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Research ArticleVibrational Spectroscopic Study of the Cocrystal ProductsFormed by Cinchona Alkaloids with 5-Nitrobarbituric Acid

Harry G Brittain

Center for Pharmaceutical Physics 10 Charles Road Milford NJ 08848 USA

Correspondence should be addressed to Harry G Brittain hbrittaincenterpharmphysicscom

Received 15 October 2014 Accepted 26 December 2014

Academic Editor Renata Diniz

Copyright copy 2015 Harry G Brittain This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

X-ray powder diffraction differential scanning calorimetry infrared absorption spectroscopy and Raman spectroscopy havebeen used to study the phenomenon of cocrystal formation in the molecular complexes formed by 5-nitrobarbituric acid withfour cinchona alkaloids The cocrystal products were found to contain varying degrees of hydration ranging from no hydrationin the nitrobarbiturate-quinidine cocrystal up to a 45-hydrate species in the nitrobarbiturate-cinchonine cocrystal For thenitrobarbiturate cocrystals with cinchonine cinchonidine and quinidine the predominant interaction was with the quinolinering system of the alkaloid However for quinine the predominant interaction was with the quinuclidine group of the alkaloidThese properties serve to demonstrate the utility of 5-nitrobarbituric acid as a preferred reagent for chemical microscopy since thediffering range of hydrate and structural types would serve to easily differentiate the cinchona alkaloids from each other even whendifferent compounds contained the same absolute configurations at their dissymmetric centers

1 Introduction

The realization that cocrystallization of drug substances withother compounds could lead to modification of physicalproperties has led to a vitalization of the crystal engineeringcommunity and to substantial interest in the part of thepharmaceutical industry [1ndash5] Aakeroy and Salmon havesummarized a useful framework to describe cocrystal forma-tion where such crystalline solids result from the assembly ofsupramolecular synthons constructed from discrete neutralcompounds (that are solids at ambient temperatures) andwhere the cocrystal is a structurally homogeneous crystallinematerial that contains these synthons in definite stoichiomet-ric amounts [6]

However the subject area of cocrystals extends muchfurther back in time than the recent activity [7] withthe properties of mixed systems being reported under thescope of a variety of definitions Herbstein has categorizedthese as molecular compounds with localized or delocalizedinteractions and has provided an extensive review of donor-acceptor complexes hydrogen-bondedmolecular complexesand 120587-molecular complexes [8] Annual reviews summariz-ing advances in crystal engineering are available [9ndash11]

Another source of unrecognized cocrystals is containedwithin the extensive scope of analytical chemistry conductedunder the general category of chemical microscopy whereanalysts would prepare derivatives or adducts of an ana-lyte species and then identify the analyte on the basis ofthe morphology of the crystalline products [12 13] Forexample Clarke developed sensitive microchemical tests forthe determination of anesthetics [14] antihistamines [15]antimalarials [16] and analgesics [17] while Chatten andcoworkers developed chemical microscopic methods for theidentification and differentiation of local anesthetics [18]muscle relaxants [19] and amine-containing compounds[20]

One of the premier chemical microscopic reagents was5-nitrobarbituric acid (also known as dilituric acid) whoseadduct complexes with basic compounds were superiorto surpass other nitroenolic reagents owing to the highdegree of crystallinity and ease of recrystallization of theproducts of [21] Plein and Dewy developed the use of thiscompound as a reagent for the identification of aliphaticamines [22] primary aromatic amines [23] autonomic drugs[24] and secondary aromatic amines [25] More recentlythe underlying crystallographic properties associated with

Hindawi Publishing CorporationJournal of SpectroscopyVolume 2015 Article ID 340460 13 pageshttpdxdoiorg1011552015340460

2 Journal of Spectroscopy

adducts of 5-nitrobarbituric acid and basic compounds thatfacilitated their utility in chemical microscopy have beenevaluated through the study of the cocrystals formed by thediliturate reagent with primary achiral phenylalkylamines[26] and resolved and racemic phenylalkylamines and pheny-lalkylamino acids [27] In these works it was establishedthat the different crystal morphologies associated with thevarious reaction products were derived from the ability of thesystems to form a variety of polymorphic and solvatomorphiccocrystal structures

In the present work the phenomenon of cocrystal for-mation in the molecular complexes of 5-nitrobarbituric acidhas been further investigated through studies of adductsformed by this reagent with four cinchona alkaloids (quininequinidine cinchonine and cinchonidine) Structures of the5-nitrobarbituric acid reagent and the alkaloids studies in thiswork are found in Figure 1 Although chemical microscopicidentification methods have been published for cinchonaalkaloids [28ndash30] the only report on the 5-nitrobarbiturateadducts simply mentioned the crystal morphologies of thequinine and cinchonine adducts [21] Since no detailed stud-ies of the cinchona alkaloid cocrystals with 5-nitrobarbituricacid have been reported the products were characterized bythe standard thermoanalytical and powder diffraction meth-ods In addition detailed vibrational spectroscopic studieswere performed in order to determine which vibrationalmodes were most affected by the cocrystal formation andto determine the magnitudes of perturbation within theinvolved vibrational modes

2 Materials and Methods

21 Reagents and Method of Cocrystal Preparation 5-Nitro-barbituric acid trihydrate quinine dihydrate quinidine cin-chonine and cinchonidine were purchased from Sigma-Aldrich and were recrystallized from 70 aqueous iso-propanol before use The products studied in this work wereprepared using solvent-drop-mediated solid-state grinding[31ndash33] where the stoichiometry of the product was deter-mined by the amounts of reactants initially taken Exactlyweighed amounts of 5-nitrobarbituric acid and alkaloidacid were weighed directly in an agate mortar (preparingapproximately 500mgof total product) andwettedwith 50120583Lof 70 aqueous isopropanol After slurry was prepared bymixing the composition was hand-ground with an agatepestle until the product was completely dry

22 X-Ray Powder Diffraction X-ray powder diffraction(XRPD) patterns were obtained using a Rigaku MiniFlexpowder diffraction system equippedwith a horizontal gonio-meter operating in the 1205792120579modeThe X-ray source was nic-kel-filtered K120572 emission of copper (154184 A) Samples werepacked into the sample holder using a back-fill procedure andwere scanned over the range of 35 to 40 degrees 2120579 at a scanrate of 05 degrees 2120579min Using a data acquisition rate of 1point per second the scanning parameters equate to a stepsize of 00084 degrees 2120579 Calibration of the diffractometersystemwas effected using purified talc as a referencematerial

23Thermal Analysis Measurements of differential scanningcalorimetry (DSC) were obtained on a TA Instruments 2910thermal analysis system Samples of approximately 1-2mgwere accuratelyweighed into an aluminumDSCpan and thencovered with an aluminum lid that was crimped in placeThesamples were then heated over the range of 20ndash175∘C at aheating rate of 10∘Cmin

Measurements of total volatile content were made usingan Ohaus model MB45 system The samples were heatedisothermally at a temperature of 125∘C for a period of15 minutes Invariably samples had desolvated to constantweight after approximately 10 minutes of heating time

24 Infrared Absorption Spectroscopy Infrared absorptionspectrawere obtained at a resolution of 4 cmminus1 using a Shima-dzu model 8400S Fourier-transform infrared spectrometerwith each spectrum being obtained as the average of 25 indi-vidual spectra The data were acquired using the attenuatedtotal reflectance sampling mode where the samples wereclamped against the ZnSe crystal of a Pike MIRacle singlereflection horizontal ATR sampling accessory

25 Raman Spectroscopy Raman spectra were obtained inthe fingerprint region using a Raman Systems model R-3000HR spectrometer operated at a resolution of 5 cmminus1 andusing a laser wavelength of 785 nm The data were acquiredusing front-face scattering from a thick powder bed kept inan aluminum sample holder

