquid-assisted grinding(LAG) technique,29,30 and preliminary characterization is carried out using powder X-ray diffraction (PXRD) (Supporting Information; Figures S1– S8).Thermal techniques and vibrational spectroscopy have been used to support the formation of molecular adducts. Single crystals of these adducts were grown using solvent evaporation technique and the structure determination confirmed the formation of molecular salts. Tables 1 and 2 list the X-ray crystallographic parameters of all the crystal structures of UA and LH have been analysed in this study. Crystal Structure Description Crystallization at 50-60 °C in an oven was carried out to prevent hydration of UA to produce single crystals of anhydrous form, (Supporting Information; Figure S9). The crystal structure of anhydrous UA, reported for the first time, depicts a +N–H∙∙∙O– heteromeric intermolecular hydrogen bond forming extended chains with the alternate chains being held by auxiliary +N– H∙∙∙O– hydrogen bonds (Figure 2). It is of interest to note that the reported structure of UA dihydrate also displays the same +N–H∙∙∙O– heteromeric intermolecular hydrogen bond forming extended chains,31 however, alternate chains are linked through two water bridges. In addition, except for UA–2,3-DHBA which is hydrated, the crystal structures of other combinations,UA– 2HBA, UA–3,5-DHBA, and UA–2,4,6-THBA are anhydrous salts. LH forms only hydrated salts as seen from the single crystal X-ray diffraction studies for the combinations, LH–3,4-DHBA, LH–3,5-DHBA, LH–3,4,5-THBA, and LH–2,4,6-THBA. Single crystals of diffraction quality could not be obtained for the combinationsUA–3,4-DHBA, UA–3,4,5-THBA,LH–2HBA and LH–2,3-DHBA. However, cognate techniques like DSC and TGA studies establish the presence or absence of hydration and FT-IR clearly shows the proton transfer suggesting the formation of molecular salts. Table 3 lists the type of molecular salts generated for each combination.
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Crystal Growth & Design
(a)
(b)
Figure 2.(a) Packing of anhydrous UA molecules in the unit cell; (b) Depiction of the hydrogen bonding with +N–H∙∙∙O– hydrogen bonds forming chains (shaded green) with alternate chains held via auxiliary +N–H∙∙∙O– hydrogen bonds (shaded blue). Table1.Crystallographic parameters of the UA adducts.
138.13
C6 H7N2O2– C7H5O3 276.25
1:1:1 UA– 2,3-DHBA– H2O C6H7N2O2– C7H5O4–H2O 310.26
Crystal system
orthorhombic
monoclinic
orthorhombic
orthorhombic
Monoclinic
Space group
Pna21
P21/n
Pbca
Pccn
P21/c
a (Å) b (Å) c (Å) α (°) β (°)
7.2445(2) 9.9086(3) 8.4781(3) 90 90
10.6003(6) 10.9341(4) 11.4815(6) 90 108.566(6)
16.3487(2) 8.18900(12) 19.8617(3) 90 90
8.3736(2) 21.2361(6) 14.5926(4) 90 90
11.8934(4) 7.5939(2) 15.4284(5) 90 109.279(3)
γ (°) Volume (Å3) Za Temperature (K)
90 608.58(3) 4 100.0(1) 1.508
90 1261.49(12) 8 100.0(1) 1.455
90 2659.08(7) 24 100.0(1) 1.550
90 2594.90(12) 16 100.0(1) 1.496
90 1315.32(7) 8 100.0(1) 1.557
μ (mm1) F (000)
0.116
0.114
0.128
0.121
0.129
288
576
1296
1216
640
hmin, max
-9, 9
-13, 13
-21, 21
-10, -10
-15, 15
kmin, max
-12, 12
-14, 14
-10, 10
-26, 27
-9, 9
lmin, max
-10, 11
-14, 14
-25, 25
-18, 18
-20, 19
No. of measuredreflections
7790
17018
34569
36150
18033
Molecular Salt
Anhydrous UA
Formula
C6H6N2O2
Formula weight
Density (g cm3)
1:1 UA–2HBA
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1:1 UA–3,5DHBA
1:1 UA– 2,4,6-THBA
C6H7N2O2– C7H5O4 292.25
C6H7N2O2– C7H5O5 308.25
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
aZ
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No. of unique reflections
1387
2888
3041
2278
3010
No. of reflections used
1353
2423
2715
1982
2688
R_all, R_obs
0.0294,0.0284
0.0505,0.0405
wR2_all, wR2_obs
0.0712,0.0705
0.0951,0.0898
min, max (eÅ3) GooF
-0.160, 0.126
-0.219, 0.271
0.0424, 0.0377 0.1001, 0.0959 -0.478, 0.441
0.0456, 0.0374 0.0863, 0.0817 -0.211, 0.195
0.0399, 0.0350 0.0888, 0.0858 -0.219, 0.294
1.084
1.059
1.026
1.089
1.051
CCDC No.