3 Results and Discussion

31 Stereochemistry of the Cinchona Alkaloids Examinationof Figure 1 reveals the structural similarity of the cinchonaalkaloids studied in the present work The configurationsof the compounds were once a matter of dispute but adetailed study of the oxirane derivatives served to establishthat all of the naturally occurring cinchona alkaloids are of theerythroconfiguration [34] The members of this series eachcontain a quinoline ring attached through a hydroxymethy-lene group to a quinuclidine ring As illustrated in the figurecinchonine and cinchonidine represent a diastereomeric pairbut the important diastereomeric phenomena related tothese compounds have been correlated with the absoluteconfiguration at carbon-9 [35] A more systematic name forcinchonine is (9S)-cinchonan-9-ol and the more systematicname for cinchonidine is (9R)-cinchonan-9-ol The absoluteconfigurations of all centers of dissymmetry are known [36]

Quinine and quinidine are also a diastereomeric pair anddiffer from cinchonine and cinchonidine by the presence of amethoxy group attached to the quinoline ringThe more sys-tematic name for quinidine is (9S)-61015840-methyoxycinchonan-9-ol while the more systematic name for quinine is (9R)-61015840-methyoxycinchonan-9-ol The absolute configuration ofquinidine has been confirmed from a single-crystal study ofone of its salts with the absolute stereochemistry being deter-mined by the Bijvoet anomalous-dispersion method [37] Asindicated in Figure 1 the dissymmetric centers of cinchonine

Journal of Spectroscopy 3

5-Nitrobarbituric acid

Cinchonine Cinchonidine

Quinidine Quinine

NH OO

O

NHO2N

N

N

H

H

HO

H2C

H3CO

N

N

H

H

HO

H2C

N

N

H

H

HO

H2C

H3CO

N

N

H

H

HO

H2C

Figure 1 Structures of 5-nitrobarbituric acid and the four cinchona alkaloids used in this study

and quinidine are the same while the dissymmetric centersof cinchonidine and quinine are the same

32 Vibrational Spectroscopy of 5-Nitrobarbituric Acid Al-though the vibrational spectra of a large number of sub-stituted barbituric acids have been reported and analyzed[38] the infrared absorption and Raman spectra of the 5-nitro derivative seem to have escaped attention Fortunatelywhen one takes into account the inductive effect of the 5-nitro group on the assignments previously published forthe energies of the vibrational modes of other barbituratederivatives [39ndash42] and with the body of group frequencyknowledge [43ndash50] one may deduce assignments for theabsorption bands that will be important in the discussionsIt may be noted that the broad but intense character ofassociated with the high-frequency vibrational modes (ie2500ndash3800 cmminus1) greatly weakened the utility of this spectralregion for evaluation of intermolecular interactions

It is known that the vibrational motions of the threecarbonyl groups on the barbituric acid moiety are observedas transitions into three-group frequency ringmodes and theatomic numbering shown in Figure 2 will be useful

The highest frequency band (observed at an energy of1705 cmminus1 in the infrared absorption spectrum of 5-nitro-barbituric acid) is identified as the 46-CO symmetric modewhere the vibrational motion is more localized on thecarbonyl groups located at carbons 4 and 6 The lowestfrequency mode corresponds to the 2-CO stretching modeand is observed at an energy of 1614 cmminus1 while the 46-CO antisymmetric mode is observed at an intermediateenergy of 1651 cmminus1 Other important absorption bands in theinfrared absorption spectrumof 5-nitrobarbituric acid are thesymmetric stretching mode associated with the nitro group(1381 cmminus1) the CndashN ring deformation mode (1246 cmminus1)and the carbonyl out-of-plane bending mode (779 cmminus1)

A number of important bands were observed in theRaman spectrum of 5-nitrobarbituric acid with these being


5 10 15 20 25 30 35 40


Cinchonine

Cocrystal

Rela

tive i

nten

sity

Scattering angle 2120579 (deg)

Figure 2

primarily associated with motions of the carbonyl groupsAn in-plane bending mode was observed at an energy of379 cmminus1 while out-of-plane bending modes were observedat 625 and 695 cmminus1 Other band assignments that will beimportant to succeeding discussion are an NndashH out-of-plane bending mode (846 cmminus1) a CndashN stretching mode(1150 cmminus1) and a CndashN deformation mode (1255 cmminus1)

33 Vibrational Spectroscopy of the Cinchona AlkaloidsWhile the vibrational modes of 5-nitrobarbituric acid aredominated by ring character the vibrational modes of thecinchona alkaloids consist mainly of ring modes associatedwith the quinoline ring and CndashC and CndashH vibrationalmodes associated with the vinylquinuclidine group and thealiphatic linkage between the two Since the vibrationalspectroscopy of both quinoline [51 52] and quinuclidine[53 54] is well understood the major transitions observedin the infrared absorption spectra and the Raman spectraof the cinchona alkaloids can be understood especiallywhen one considers studies that have been conducted oncinchonine [55] cinchonidine [56] and quinine [57] Owingto the delocalized nature of the vibrational modes in thesemolecules it is difficult to separate out individual modesthat are localized on one of the important functional groupsHowever the consensus opinion is that a nonprotonatedquinuclidine will exhibit a vibrational mode in the rangeof approximately 1355ndash1365 cmminus1 that shifts to a range ofapproximately 1380ndash1390 cmminus1 upon protonation A nonpro-tonated quinoline will exhibit a characteristic transition inthe range of approximately 1570ndash1580 cmminus1 which will shiftto approximately 1600ndash1610 cmminus1 upon protonation

Unfortunately were the protonated cinchona bands to bepresent in the absorption spectrum of a cocrystal productthey would be overwhelmed by the more intense absorption

600 800 1000 1200 1400 1600 1800

Cinchonine

Cocrystal

Rela

tive i

nten

sity

Energy (cmminus1)


Figure 3 X-ray powder diffraction patterns of 5-nitrobarbituricacid cinchonine and the 1 1 nitrobarbituric-cinchonine cocrystal

bands associated with the 5-nitrobarbituric acid Fortunatelythe Raman spectrum of the cinchona alkaloids is not socompromised and one may readily assess the interactionsexisting in the cocrystal by tracking the energies of the keyquinoline and quinuclidine vibrational modes

34 The 1 1 Cinchonine Cocrystal Formed with 5-Nitrobarbi-turic Acid XRPD patterns obtained for 5-nitrobarbituricacid cinchonine and the nitrobarbiturate-cinchonine cocry-stal product are shown in Figure 3 The differences betweenthe diffraction patterns demonstrated that the three crystalstructures are different and established the formation of acrystalline cocrystal product

The nitrobarbiturate-cinchonine cocrystal product wasfound to evolve 148 of its mass when heated isothermallyat 125∘C which would correspond to the existence of a 45-hydrate form of the cocrystal The DSC thermogram of thecocrystal product consisted of a strong desolvation endother-mic transition characterized by a temperature maximum of80∘C and an enthalpy of fusion equal to 246 Jg The desol-vated compound formed upon completion of this thermalreaction did not exhibit a melting endothermic transitionindicating that an amorphous substance formed upon desol-vationThe only other thermally induced transition observedin the DSC thermogram was the onset of decompositionwhich began at a temperature of approximately 220∘C

The infrared absorption spectra obtained for 5-nitro-barbituric acid cinchonine and the 1 1 nitrobarbituric-cinchonine cocrystal within the fingerprint region are shownin Figure 4 and the correlation between the energies of theimportant absorption bands is shown in Table 1 All of thestrong 5-nitrobarbiturate absorption bandswere visible in thespectrum of the cocrystal and most of these were found tobe considerably shifted in energy relative to the free acid


Table 1 Assignments of the major bands in the fingerprint region of the infrared absorption spectra of 5-nitrobarbituric acid cinchonineand their 1 1 cocrystal product

Assignment Nitrobarbituric (cmminus1) Cocrystal (cmminus1) Cinchonine (cmminus1) AssignmentCarbonyl out-of-planebending mode 779 756

CndashN ring deformation mode 1246 1286

Obscured and not observed 1360 Nonprotonated quinuclidinemode

Nitro group symmetricstretching mode 1381 1377

Obscured and not observed 1566 Nonprotonated quinolinemode

2-CO stretching mode 1614 162246-CO antisymmetric mode 1651 Not observed46-CO symmetric mode 1705 1701

250

450

650

850

1050

1250

1450

1650

1850

Cinchonine

Cocrystal

Rela

tive i

nten

sity

Raman shift (cmminus1)


Figure 4 Infrared absorption spectra within the fingerprint regionof 5-nitrobarbituric acid cinchonine and the 1 1 nitrobarbituric-cinchonine cocrystal

This finding demonstrates that the entire ring system of theacid is involved in the cocrystal formation Unfortunately thetwo key absorption bands of the quinuclidine and quinolinemoieties of cinchonine were obscured by the nitrobarbiturateabsorption bands and thus could not be used in an interpre-tative analysis

The Raman spectra obtained for 5-nitrobarbituric acidcinchonine and the 1 1 nitrobarbituric-cinchonine cocrystalwithin the fingerprint region are shown in Figure 5 and thecorrelation between the energies of the important absorptionbands is shown in Table 2 Once again all of the strong 5-nitrobarbiturate vibrational modes were noted to undergoshifts in energy relative to the free acid providing a furtherdemonstration that the entire ring system of the acid is

Cinchonidine

Cocrystal

Rela

tive i

nten

sity

5 10 15 20 25 30 35 40Scattering angle 2120579 (deg)


Figure 5 Raman spectra within the fingerprint region of 5-nitro-barbituric acid cinchonine and the 1 1 nitrobarbituric-cinchoninecocrystal

involved in the cocrystal formation More importantly thekey Raman bands associated with cinchonine were visiblein the spectrum of the cocrystal The energy of the quinu-clidine mode was not found to shift in the spectrum of thecocrystal indicating that the degree of interaction with 5-nitrobarbituric acid at the tertiary nitrogen wasminimalThevibrational mode of the quinoline moiety did undergo a sig-nificant increase in energy indicating that the predominantinteraction with the acid took place at this group

35The 1 1 Cinchonidine Cocrystal Formedwith 5-Nitrobarbi-turic Acid TheXRPDpatterns obtained for 5-nitrobarbituricacid cinchonidine and the nitrobarbiturate-cinchonidinecocrystal product are shown in Figure 6 The fact that thepowder pattern of the 1 1 stoichiometric reaction product


Table 2 Assignments of the major bands in the fingerprint region of the Raman spectra of 5-nitrobarbituric acid cinchonine and their 1 1cocrystal product

Assignment Nitrobarbituric (cmminus1) Cocrystal (cmminus1) Cinchonine (cmminus1) AssignmentCarbonyl in-plane bending mode 379 357Carbonyl out-of-plane bending mode 625 609Carbonyl out-of-plane bending mode 695 681NndashH out-of-plane bending mode 846 838CndashN stretching mode 1150 1137CndashN deformation mode 1255 1248

1361 1360 Nonprotonated quinuclidine mode1572 1566 Nonprotonated quinoline mode

Table 3 Assignments of the major bands in the fingerprint region of the infrared absorption spectra of 5-nitrobarbituric acid cinchonidineand their 1 1 cocrystal product

Assignment Nitrobarbituric (cmminus1) Cocrystal (cmminus1) Cinchonidine (cmminus1) AssignmentCarbonyl out-of-plane bendingmode 779 762





2-CO stretching mode 1614 159546-CO antisymmetric mode 1651 166646-CO symmetric mode 1705 1691

cannot be obtained by a simple averaging of the XRPDpatterns of the two reactants establishes the formation of acrystalline cocrystal product

The nitrobarbiturate-cinchonidine cocrystal product wasfound to evolve 55 of its mass when heated isothermallyat 125∘C which would correspond to the existence of a 15-hydrate form of the cocrystal The DSC thermogram of thecocrystal product consisted of a strong desolvation endother-mic transition characterized by a temperature maximum of101∘Cand an enthalpy of fusion equal to 97 JgThedesolvatedcompound formed upon completion of this thermal reactionwas found to exhibit amelting endothermic transition havinga temperature maximum of 219∘C but as this transitionwas coupled with an exothermic decomposition reaction noestimation of enthalpy could be made

The fingerprint region infrared absorption spectra obtai-ned for 5-nitrobarbituric acid cinchonidine and the cocrys-tal product are shown in Figure 7 and the correlation betweenthe energies of the important absorption bands is shown inTable 3 As had been noted for the 5-nitrobarbituric acidcocrystal with cinchonine all of the strong nitrobarbiturateabsorption bands in the spectrum of the cocrystal werefound to be shifted in energy relative to the free acid Asbefore the two key absorption bands of the quinuclidineand quinoline moieties of cinchonidine were obscured by thenitrobarbiturate absorption bands and were not available foranalysis

The fingerprint region Raman spectra obtained for 5-nitrobarbituric acid cinchonidine and the 1 1 nitrobarbi-turic-cinchonidine cocrystal are shown in Figure 8 and thecorrelation between the energies of the important absorptionbands is shown in Table 4 All of the strong 5-nitrobarbituratevibrational modes were noted to undergo shifts in energyrelative to the free acid providing a further demonstrationthat the entire ring system of the acid is involved in thecocrystal formation The energy of the quinuclidine modewas barely shifted in the spectrum of the cocrystal whilethe vibrational mode of the quinoline moiety was noted toundergo a significant increase in energy These findings indi-cate that the predominant interaction with 5-nitrobarbituricacid took place at the quinoline group and that the degreeof interaction with the tertiary nitrogen of the quinuclidinegroup was minimal

36 The 1 1 Quinine Cocrystal Formed with 5-NitrobarbituricAcid TheXRPDpatterns obtained for 5-nitrobarbituric acidquinine and the nitrobarbiturate-quinine cocrystal productare shown in Figure 9 In this system formation of the1 1 stoichiometric reaction product is very evident in thenonequivalence of the powder patterns especially when thequinine-free base used to form the cocrystal could onlybe obtained in a quasicrystalline form regardless of itsinitial processing It is interesting to note that even though


Table 4 Assignments of the major bands in the fingerprint region of the Raman spectra of 5-nitrobarbituric acid cinchonidine and their1 1 cocrystal product

Assignment Nitrobarbituric (cmminus1) Cocrystal (cmminus1) Cinchonidine (cmminus1) AssignmentCarbonyl in-plane bending mode 379 373Carbonyl out-of-plane bending mode 625 617Carbonyl out-of-plane bending mode 695 681NndashH out-of-plane bending mode 846 843CndashN stretching mode 1150 1132CndashN deformation mode 1255 1252


Cinchonidine

Cocrystal

Rela

tive i

nten

sity

600 800 1000 1200 1400 1600 1800Energy (cmminus1)


Figure 6 X-ray powder diffraction patterns of 5-nitrobarbituricacid cinchonidine and the 1 1 nitrobarbituric-cinchonidine cocrys-tal

the absolute configurations at the dissymmetric carbons ofquinine and cinchonidine are the same the XRPD patternsof their cocrystal products with 5-nitrobarbituric are onlyqualitatively similar and each exhibits peaks not contained inthe pattern of the other