1821494
1821501
1821502
1821500
1821496
= Z″ (no. of crystallographically non-equivalent molecules of any type in the asymmetric unit)32 no. of independent general positions of the space group.
Table 2. Crystallographic parameters of the LH adducts. Molecular Salt
1:1:0.33 LH–3,4DHBA–H2O
1:1:1 LH–3,5DHBA–H2O
Formula
C6H10N3O2– C7H5O4–0.33(H2O)
C6H10N3O2– C7H5O4–H2O
Formula weight
315.25
327.30
C6H10N3O2– C7H5O5– 1.20(H2O) 346.82
Crystal system
orthorhombic
monoclinic
monoclinic
Monoclinic
Space group
P212121
P21
P21
P21
a (Å) b (Å) c (Å) α (°) β (°)
6.9614(2) 9.2870(2) 21.2145(5) 90 90
8.1947(3) 5.2121(2) 16.8396(5) 90 102.492(3)
10.2504(6) 6.9367(3) 11.4961(6) 90 103.054(6)
9.2125(3) 6.9354(2) 12.1510(3) 90 91.326(3)
γ (°) Volume (Å3) Za Temperature (K)
90 1371.53(6) 12 100.0(1) 1.5264
90 702.22(4) 6 100.0(1) 1.5478
90 796.29(7) 8 100.0(1) 1.446
90 776.15(4) 8 100.0(1) 1.5459
Density (g cm3)
1:1:1.20 LH– 2,4,6-THBA–H2O
1:1:2 LH–3,4,5THBA–H2O C6H10N3O2– C7H5O5–2H2O 361.31
μ (mm1) F (000)
0.124
0.127
0.122
0.132
661.6806
344.2283
364.1645
380.2720
hmin, max
-9, 9
-10, 10
-12, 13
-11, 11
kmin, max
-12, 12
-6, 6
-8, 8
-9, 8
lmin, max
-27, 27
-21, 21
-12, 14
-15, 15
No. of measuredreflections
19104
9833
5700
10795
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Crystal Growth & Design
No. of unique reflections No. of reflections used R_all, R_obs wR2_all, wR2_obs min, max (eÅ3) GooF CCDC No. aZ
3123
3218
3624
3474
3025
3034
3221
3334
0.0310, 0.0296 0.0766, 0.0759 -0.1774,0.2245
0.0372, 0.0342 0.0774, 0.0756 -0.1876,0.2616
0.0517, 0.0445 0.1045, 0.0991 -0.4021, 0.3686
0.0355,0.0334 0.0757,0.0744 -0.2358, 0.2398
1.0366
1.0744
1.0320
1.0617
1821497
1821495
1821499
1821498
= Z″ (no. of crystallographically non-equivalent molecules of any type in the asymmetric unit)32 no. of independent general positions of the space group.