However like the nitrobarbiturate-cinchonidine cocrys-tal the nitrobarbiturate-quinine cocrystal product was alsofound to be a 15-hydrate form since it evolved 52 ofits mass when heated isothermally at 125∘C The DSC ther-mogram of the nitrobarbiturate-quinine cocrystal productconsisted of a strong desolvation endothermic transitioncharacterized by a temperature maximum of 98∘C and anenthalpy of fusion equal to 74 JgThe thermal characteristicsof this desolvation endotherm are fairly similar to those ofthe nitrobarbiturate-cinchonidine cocrystal Also akin to itsstereochemical equivalent the desolvated nitrobarbiturate-quinine cocrystal formed after completion of the desolvationthermal reaction exhibited a melting endothermic transition(temperature maximum of 217∘C) that was accompanied by astrong exothermic decomposition reaction

Cinchonidine

CocrystalRe

lativ

e int

ensit

y25

0

450

650

850

1050

1250

1450

1650

1850



Figure 7 Infrared absorption spectra within the fingerprint regionof 5-nitrobarbituric acid cinchonidine and the 1 1 nitrobarbituric-cinchonidine cocrystal

The fingerprint region infrared absorption spectra obtai-ned for 5-nitrobarbituric acid quinine and the cocrystalproduct are shown in Figures 10 and 11 and the correlationbetween the energies of the important absorption bandsis shown in Table 5 While the strong nitrobarbiturateabsorption bands in the spectrum of the cocrystal wereshifted in energy relative to the free acid the pattern ofshifting was somewhat different for the quinine cocrystal Forexample the energy of the carbonyl out-of-plane bendingmode increased upon formation of the cocrystal whereas inthe two preceding systems the energy of this vibrationalmodedecreased

Even more interesting was the behavior of the two keyabsorption bands of the quinuclidine and quinoline moietiesof quinineWhile these were obscured by the nitrobarbiturateabsorption bands in the infrared absorption spectra of thecinchonine and cinchonidine cocrystal products they wereobserved in the spectrum of the quinine cocrystal However


Table 5 Assignments of the major bands in the fingerprint region of the infrared absorption spectra of 5-nitrobarbituric acid quinine andtheir 1 1 cocrystal product

Assignment Nitrobarbituric (cmminus1) Cocrystal (cmminus1) Quinine (cmminus1) AssignmentCarbonyl out-of-plane bending mode 779 791CndashN ring deformation mode 1246 1234

1364 1371 Nonprotonated quinuclidine modeNitro group symmetric stretching mode 1381 1359

1575 1576 Nonprotonated quinoline mode2-CO stretching mode 1614 162046-CO antisymmetric mode 1651 166146-CO symmetric mode 1705 1691

Quinine

Cocrystal

Rela

tive i

nten

sity



Figure 8 Raman spectra within the fingerprint region of 5-nitrobarbituric acid cinchonidine and the 1 1 nitrobarbituric-cinchonidine cocrystal

the energy of the nonprotonated quinoline vibrational modewas only barely shifted in the spectrum of the cocrystal(1576 cmminus1 for quinine versus 1575 cmminus1 for its cocrystal)while the energy of the nonprotonated quinuclidine vibra-tional mode was definitely shifted (1371 cmminus1 for quinine ver-sus 1364 cmminus1 for its cocrystal)This finding would imply thatwhile the dominant interaction between 5-nitrobarbituricacid and cinchonine or cinchonidine was between the acidand the quinoline ring the dominant interaction between 5-nitrobarbituric acid and quininewas between the acid and thequinuclidine ring nitrogen

Quinine also contains a methoxy group bound on thequinoline ring that is not present for either cinchonineor cinchonidine In the spectrum of the free base thevibrational bands associated with the methoxy group wereobserved as a strong doublet of peaks (having energies of1227 and 1240 cmminus1) that each underwent significant shiftingin the spectrum of the cocrystal (1234 and 1252 cmminus1) This

Quinine

CocrystalRe

lativ

e int

ensit

y

600 800 1000 1200 1400 1600 1800Energy (cmminus1)


Figure 9 X-ray powder diffraction patterns of 5-nitrobarbituricacid quinine and the 1 1 nitrobarbituric-quinine cocrystal

observation indicates that while the quinoline ring nitrogenwas not strongly involved in the intermolecular interactionsof the synthon its methoxy group certainly was

The fingerprint region Raman spectra obtained for 5-nitrobarbituric acid quinine and the 1 1 nitrobarbituric-quinine cocrystal are shown in Figure 10 and the correlationbetween the energies of the important absorption bands isshown in Table 6 The strong 5-nitrobarbiturate vibrationalmodes were found to undergo shifts in energy relative to thefree acid as would be expected since the entire ring systemof the 5-nitrobarbituric acid is involved in the cocrystalformation As had been noted in the infrared absorptionspectra the energy of the nonprotonated quinuclidine modewas significantly shifted in the spectrum of the cocrystalwhile the vibrational mode of the nonprotonated quinolinegroup barely underwent any change in energyThese findingsprovide further support that the predominant interactionwith 5-nitrobarbituric acid took place at the quinuclidinegroup


Table 6 Assignments of the major bands in the fingerprint region of the Raman spectra of 5-nitrobarbituric acid quinine and their 1 1cocrystal product

Assignment Nitrobarbituric (cmminus1) Cocrystal (cmminus1) Quinine (cmminus1) AssignmentCarbonyl in-plane bending mode 379 368Carbonyl out-of-plane bending mode 625 610Carbonyl out-of-plane bending mode 695 679NndashH out-of-plane bending mode 846 834CndashN stretching mode 1150 1125CndashN deformation mode 1255 1242


Quinine

Cocrystal

Rela

tive i

nten

sity

250

450

650

850

1050

1250

1450

1650

1850



Figure 10 Infrared absorption spectra within the fingerprint regionof 5-nitrobarbituric acid quinine and the 1 1 nitrobarbituric-quinine cocrystal

37 The 1 1 Quinidine Cocrystal Formed with 5-Nitrobarbi-turic Acid TheXRPDpatterns obtained for 5-nitrobarbituricacid quinidine and the nitrobarbiturate-quinidine cocrystalproduct are shown in Figure 12 where it may be noted thatthe degree of crystallinity associated with the cocrystal wassubstantially less than that of the reactants Nevertheless theunique diffraction pattern obtained for the 1 1 stoichiometricreaction pattern relative to those of the reactants establishesthe existence of a genuine cocrystal

The nitrobarbiturate-quinidine cocrystal product provedto be unique in that it barely evolved 025 of its mass whenheated isothermally at 125∘C and was therefore determinedto be a nonsolvated solid-state form This type of cocrystalproduct is totally different from that of its stereochemicalanalogue as the nitrobarbiturate-cinchonine cocrystal prod-uct was characterized by the highest degree of hydrationamong the cocrystals studied The DSC thermogram of thenitrobarbiturate-quinidine cocrystal product did not containa desolvation endotherm and instead consisted of a weak

Quinidine

CocrystalRe

lativ

e int

ensit

y



Figure 11 Raman spectra within the fingerprint region of 5-nitrobarbituric acid quinine and the 1 1 nitrobarbituric-quininecocrystal

melting endothermic transition having a temperature max-imum of 196∘C and an enthalpy of fusion equal to 15 Jg Ata temperature of 230∘C the cocrystal was found to undergo astrong exothermic decomposition reaction

The fingerprint region infrared absorption spectra obtai-ned for 5-nitrobarbituric acid quinidine and the cocrystalproduct are shown in Figure 13 and the correlation betweenthe energies of the important absorption bands is shownin Table 7 The trends in vibrational energies of the strongnitrobarbiturate absorption bands in the spectrum of thecocrystal were found to be consistent with those of thecocrystals with cinchonine and cinchonidine and the twokey absorption bands of the quinuclidine and quinolinemoieties of quinidine were obscured by the nitrobarbiturateabsorption bands