Table 3. Cocrystallization experiments resulted in hydrated and anhydrous molecular salts as listed below. UA and LH Molecular salts
2-Hydroxy Benzoic acid (2HBA)
2,3-Dihydroxy Benzoic acid (2,3-DHBA)
3,5-Dihydroxy Benzoic acid (3,5-DHBA)
3,4-Dihydroxy Benzoic acid (3,4-DHBA)
2,4,6Trihydroxy Benzoic acid (2,4,6-THBA)
3,4,5Trihydroxy Benzoic acid (3,4,5-THBA)
Urocanic acid (UA)
Anhydrous Molecular salt
Hydrated Molecular salt
Anhydrous Molecular salt
Hydrated Molecular salt
Anhydrous Molecular salt
Hydrated Molecular salt
L-Histidine (LH)
Anhydrous Molecular salt
Hydrated Molecular salt
Hydrated Molecular salt
Hydrated Molecular salt
Hydrated Molecular salt
Dihydrated Molecular salt
UA–2HBA/3,5–DHBA/2,4,6–THBA (1:1) anhydrous molecular salts It is of interest to note that the hydrogen bonding pattern seen in UA is retained except that the interaction motif is generated by heteromeric +N–H∙∙∙O– contacts in all three cases (Figure 3). Further stability in UA–2HBA packing is brought with strong dimeric O–H∙∙∙O hydrogen bonds along with a heteromeric +N–H∙∙∙O– interactions extending the chains and supported by an intramolecular O–H∙∙∙O– contact (Figure 3a). The nature of the heteromeric interactions in UA– 3,5-DHBA is different and the presence of two hydroxyl groups offers additional hydrogen bonding motifs in the lattice. Two N–H∙∙∙O heteromeric interactions, one with the hydroxyl group of 3,5-DHBA (+N–H∙∙∙O) and the other with the COO– group of UA (+N–H∙∙∙O–) form an infinite chain (Figure 3b). Further, a heteromeric O–H∙∙∙O– and a weak C–H∙∙∙O auxiliary interaction link the chains alternately to form a stable 2D network in the crystal structure of UA–3,5-DHBA (Figure 3b). The presence of three hydroxyl groups on alternate carbon atoms in UA–2,4,6THBA generates a robust tetrameric packing moiety (Figure 3c), involving a pair of N–H∙∙∙O
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heteromeric interactions, one with the hydroxyl group of 2,4,6-THBA (+N–H∙∙∙O) and the other with the COO– group of 2,4,6-THBA (+N–H∙∙∙O–) interlinked by another pair of intramolecular O–H∙∙∙O– interactions. The cyclic tetramer propagates through an additional O–H∙∙∙O heteromeric interaction (Figure 3c). The requirement in all these packing motifs is to connect alternate layers of the chains generated by +N–H∙∙∙O– charge assisted bonds via suitable hydrogen bonds. These hydrogen bonds are provided by the –OH groups on the periphery of differently substituted benzoic acids. It is of importance to note that since the hydroxyl groups provide all the required stability negating the requirement of hydration the resulting products are anhydrous in nature.
(a)
(b)
(c) Figure 3.Packing diagrams (with hydrogen bonded regions highlighted) of (a) UA–2HBA; (b) 3,5–DHBA; (c) 2,4,6–THBA molecular salts.
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Crystal Growth & Design
UA–2,3-DHBA–H2O hydrated molecular salt Unlike the above examples, the crystal structure of UA–2,3-DHBA forms a hydrated molecular salt with a 1:1:1 stoichiometry. It is to be noted that the vicinity of the hydroxyl substituents on the benzoic acid moiety forces a charge assisted bifurcated hydrogen bonding involving the – NH group of UA due to the occurrence of adjacent –OH groups in 2,3-DHBA. Even though this results in an extended bifurcated hydrogen bonded network propagating along the a-axis, there is no available packing force in the perpendicular direction (c-direction). The presence of a water molecule is thus necessitated to bridge alternate networks and hence this particular molecular salt combination is hydrated (Figure 4).
Figure4.Depiction of hydrogen bonded network columns in UA–2,3-DHBAwith one of them held by water bridges. LH–3,4-DHBA/3,5-DHBA/3,4,5-THBA/2,4,6-THBA hydrated molecular salts All combinations with LH are hydrated (except LH–2HBA) and the packing is through water bridges connecting hydrogen bonded chains. The additional –NH2 group provides the required directional preferences for hydrogen bonds such that the presence of water molecule(s) becomes a requisite for holding the chains together. Indeed, LH–3,4-DHBA-H2O combination crystallizes in a1:1:0.33 non-stoichiometry as a hydrated molecular salt with heteromeric
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–O∙∙∙H–O
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interactions on either side of the carboxylate ion generating a chain, and a bifurcated +N–H∙∙∙O heteromeric interaction linking the chain across to result in a 2D network. The water bridge extends the packing via hydrogen bonding through homomeric interactions involving the carboxylate ion generating a chain which in turn accepts the hydrogen bonding with the protonated amino group as shown in Figure 5a. The LH–3,5-DHBA-H2O hydrated molecular salt (1:1:1) packs with similar hydrogen bonded network, however the placing of the –OH moiety at the 3rd and 5th positions reorganize the packing features as shown in Figure 5b. It is to be noted that the closure of the network is now through hydrogen bonding introduced by NH3+ moiety and in order to stabilize the supramolecular framework bridging water molecule becomes a necessity. The LH–3,4,5-THBA-H2O combination is crystallized as a dihydrated molecular salt in a 1:1:2 stoichiometry. A similar set of hydrogen bonds as before form the packing with the two water molecules bridging the alternate layers. Interestingly the two water molecules act differently, one connecting alternating chains through THBA molecules and the other connecting alternating LH and THBA molecules as shown in Figure 5c. Additionally, the alternate heteromeric interactions connecting LH and THBA molecules are further stabilized via O–H∙∙∙O– , +N–H∙∙∙O interactions. On the other hand, LH–2,4,6-THBA crystallizes as a fractional hydrate, with hydrogen bonded contacts (Figure 5d) bridging alternate layers of LH and THBA via charge assisted hydrogen bonds.