The fingerprint region Raman spectra obtained for 5-nitrobarbituric acid quinidine and the 1 1 nitrobarbituric-quinidine cocrystal are shown in Figure 14 and the cor-relation between the energies of the important absorption


Table 7 Assignments of the major bands in the fingerprint region of the infrared absorption spectra of 5-nitrobarbituric acid quinidine andtheir 1 1 cocrystal product

Assignment Nitrobarbituric (cmminus1) Cocrystal (cmminus1) Quinidine (cmminus1) AssignmentCarbonyl out-of-planebending mode 779 756

CndashN ring deformationmode 1246 1240

Obscured and not observed 1360 Nonprotonatedquinuclidine mode



2-CO stretching mode 1614 162246-CO antisymmetricmode 1651 Not observed

46-CO symmetric mode 1705 1690

Table 8 Assignments of the major bands in the fingerprint region of the Raman spectra of 5-nitrobarbituric acid quinidine and their 1 1cocrystal product

Assignment Nitrobarbituric (cmminus1) Cocrystal (cmminus1) Quinidine (cmminus1) AssignmentCarbonyl in-plane bending mode 379 365Carbonyl out-of-plane bending mode 625 608Carbonyl out-of-plane bending mode 695 681NndashH out-of-plane bending mode 846 836CndashN stretching mode 1150 1144CndashN deformation mode 1255 1243


Quinidine

Cocrystal

Rela

tive i

nten

sity

600 800 1000 1200 1400 1600 1800Energy (cmminus1)


Figure 12 X-ray powder diffraction patterns of 5-nitrobarbituricacid quinidine and the 1 1 nitrobarbituric-quinidine cocrystal

bands is shown in Table 8 All of the strong 5-nitrobarbituratevibrational modes were noted to undergo shifts in energy

relative to the free acid confirming as before that the entirering system of the acid is involved in the cocrystal forma-tion The energy of the nonprotonated quinuclidine mode(1363 cmminus1) was barely shifted in the spectrum of the cocrys-tal (1362 cmminus1) while the vibrational mode of the quinolinemoiety was noted to undergo a significant increase in energyfrom 1561 cmminus1 to 1570 cmminus1 These findings indicate that inthis cocrystal system the predominant interaction with 5-nitrobarbituric acid took place at the quinoline group andthat the degree of interaction with the tertiary nitrogen of thequinuclidine group was minimal

4 Conclusions

X-ray powder diffraction and thermal analysis have beenused to demonstrate the existence of new solid-state formsgenerated by the cocrystallization of 5-nitrobarbituric acidwith four cinchona alkaloids The cocrystal products werefound to contain varying degrees of hydration ranging fromno hydration in the nitrobarbiturate-quinidine cocrystal upto a 45-hydrate species in the nitrobarbiturate-cinchoninecocrystal Raman spectra of the products were used todetermine the predominant mode of interaction in thenitrobarbiturate-cinchona synthon For the nitrobarbituratecocrystals with cinchonine cinchonidine and quinidine


Quinidine

Cocrystal

Rela

tive i

nten

sity

250

450

650

850

1050

1250

1450

1650

1850



Figure 13 Infrared absorption spectra within the fingerprint regionof 5-nitrobarbituric acid quinidine and the 1 1 nitrobarbituric-quinidine cocrystal

NH OO

O

NHO2N

216

5 4 3

Figure 14 Raman spectra within the fingerprint region of 5-nitro-barbituric acid quinidine and the 1 1 nitrobarbituric-quinidinecocrystal

the predominant interaction was with the quinoline ring sys-tem of the alkaloid However for quinine the predominantinteraction was with the quinuclidine group of the alkaloid

Previous papers in this series [26 27] have establishedthat the variety of morphologies encountered for themolecu-lar complexes of basic substances with 5-nitrobarbituric acid(dilituric acid) arises from the ability of the nitrobarbituratereagent to form differing structural types andor hydratesupon crystallization The nonequivalence observed for thepowder X-ray diffraction patterns demonstrates that eachisolated adduct exhibits a unique crystal structure whichin turn yields differing crystal morphologies This behaviorhas been further verified in the present study where thediffering range of hydrate and structural types would serveto easily differentiate the cinchona alkaloids from each othereven when different compounds contained the same absoluteconfigurations at their dissymmetric centers

Conflict of Interests

The author declares that there is no conflict of interestsregarding the publication of this paper

References

[1] P Vishweshwar J A McMahon J A Bis and M J ZaworotkoldquoPharmaceutical co-crystalsrdquo Journal of Pharmaceutical Sci-ences vol 95 no 3 pp 499ndash516 2006

[2] N BlagdenM deMatas P T Gavan and P York ldquoCrystal engi-neering of active pharmaceutical ingredients to improve solu-bility and dissolution ratesrdquo Advanced Drug Delivery Reviewsvol 59 no 7 pp 617ndash630 2007

[3] N Schultheiss andA Newman ldquoPharmaceutical cocrystals andtheir physicochemical propertiesrdquo Crystal Growth and Designvol 9 no 6 pp 2950ndash2967 2009

[4] T Friscic and W Jones Journal of Pharmacology and Pharma-cotherapeutics vol 5 pp 1547ndash1559 2010

[5] H G Brittain ldquoPharmaceutical cocrystals the coming wave ofnew drug substancesrdquo Journal of Pharmaceutical Sciences vol102 no 2 pp 311ndash317 2013

[6] C B Aakeroy and D J Salmon ldquoBuilding co-crystals withmolecular sense and supramolecular sensibilityrdquo CrystEng-Comm vol 7 pp 439ndash448 2005

[7] A I KitaigorodskyMixed Crystals Springer Berlin Germany1984

[8] F H Herbstein Crystalline Molecular Complexes and Com-pounds vol 2 Oxford University Press Oxford UK 2005

[9] G P Stahly ldquoA survey of cocrystals reported prior to 2000rdquoCrystal Growth and Design vol 9 no 10 pp 4212ndash4229 2009

[10] H G Brittain ldquoCocrystal systems of pharmaceutical interest2010rdquo Crystal Growth and Design vol 12 no 2 pp 1046ndash10542012


[12] E M Chamot and C W Mason Handbook of ChemicalMicroscopy vol 2 JohnWiley amp Sons New York NY USA 2ndedition 1940

[13] R E Stevens ldquoOrganic chemical microscopy a monographrdquoMicrochemical Journal vol 13 no 1 pp 42ndash65 1968

[14] E G C Clarke ldquoMicrochemical identification of local anaeligs-thetic drugsrdquo Journal of Pharmacy and Pharmacology vol 8 no1 pp 202ndash206 1956

[15] E G C Clarke ldquoMicrochemical identification of some antihis-tamine drugsrdquo Journal of Pharmacy and Pharmacology vol 9no 11 pp 752ndash758 1957

[16] E G C Clarke ldquoA note on the identification of some antimalar-ial drugsrdquo Journal of Pharmacy and Pharmacology vol 10 no 1pp 194ndash196 1958

[17] E G C Clarke ldquoMicrochemical differentiation between opticalisomers of N-methylmorphinan analgesicsrdquo Journal of Phar-macy and Pharmacology vol 10 pp 642ndash644 1958

[18] NW Rich and L G Chatten ldquoIdentification and differentiationof organic medicinal agents I Local anestheticsrdquo Journal ofPharmaceutical Sciences vol 54 no 7 pp 995ndash1002 1965

[19] L ADoan and L G Chatten ldquoIdentification and differentiationof organic medicinal agents II Muscle relaxantsrdquo Journal ofPharmaceutical Sciences vol 54 no 11 pp 1605ndash1609 1965


[20] L G Chatten and L A Doan ldquoIdentification and differ-entiation of organic medicinal agents 3 Amine-containingantiparkinson agents and newer muscle relaxantsrdquo Journal ofPharmaceutical Sciences vol 55 no 4 pp 372ndash376 1966

[21] C E Redemann and C Niemann ldquoThe diliturates (5-nitro-barbiturates) of some physiologically important basesrdquo Journalof the American Chemical Society vol 62 no 3 pp 590ndash5931940

[22] E M Plein and B T Dewey ldquoIdentification of organic basesby means of optical properties of diliturates (nitrobarbiturates)aliphatic aminesrdquo IndustrialampEngineeringChemistryAnalyticalEdition vol 15 no 8 pp 534ndash536 1943

[23] B T Dewey and E M Plein ldquoIdentification of organic basesby means of optical properties of diliturates (nitrobarbitura-tes)primary aromatic aminesrdquo Industrial amp Engineering Chem-istry Analytical Edition vol 18 no 8 pp 515ndash520 1946

[24] E M Plein ldquoThe identification of some autonomic drugs bymeans of the optical properties of the dilituratesrdquo Journal of theAmerican Pharmaceutical Association vol 38 no 10 pp 535ndash537 1949

[25] B T Dewey and E M Plein ldquoCrystallographic data Iden-tification of organic bases by means of optical properties ofdiliturates (nitrobarbiturates)rdquoAnalytical Chemistry vol 27 no5 pp 862ndash863 1955

[26] H G Brittain ldquoFoundations of chemical microscopy 2 Deriva-tives of primary phenylalkylamineswith 5-nitrobarbituric acidrdquoJournal of Pharmaceutical and Biomedical Analysis vol 19 no6 pp 865ndash875 1999

[27] H G Brittain and M Rehman ldquoFoundations of chemicalmicroscopy 3 Derivatives of some chiral phenylalkylaminesand phenylalkylamino acids with 5-nitrobarbituric acidrdquo Chi-rality vol 17 no 2 pp 89ndash98 2005

[28] E T Wherry and E Yanovsky ldquoThe identification of thecinchona alkaloids by optical-crystallographic measurementsrdquoJournal of the American Chemical Society vol 40 no 7 pp1063ndash1074 1918

[29] B E Nelson and H A Leonard ldquoIdentification of alkaloidsunder the microscope from the form of their picrate crystalsrdquoJournal of the American Chemical Society vol 44 no 2 pp 369ndash373 1922

[30] M L Shaner and M L Willard ldquoOptical crystallographic datafor some salts of the cinchona alkaloidsrdquo Journal of theAmericanChemical Society vol 58 no 10 pp 1977ndash1978 1936

[31] V R Pedireddi W Jones A P Chorlton and R DochertyldquoCreation of crystalline supramolecular arrays a comparison ofco-crystal formation from solution and by solid-state grindingrdquoChemical Communications no 8 pp 987ndash988 1996

[32] N Shan F Toda and W Jones ldquoMechanochemistry andco-crystal formation effect of solvent on reaction kineticsrdquoChemical Communications no 20 pp 2372ndash2373 2002

[33] A V Trask and W Jones ldquoCrystal engineering of organiccocrystals by the solid-state grinding approachrdquo in OrganicSolid State Reactions vol 254 of Topics in Current Chemistrypp 41ndash70 Springer Berlin Germany 2005

[34] G G Lyle and L K Keefer ldquoThe configurations at C-9 ofthe cinchona alkaloids NMR spectral study of the derivedoxiranesrdquo Tetrahedron vol 23 no 8 pp 3253ndash3263 1967

[35] H G Brittain ldquoCircularly polarized luminescence studies ofthe optical activity induced in the europium(III) chelate of444-trifluoro-1-(2-thienyl)butane-13-dionate through adductformation with cinchona alkaloidsrdquo Journal of the ChemicalSociety Dalton Transactions vol 1980 pp 2369ndash2373 1980

[36] W Klyne and J Buckingham Atlas of Stereochemistry vol 1Oxford University Press New York NY USA 1974

[37] O L Carter A T McPhail and G A Sim ldquoOptically activeorganometallic compounds Part I Absolute configuration of (-)-11 1015840-dimethylferrocene-3-carboxylic acid by X-ray analysis ofits quinidine saltrdquo Journal of the Chemical Society A InorganicPhysical and Theoretical Chemistry pp 365ndash373 1967

[38] J T Bojarski J L Mokrosz H J Barton and M HPaluchowska ldquoRecent progress in barbituric acid chemistryrdquoAdvances in Heterocyclic Chemistry vol 38 pp 229ndash297 1985

[39] W C Price J E S Bradley and R D B Fraser ldquoThe rela-tionship between the infra-red absorption spectra of some 551015840-substituted barbituric acids and their pharmacological activityrdquoThe Journal of Pharmacy and Pharmacology vol 6 no 8 pp522ndash528 1954

[40] S Pinchas ldquoCharge transfer interaction between 23 dichloro56 dicyano p-benzoquinone and aromatic hydrocarbonsrdquo Spec-trochimica Acta vol 22 no 11 pp 1869ndash1895 1966

[41] R J Mesley ldquoSpectra-structure correlations in polymorphicsolidsmdashII 55-Disubstituted barbituric acidsrdquo SpectrochimicaActa Part AMolecular Spectroscopy vol 26 no 7 pp 1427ndash14481970

[42] A J Barnes L Le Gall and J Lauransan ldquoVibrational spectraof barbituric acid derivatives in low-temperature matrices part2 Barbituric acid and 13-dimethyl barbituric acidrdquo Journal ofMolecular Structure vol 56 pp 15ndash27 1979

[43] N B Colthup L H Daly and S E Wiberley Introduction toInfrared and Raman Spectroscopy Academic Press New YorkNY USA 1964

[44] R T Conley Infrared Spectroscopy Allyn and Bacon BostonMass USA 1966

[45] F F Bentley L D Smithson and A L Rozel Infrared Spectraand Characteristic Frequencies 700-300 cmminus1 Interscience NewYork NY USA 1968

[46] L J Bellamy Advances in Infrared Group Frequencies Methuenamp Co London UK 1968

[47] F R Dollish W G Fateley and F F Bentley CharacteristicRaman Frequencies of Organic Compounds JohnWiley amp SonsNew York NY USA 1974

[48] J G Grasselli M K Snavely and B J Bulkin ChemicalApplications of Raman Spectroscopy John Wiley amp Sons NewYork NY USA 1981

[49] G Socrates Infrared and Raman Characteristic Group Frequen-cies John Wiley amp Sons Chichester UK 3rd edition 2001

[50] I R Lewis and H G M Edwards Handbook of RamanSpectroscopy Marcel Dekker New York NY USA 2001

[51] S CWait Jr and J CMcNerney ldquoVibrational spectra and assig-nments for quinoline and isoquinolinerdquo Journal of MolecularSpectroscopy vol 34 no 1 pp 56ndash77 1970

[52] A E Ozel Y Buyukmurat and S Akyuz ldquoInfrared-spectraand normal-coordinate analysis of quinoline and quinolinecomplexesrdquo Journal of Molecular Structure vol 565-566 pp455ndash462 2001

[53] P Bruesch ldquoX-ray and infrared studies of bicyclo(222) octanetriethylenediamine and quinuclidinemdashII Normal co-ordinatecalculations of bicyclo(222)octane triethylenediamine andquinuclidinerdquo Spectrochimica Acta vol 22 no 5 pp 867ndash8751966

[54] P Bruesch and H H Gunthard ldquoX-ray and infra-red studiesof bicyclo(222)octane triethylenediamine and quinuclidinemdashIII Assignments of high and low temperature infra-red spectra


Comparison with X-ray resultsrdquo Spectrochim Acta vol 22 no5 pp 877ndash887 1966