(a)
(b)
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Crystal Growth & Design
(b)
(d)
Figure 5.Crystal structure of (a) LH–3,4-DHBA; (b) LH–3,5-DHBA; (c)LH–3,4,5-THBA; (d) LH–2,4,6-THBA depicting hydrogen bonding linking alternate layers of LH and THBA via charge assisted hydrogen bonds involving water. Validation of salt formation using the ΔpKarule Table 4 lists the ΔpKa values for all the combinations showing a wide range of values, however the crystallographic and spectral studies indicate all combinations form molecular salts. All ΔpKa values are greater than 1, with a majority being closer or greater than 3 supporting the formation of molecular salts.33−36 It is indicative that the ΔpKa values are provide pointers to the nature of formation of cocrystals and salts and certainly are not absolute indicators, a feature of relevance to be noted by the pharmaceutical industry. Table4. pKa values of compounds and nature of adducts formed. pKa of Coformer 1 2HBA 2.98 2 2,3-DHBA 2.91 3 3,5-DHBA 4.04 4 3,4-DHBA 4.48 5 2,4,6-THBA 1.68 6 3,4,5-THBA 4.41 7 2HBA 2.98 8 2,3-DHBA 2.91 9 3,5-DHBA 4.04 10 3,4-DHBA 4.48 11 2,4,6-THBA 1.68 12 3,4,5-THBA 4.41 a= pK value of UA;b = pK value of LH a a S. No.
Coformer
pKaof UA/LH 6.13a -do-do-do-do-do6.50b -do-do-do-do-do-
ΔpKa pKa(base)– pKa (acid) 3.15 3.22 2.09 1.65 4.45 1.72 3.52 3.59 2.46 2.02 4.82 2.09
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Adduct Molecular Salt Molecular Salt Molecular Salt Molecular Salt Molecular Salt Molecular Salt Molecular Salt Molecular Salt Molecular Salt Molecular Salt Molecular Salt Molecular Salt
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The other polycrystalline products Cocrystallization of UA–3,4-DHBA/3,4,5-THBA and LH–2HBA/2,3-DHBA did not yield good quality crystals and hence other cognate techniques like PXRD, FT-IR, DSC and TGA were employed for the characterization. It must be emphasized that no in depth analysis of the results from PXRD, IR and DSC/TGA have been attempted and the conclusions are hence purely qualitative in nature. A crude examination of PXRD patterns confirm the formation of new adducts (Supporting Information; Figures S10–S13), however the formation of a molecular salt can be ascertained only by IR spectroscopy.37 IR spectra of both 1:1 UA–3,4-DHBA and 1:1 UA–3,4,5-THBA exhibit the aromatic 2°-amine +N–H(stretching), C–N(stretching), carboxylic acid(UA) and 2°-amine(bending) frequencies 3500, 1342, 1670 and 1586 cm–1respectively and two peaks in the range 1525-1580 and 1400-1440cm-1, characteristic feature of asymmetric and symmetric stretching frequencies of the COO– group respectively (Supporting Information; Figures S14a– b). The hydrate formation is confirmed by DSC/TGA analysis (Supporting Information; Figures S15–S16) with the appearance of an endo peak in DSC before melting and a corresponding weight loss for dehydration before decomposition in TGA. The analysis of the LH combinations reveal that 1:1 LH–2HBA, LH–2,3-DHBA show the presence of primary +NH3(stretching), aromatic 2°-amine +N–H(stretching), C–N(stretching) frequencies at 3090, 3445, 1270 cm–1 respectively and asymmetric and symmetric stretching frequencies of the carboxylate moiety in the range 15401590 and 1385-1440 cm–1 (Supporting Information; Figures S17a–b) suggesting molecular salt formation. In case of LH–2HBA, DSC and TGA do not indicate any endo peak before melting and also no weight loss before decomposition suggesting that the molecular salt is anhydrous (Supporting Information; Figure S18). The hydrate formation is confirmed for LH–2,3-DHBA combination by DSC/TGA as evidenced by the presence of an endo peak in DSC and a corresponding weight loss for dehydration in TGA (Supporting Information; Figure S19). CONCLUSIONS Cocrystallization experiments involving UA and LH with hydroxy substituted benzoic acid have brought the importance of intermolecular interactions, in particular charge assisted hydrogen bonds in dictating packing characteristics in molecular crystals. A common template (synthon) is the formation of extended chains generated through well-defined +N–H∙∙∙O– hydrogen bonds in all structures including native UA and LH. The differences in the nature of packing induced by the presence of –OH groups at different positions in UA containing salts generates stable supramolecular assemblies without hydration except in one case whereas the presence of the NH2 group (as NH3+) dictates the packing characteristics demanding the presence of hydration.