[55] A Weselucha-Birczynska and M Ciechanowicz-RutkowskaldquoExperimental and calculated structure of vibrational spectraof cinchoninerdquo Journal of Molecular Structure vol 555 pp 391ndash395 2000

[56] W Chu R J LeBlanc and C TWilliams ldquoIn-situ Raman inves-tigation of cinchonidine adsorption onpolycrystalline platinumin ethanolrdquo Catalysis Communications vol 3 no 12 pp 547ndash552 2002

[57] T FroschM Schmtt and J Popp ldquoIn situUV resonance Ramanmicro-spectroscopic localization of the antimalarial quinine incinchona barkrdquo Journal of Physical Chemistry B vol 111 no 16pp 4171ndash4177 2007

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy


Carbohydrate Chemistry

International Journal of


Journal of

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Advances in

Physical Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

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Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of


Chromatography Research International


Applied ChemistryJournal of



Theoretical ChemistryJournal of


Journal of

Spectroscopy

Analytical ChemistryInternational Journal of


Journal of


Quantum Chemistry


Organic Chemistry International

ElectrochemistryInternational Journal of



CatalystsJournal of


adducts of 5-nitrobarbituric acid and basic compounds thatfacilitated their utility in chemical microscopy have beenevaluated through the study of the cocrystals formed by thediliturate reagent with primary achiral phenylalkylamines[26] and resolved and racemic phenylalkylamines and pheny-lalkylamino acids [27] In these works it was establishedthat the different crystal morphologies associated with thevarious reaction products were derived from the ability of thesystems to form a variety of polymorphic and solvatomorphiccocrystal structures

In the present work the phenomenon of cocrystal for-mation in the molecular complexes of 5-nitrobarbituric acidhas been further investigated through studies of adductsformed by this reagent with four cinchona alkaloids (quininequinidine cinchonine and cinchonidine) Structures of the5-nitrobarbituric acid reagent and the alkaloids studies in thiswork are found in Figure 1 Although chemical microscopicidentification methods have been published for cinchonaalkaloids [28ndash30] the only report on the 5-nitrobarbiturateadducts simply mentioned the crystal morphologies of thequinine and cinchonine adducts [21] Since no detailed stud-ies of the cinchona alkaloid cocrystals with 5-nitrobarbituricacid have been reported the products were characterized bythe standard thermoanalytical and powder diffraction meth-ods In addition detailed vibrational spectroscopic studieswere performed in order to determine which vibrationalmodes were most affected by the cocrystal formation andto determine the magnitudes of perturbation within theinvolved vibrational modes

2 Materials and Methods

21 Reagents and Method of Cocrystal Preparation 5-Nitro-barbituric acid trihydrate quinine dihydrate quinidine cin-chonine and cinchonidine were purchased from Sigma-Aldrich and were recrystallized from 70 aqueous iso-propanol before use The products studied in this work wereprepared using solvent-drop-mediated solid-state grinding[31ndash33] where the stoichiometry of the product was deter-mined by the amounts of reactants initially taken Exactlyweighed amounts of 5-nitrobarbituric acid and alkaloidacid were weighed directly in an agate mortar (preparingapproximately 500mgof total product) andwettedwith 50120583Lof 70 aqueous isopropanol After slurry was prepared bymixing the composition was hand-ground with an agatepestle until the product was completely dry

22 X-Ray Powder Diffraction X-ray powder diffraction(XRPD) patterns were obtained using a Rigaku MiniFlexpowder diffraction system equippedwith a horizontal gonio-meter operating in the 1205792120579modeThe X-ray source was nic-kel-filtered K120572 emission of copper (154184 A) Samples werepacked into the sample holder using a back-fill procedure andwere scanned over the range of 35 to 40 degrees 2120579 at a scanrate of 05 degrees 2120579min Using a data acquisition rate of 1point per second the scanning parameters equate to a stepsize of 00084 degrees 2120579 Calibration of the diffractometersystemwas effected using purified talc as a referencematerial

23Thermal Analysis Measurements of differential scanningcalorimetry (DSC) were obtained on a TA Instruments 2910thermal analysis system Samples of approximately 1-2mgwere accuratelyweighed into an aluminumDSCpan and thencovered with an aluminum lid that was crimped in placeThesamples were then heated over the range of 20ndash175∘C at aheating rate of 10∘Cmin

Measurements of total volatile content were made usingan Ohaus model MB45 system The samples were heatedisothermally at a temperature of 125∘C for a period of15 minutes Invariably samples had desolvated to constantweight after approximately 10 minutes of heating time

24 Infrared Absorption Spectroscopy Infrared absorptionspectrawere obtained at a resolution of 4 cmminus1 using a Shima-dzu model 8400S Fourier-transform infrared spectrometerwith each spectrum being obtained as the average of 25 indi-vidual spectra The data were acquired using the attenuatedtotal reflectance sampling mode where the samples wereclamped against the ZnSe crystal of a Pike MIRacle singlereflection horizontal ATR sampling accessory

25 Raman Spectroscopy Raman spectra were obtained inthe fingerprint region using a Raman Systems model R-3000HR spectrometer operated at a resolution of 5 cmminus1 andusing a laser wavelength of 785 nm The data were acquiredusing front-face scattering from a thick powder bed kept inan aluminum sample holder

3 Results and Discussion

31 Stereochemistry of the Cinchona Alkaloids Examinationof Figure 1 reveals the structural similarity of the cinchonaalkaloids studied in the present work The configurationsof the compounds were once a matter of dispute but adetailed study of the oxirane derivatives served to establishthat all of the naturally occurring cinchona alkaloids are of theerythroconfiguration [34] The members of this series eachcontain a quinoline ring attached through a hydroxymethy-lene group to a quinuclidine ring As illustrated in the figurecinchonine and cinchonidine represent a diastereomeric pairbut the important diastereomeric phenomena related tothese compounds have been correlated with the absoluteconfiguration at carbon-9 [35] A more systematic name forcinchonine is (9S)-cinchonan-9-ol and the more systematicname for cinchonidine is (9R)-cinchonan-9-ol The absoluteconfigurations of all centers of dissymmetry are known [36]

Quinine and quinidine are also a diastereomeric pair anddiffer from cinchonine and cinchonidine by the presence of amethoxy group attached to the quinoline ringThe more sys-tematic name for quinidine is (9S)-61015840-methyoxycinchonan-9-ol while the more systematic name for quinine is (9R)-61015840-methyoxycinchonan-9-ol The absolute configuration ofquinidine has been confirmed from a single-crystal study ofone of its salts with the absolute stereochemistry being deter-mined by the Bijvoet anomalous-dispersion method [37] Asindicated in Figure 1 the dissymmetric centers of cinchonine




Quinidine Quinine

NH OO

O

NHO2N

N

N

H

H

HO

H2C

H3CO

N

N

H

H

HO

H2C

N

N

H

H

HO

H2C

H3CO

N

N

H

H

HO

H2C








5 10 15 20 25 30 35 40


Cinchonine

Cocrystal

Rela

tive i

nten

sity


Figure 2




600 800 1000 1200 1400 1600 1800

Cinchonine

Cocrystal

Rela

tive i

nten

sity

Energy (cmminus1)















250

450

650

850

1050

1250

1450

1650

1850

Cinchonine

Cocrystal

Rela

tive i

nten

sity






Cinchonidine

Cocrystal

Rela

tive i

nten

sity


























Cinchonidine

Cocrystal

Rela

tive i

nten

sity

600 800 1000 1200 1400 1600 1800Energy (cmminus1)





Cinchonidine

CocrystalRe

lativ

e int

ensit

y25

0

450

650

850

1050

1250

1450

1650

1850











Quinine

Cocrystal

Rela

tive i

nten

sity






Quinine

CocrystalRe

lativ

e int

ensit

y

600 800 1000 1200 1400 1600 1800Energy (cmminus1)