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The ability to control hydration or otherwise in terms of analyzing the hydrogen bond propensities, particularly with charge assisted hydrogen bond as found in the current study, would help in the design of hydrated pharmaceutical salts. EXPERIMENTAL SECTION Materials All starting materials were purchased from well-known chemical suppliers (Sigma-Aldrich and Alfa Aesar, Bengaluru, India) and were used without further purification. Solvents used were of analytical or chromatographic grade from local suppliers, and distilled water was used for experiments from a Siemens Ultra Clear water purification system. Methods Liquid-Assisted grinding (LAG) All the combinations in a molar ratios combined on the mg scale were physically ground using a mortar-pestle for 15-20 min by adding 1-2 mL methanol. The ground adducts were analyzed by PXRD, thermal, and IR spectroscopy techniques to ascertain the formation of adduct. The molecular salts were exhibited distinct PXRD pattern, melting behavior, and vibrational frequencies. Evaporation crystallization Anhydrous UA: The molecule was dissolved in 5mL of Acetonitrile and left for slow evaporation at 50-60°C temperature. The colorless plate shaped crystals were obtained after a few days upon solvent evaporation. m.p. 228-230 °C. 1:1 UA–2HBA salt: A ground mixture of UA (14mg, 0.1 mmol) and 2HBA (14mg, 0.1 mmol) was dissolved in 5mL of methanol and left for slow evaporation at room temperature. The colorless needle type of crystals obtained after a few days upon solvent evaporation. m.p. 167170 °C. 1:1:1 UA–2,3-DHBA–H2O salt: A ground mixture of UA (14mg, 0.1 mmol) and 2,3-DHBA (15mg, 0.1 mmol) was dissolved in 5mL of Acetonitrile and left for slow evaporation at room temperature. The colorless plate shaped crystals obtained after a few days upon solvent evaporation. m.p. 135-138 °C.
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1:1 UA–3,5-DHBA salt: A ground mixture of UA (14mg, 0.1 mmol) and 3,5-DHBA (15mg, 0.1 mmol) was dissolved in 5mL of Methanol and left for slow evaporation at room temperature. The colorless needle shaped crystals obtained after a few days upon solvent evaporation. m.p. 228-230 °C. 1:1 UA–2,4,6-THBA salt: A ground mixture of UA (14mg, 0.1 mmol) and 2,4,6-THBA (18mg, 0.1 mmol) was dissolved in 5mL of Ethanol and left for slow evaporation at room temperature. The colorless needle shaped crystals obtained after a few days upon solvent evaporation. m.p. 165-168 °C. 1:1:0.33 LH–3,4-DHBA–H2O salt: A ground mixture of LH (15mg, 0.1 mmol) and 3,4-DHBA (15mg, 0.1 mmol) was dissolved in 5mL of Water and left for slow evaporation at room temperature. The colorless plate shaped crystals obtained after a few days upon solvent evaporation. m.p. 218-220 °C. 1:1:1 LH–3,5-DHBA–H2O salt: A ground mixture of LH (15mg, 0.1 mmol) and 3,5-DHBA (15mg, 0.1 mmol) was dissolved in 5mL of 1,4-Dioxane and left for slow evaporation at room temperature. The colorless plate shaped crystals obtained after a few days upon solvent evaporation. m.p. 157-159 °C. 1:1:2 LH–3,4,5-THBA–H2O salt: A ground mixture of LH (15mg, 0.1 mmol) and 3,4,5-THBA (18mg, 0.1 mmol) was dissolved in 5mL of water and left for slow evaporation at room temperature. The colorless needle shaped crystals obtained after a few days upon solvent evaporation. m.p. 240-242 °C. 1:1:1.20 LH–2,4,6-THBA–H2O salt: A ground mixture of LH (15mg, 0.1 mmol) and 2,4,6THBA (18mg, 0.1 mmol) was dissolved in 5mL of Ethanol and left for slow evaporation at room temperature. The colorless needle shaped crystals obtained after a few days upon solvent evaporation. m.p. 146-150 °C. Single crystal X-ray diffraction X-ray reflections on diffracted quality single crystals were collected on an Oxford Xcalibur (Mova) diffractometer equipped with an EOS CCD detector and a microfocus sealed tube using Mo Kα radiation (λ = 0.71073 Å) at 100K using an Oxford Cobra open stream non-liquid nitrogen cooling device. Data collection and reduction were performed using CrysAlisPro (version 1.171.36.32)38and OLEX2 (version 1.2)39 was used to solve and refine the crystal
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structures. All non-hydrogen atoms were refined anisotropically. Hydrogen atoms on heteroatoms were located from difference electron density maps and all C–H atoms were fixed geometrically using HFIX command. The WinGX package40 was used for final refinement and production of CIFs and crystallographic table. Packing diagrams were generated by using MERCURY.41 Powder X-ray diffraction PXRD were recorded on PANalytical diffractometer using Cu-Kα X-radiation ( = 1.5406 Å) at 45 kV and 30 mA. Diffraction patterns were collected over 2θ range of 5-40° using a step size of 0.06° 2θ and time per step of 1 sec. X'Pert High Score Plus (version 1.0d)42 was used to collect and plot the diffraction patterns. IR spectroscopy IR spectra were recorded using PerkinElmer Frontier FT-IR spectrometer on samples dispersed in potassium bromide pellets.
Thermal analysis Melting behavior of all the combinations was analyzed on a Labindia visual melting range apparatus (MR 13300710) equipped with a camera and a LCD monitor. Differential scanning calorimetry (DSC) DSC was performed by placing a sample size of 2-5 mg using a Mettler Toledo DSC 822e module. A standard 40 µL aluminum pan was used for keeping the sample such that the bottom of the pan was uniformly covered with sample. Samples were heated with a scan rate of 10 °C /min in the temperature range 30–400 °C under ultra high pure nitrogen environment purged at 50 mL/min was used for the analysis. Mettler Toledo STARe software (Version 8) was used for the data analysis of thermograms obtained. Thermogravimetric analysis (TGA) TGA was performed by placing a sample size of 3-6 mg using a Mettler Toledo TGA/SDTA851e/SF/1100 in a standard 80 µL aluminium pan was used for keeping the sample. Samples were heated with a scan rate of 10 °C /min in the temperature range 30–600 °C with an air purged at 50 mL/min was used for the analysis. Mettler Toledo STARe software (Version 8) was used for data analysis of thermograms.
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ASSOCIATED CONTENT Supporting Information PXRD patterns, IR spectra, DSC, TGA thermograms of UA and LH combinations and CIFs.This material is available free of charge via the Internet athttp://pubs.acs.org. AUTHOR INFORMATION Corresponding Author E-mail:
[email protected] Notes The authors declare no competing financial interest. ACKNOWLEDGEMENTS R.G. thanks the CSIR for Senior Research Fellowship, D.S. thanks the DST for Fellowship and S.C. thanks the SERB for Start-Up Research Grant. T.N.G.R. thanks the DST for J. C. Bose Fellowship. We thank the Institute for providing infrastructural facilities. REFERENCES (1) Davies, G. Changing the salt, changing the drug. Pharm. J. 2001, 266, 322−323. (2) Ganduri, R.; Cherukuvada, S.; Row, T. N. G. multicomponent adducts of Pyridoxine: An evaluation of the formation of eutectics and molecular salts. Cryst. Growth Des. 2015, 15, 3474−3480. (3) Ganduri, R.; Cherukuvada, S.; Sarkar, S.; Row, T. N. G. Manifestation of cocrystals and eutectics among structurally related molecules: towards understanding the factors that control their formation. CrysEngComm2017, 19, 1123−1132and references therein. (4) Schultheiss, N.; Newman, A. Pharmaceutical Cocrystals and Their Physicochemical Properties. Cryst. Growth Des. 2009, 9, 2950−2967. (5) Cherukuvada, S.; Kaur, R.; Row, T. N. G. Co-crystallization and small molecule crystal form diversity: from pharmaceutical to materials applications. CrystEngComm2016, 18, 8528−8555. (6) Thipparaboina, R.; Thumuri, D.; Chavan, R.; Naidu, V. G. M.; Shastri, N. R. Fast dissolving drug-drug eutectics with improved compressibility and synergistic effects. Eur. J. Pharm. Sci.2017, 104, 82−89. (7) Gupta, D.; Bhatia, D.; Dave, V.; Sutariya, V.; Gupta, S. V. Salts of Therapeutic Agents: Chemical, Physicochemical, and Biological Considerations. Molecules2018, 23, 1719. (8) Haynes, D. A.; Jones, W.; Motherwell, W. D. S. Occurrence of pharmaceutically acceptable anions and cations in the Cambridge Structural Database. CrystEngComm2005, 7, 342−345. (9) Allen, F. The Cambridge Structural Database: a quarter of a million crystal structures and rising. Acta Crystallogr. B2002, 58, 380−388.
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(10) Clarke, H. D.; Arora, K. K.; Bass H.; Kavuru, P.; Ong, T. T.; Pujari, T.; Wojtas, L.; Zaworotko, M. J.Structure-Stability Relationships in Cocrystal Hydrates: Does the Promiscuity of Water Make Crystalline Hydrates the Nemesis of Crystal Engineering?. Cryst. Growth Des. 2010, 10, 2152−2167. (11) Varughese, S.; Desiraju, G. R.Using Water as a Design Element in Crystal Engineering.Host-Guest Compounds of Hydrated 3,5-Dihydroxybenzoic Acid. Cryst. Growth Des.2010, 10, 4184−4196. (12) Graton, J.; Berthelot, M.; Besseau, F.; Laurence, C. An Enthalpic Scale of HydrogenBond Basicity. 3. Ammonia, Primary, Secondary, and Tertiary Amines. J. Org. Chem. 2005, 70, 7892−7901. (13) Aitipamula, S.; Wong, A. B. H.; Chow, P. S.; Tan, R. B. H. Pharmaceutical Salts of Haloperidol with Some Carboxylic Acids and Artificial Sweeteners: Hydrate Formation, Polymorphism, and Physicochemical Properties. Cryst. Growth Des. 2014, 14, 2542−2556. (14) Jaffe. M.;Concerning a new constituent in the urine ofdogs.Brr. Deiir. Clirni. Ges.1874,7, 1669−1673. (15) Gibbs, N. K.; Tye, J.; Norval, M.Recent advances in urocanic acid photochemistry, photobiology and photoimmunology. Photochem. Photobiol. Sci.2008, 7, 655−667. (16) Anglin. Jr., J. H.; Batten, W. H. Structure of Urocanic acid Photodimers.Photochem. Photobiol.1970, 11, 271−277. (17) Ingle, R. A. Histidine Biosynthesis.The Arabidopsis Book. 9: e0141. 2011. (18) Stepansky, A.; Leustek, T.Amino Acids2006, 30, 127−142. (19) Safe chemicals that can be used in drugs and food can be selected from GRAS and EAFUSsubstances list available at http://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/andhttp://www.fda.gov /food/ingredientspackaginglabeling/foodadditivesingredients/ucm115326.hmt. (20) The Cambridge Structural Database (CSD) Version 5.39; May 2018, https://www.ccdc.cam.ac.uk/support-and-resources/ccdcresources/csd-2018-updates/. (21) Groom, C. R.; Bruno, I. T.; Lightfoot, M. P.; Ward, S. C. The Cambridge Structural Database. Acta Crystallogr. B2016, 72, 171−179. (22) Gorbitz, C. H.; Husdal, J.Cocrystallizing Agents for Amino Acids. II. The Crystal Structures of L-Histidine.4,5-Imidazoledicarboxylic Acid (1:1) and L-Lysine.4,5Imidazoledicarboxylic Acid (1:1).Acta Chem. Scand.1998, 52, 218−226. (23) Ganduri, R.; Cherukuvada, S.; Row, T. N. G. Molecular salts of urocanic acid and L– histidine. Acta Crystallogr. A2017, 73, C417. (24) Galek, P. T. A.; Fábián, L.; Motherwell, W. D. S.; Allen, F. H.; Feeder, N.Knowledgebased model of hydrogen-bonding propensity in organic crystals. Acta Crystallogr. B2007, 63, 768−782. (25) Galek, P. T. A.; Fábián, L.; Allen, F. H. Universal prediction of intramolecular hydrogen bonds in organic crystals. Acta Crystallogr. B2010, 66, 237−252. (26) Fábián, L.Cambridge Structural Database Analysis of Molecular Complementarity in Cocrystals. Cryst. Growth Des. 2009, 9, 1436−1443. (27) Rehman, A.; Delori, A.; Hughes, D. S.; Jones, W.Structural studies of crystalline forms of triamterene with carboxylic acid, GRAS and API molecules. IUCrJ2018, 5, 309−324.
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(28) Sharma, B.; Nath, N. K.; Bhogala, B. R.; Nangia, A. Synthon Competition and Cooperation in Molecular Salts of Hydroxybenzoic Acids and Aminopyridines. Cryst. Growth Des. 2009, 9, 1546−1557. (29) Friščić, T.; Trask, A. V.; Jones, W.; Motherwell, W. D. S. Screening of Inclusion compounds and systematic construction of three-component solids by Liquid-Assisted Grinding. Angew. Chem. Int. Ed. 2006, 45, 7546−7550. (30) Shan, N.; Toda, F.; Jones, W. Mechanochemistry and co-crystal formation: effect of solvent on reaction kinetics. Chem. Commun. 2002, 2372−2373. (31) Svinning, T.; Sørum, H.Structure of urocanic acid dihydrate. Acta Crystallogr. B1979, 35, 2813−2815. (32) van Eijck, B. P.; Kroon, J.Structure predictions allowing more than one molecule in the asymmetric unit. Acta Crystallogr. B2000, 56, 535−542. (33) Johnson, S. L.; Rumon, K. A. Infrared Spectra of Solid 1:1 Pyridine-Benzoic Acid Complexes; the Nature of the Hydrogen Bond as a Function of the Acid-Base Levels in the Complex. J. Phys. Chem. 1965, 69, 74−86. (34) Bhogala, B. R.; Basavoju, S.; Nangia, A.Tape and layer structures in cocrystals of some di- and tricarboxylic acids with 4,4′-bipyridines and isonicotinamide. From binary to ternary cocrystals. CrystEngComm2005, 7, 551−562. (35) Childs, S. L.; Stahly, G. P.; Park, A. The Salt-Cocrystal Continuum: The Influence of Crystal Structure on Ionization State. Mol. Pharm.2007, 4, 323−338. (36) Cruz-Cabeza, A. J.Acid–base crystalline complexes and the pKa rule. CrystEngComm2012, 14, 6362−6365. (37) Silverstein, R. M.; Webster, F. X.; Kiemle, D. J. Spectrometric Identification of Organic Compounds, John Wiley & Sons: NJ, 2005. (38) CrysAlisPro, ver. 1.171.36.32, Agilent Technologies UK Ltd: Yarnton, England, 2011. (39) Dolomanov, O. V.; Blake, A. J.; Champness, N. R.; Schröder, M. OLEX: new software for visualization and analysis of extended crystal structures. J. Appl. Crystallogr.2003, 36, 1283−1284. (40) Farrugia, L. J. WinGX suite for small-molecule single-crystal crystallography. J. Appl. Crystallogr.1999, 32, 837−838. (41) Macrae, C. F.; Edgington, P. R.; McCabe, P.; Pidcock, E.; Shields, G. P.; Taylor, R.; Towler, M.; Van de Streek, J.Mercury: visualization and analysis of crystal structures. J. Appl. Crystallogr. 2006, 39, 453–457. (42) X'Pert HighScore Plus, The complete powder analysis tool, PANalytical B. V., 2003.
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Role of functionalities in structural analogues, Urocanic acid and L-Histidine, towards the formation of anhydrous and hydrated molecular salts Ramesh Ganduri, Diptikanta Swain, Suryanarayan Cherukuvada and Tayur N. Guru Row*
Synopsis: The rationale for the formation of hydrated and anhydrous molecular salts in Urocanic acid and L-Histidine is evaluated in terms of the hydroxyl substituents on benzoic acids, the amino group in L-histidine and the requirement of extended hydrogen bonding in the lattice with and without water.
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