Quinine

Cocrystal

Rela

tive i

nten

sity

250

450

650

850

1050

1250

1450

1650

1850






Quinidine

CocrystalRe

lativ

e int

ensit

y



















Quinidine

Cocrystal

Rela

tive i

nten

sity

600 800 1000 1200 1400 1600 1800Energy (cmminus1)





4 Conclusions



Quinidine

Cocrystal

Rela

tive i

nten

sity

250

450

650

850

1050

1250

1450

1650

1850




NH OO

O

NHO2N

216

5 4 3






References






































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of




Quinidine Quinine

NH OO

O

NHO2N

N

N

H

H

HO

H2C

H3CO

N

N

H

H

HO

H2C

N

N

H

H

HO

H2C

H3CO

N

N

H

H

HO

H2C








5 10 15 20 25 30 35 40


Cinchonine

Cocrystal

Rela

tive i

nten

sity


Figure 2




600 800 1000 1200 1400 1600 1800

Cinchonine

Cocrystal

Rela

tive i

nten

sity

Energy (cmminus1)















250

450

650

850

1050

1250

1450

1650

1850

Cinchonine

Cocrystal

Rela

tive i

nten

sity






Cinchonidine

Cocrystal

Rela

tive i

nten

sity


























Cinchonidine

Cocrystal

Rela

tive i

nten

sity

600 800 1000 1200 1400 1600 1800Energy (cmminus1)





Cinchonidine

CocrystalRe

lativ

e int

ensit

y25

0

450

650

850

1050

1250

1450

1650

1850











Quinine

Cocrystal

Rela

tive i

nten

sity






Quinine

CocrystalRe

lativ

e int

ensit

y

600 800 1000 1200 1400 1600 1800Energy (cmminus1)









Quinine

Cocrystal

Rela

tive i

nten

sity

250

450

650

850

1050

1250

1450

1650

1850






Quinidine

CocrystalRe

lativ

e int

ensit

y



















Quinidine

Cocrystal

Rela

tive i

nten

sity

600 800 1000 1200 1400 1600 1800Energy (cmminus1)





4 Conclusions



Quinidine

Cocrystal

Rela

tive i

nten

sity

250

450

650

850

1050

1250

1450

1650

1850




NH OO

O

NHO2N

216

5 4 3






References






































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


5 10 15 20 25 30 35 40


Cinchonine

Cocrystal

Rela

tive i

nten

sity


Figure 2




600 800 1000 1200 1400 1600 1800

Cinchonine

Cocrystal

Rela

tive i

nten

sity

Energy (cmminus1)















250

450

650

850

1050

1250

1450

1650

1850

Cinchonine

Cocrystal

Rela

tive i

nten

sity






Cinchonidine

Cocrystal

Rela

tive i

nten

sity


























Cinchonidine

Cocrystal

Rela

tive i

nten

sity

600 800 1000 1200 1400 1600 1800Energy (cmminus1)





Cinchonidine

CocrystalRe

lativ

e int

ensit

y25

0

450

650

850

1050

1250

1450

1650

1850











Quinine

Cocrystal

Rela

tive i

nten

sity






Quinine

CocrystalRe

lativ

e int

ensit

y

600 800 1000 1200 1400 1600 1800Energy (cmminus1)









Quinine

Cocrystal

Rela

tive i

nten

sity

250

450

650

850

1050

1250

1450

1650

1850






Quinidine

CocrystalRe

lativ

e int

ensit

y



















Quinidine

Cocrystal

Rela

tive i

nten

sity

600 800 1000 1200 1400 1600 1800Energy (cmminus1)





4 Conclusions



Quinidine

Cocrystal

Rela

tive i

nten

sity

250

450

650

850

1050

1250

1450

1650

1850




NH OO

O

NHO2N

216

5 4 3






References






































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of









250

450

650

850

1050

1250

1450

1650

1850

Cinchonine

Cocrystal

Rela

tive i

nten

sity






Cinchonidine

Cocrystal

Rela

tive i

nten

sity


























Cinchonidine

Cocrystal

Rela

tive i

nten

sity

600 800 1000 1200 1400 1600 1800Energy (cmminus1)





Cinchonidine

CocrystalRe

lativ

e int

ensit

y25

0

450

650

850

1050

1250

1450

1650

1850











Quinine

Cocrystal

Rela

tive i

nten

sity






Quinine

CocrystalRe

lativ

e int

ensit

y

600 800 1000 1200 1400 1600 1800Energy (cmminus1)









Quinine

Cocrystal

Rela

tive i

nten

sity

250

450

650

850

1050

1250

1450

1650

1850






Quinidine

CocrystalRe

lativ

e int

ensit

y



















Quinidine

Cocrystal

Rela

tive i

nten

sity

600 800 1000 1200 1400 1600 1800Energy (cmminus1)





4 Conclusions



Quinidine

Cocrystal

Rela

tive i

nten

sity

250

450

650

850

1050

1250

1450

1650

1850




NH OO

O

NHO2N

216

5 4 3






References






































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of





















Cinchonidine

Cocrystal

Rela

tive i

nten

sity

600 800 1000 1200 1400 1600 1800Energy (cmminus1)





Cinchonidine

CocrystalRe

lativ

e int

ensit

y25

0

450

650

850

1050

1250

1450

1650

1850











Quinine

Cocrystal

Rela

tive i

nten

sity






Quinine

CocrystalRe

lativ

e int

ensit

y

600 800 1000 1200 1400 1600 1800Energy (cmminus1)









Quinine

Cocrystal

Rela

tive i

nten

sity

250

450

650

850

1050

1250

1450

1650

1850






Quinidine

CocrystalRe

lativ

e int

ensit

y



















Quinidine

Cocrystal

Rela

tive i

nten

sity

600 800 1000 1200 1400 1600 1800Energy (cmminus1)





4 Conclusions



Quinidine

Cocrystal

Rela

tive i

nten

sity

250

450

650

850

1050

1250

1450

1650

1850




NH OO

O

NHO2N

216

5 4 3






References






































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of





Cinchonidine

Cocrystal

Rela

tive i

nten

sity

600 800 1000 1200 1400 1600 1800Energy (cmminus1)





Cinchonidine

CocrystalRe

lativ

e int

ensit

y25

0

450

650

850

1050

1250

1450

1650

1850











Quinine

Cocrystal

Rela

tive i

nten

sity






Quinine

CocrystalRe

lativ

e int

ensit

y

600 800 1000 1200 1400 1600 1800Energy (cmminus1)









Quinine

Cocrystal

Rela

tive i

nten

sity

250

450

650

850

1050

1250

1450

1650

1850






Quinidine

CocrystalRe

lativ

e int

ensit

y



















Quinidine

Cocrystal

Rela

tive i

nten

sity

600 800 1000 1200 1400 1600 1800Energy (cmminus1)





4 Conclusions



Quinidine

Cocrystal

Rela

tive i

nten

sity

250

450

650

850

1050

1250

1450

1650

1850




NH OO

O

NHO2N

216

5 4 3






References






































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of






Quinine

Cocrystal

Rela

tive i

nten

sity






Quinine

CocrystalRe

lativ

e int

ensit

y

600 800 1000 1200 1400 1600 1800Energy (cmminus1)









Quinine

Cocrystal

Rela

tive i

nten

sity

250

450

650

850

1050

1250

1450

1650

1850






Quinidine

CocrystalRe

lativ

e int

ensit

y



















Quinidine

Cocrystal

Rela

tive i

nten

sity

600 800 1000 1200 1400 1600 1800Energy (cmminus1)





4 Conclusions



Quinidine

Cocrystal

Rela

tive i

nten

sity

250

450

650

850

1050

1250

1450

1650

1850




NH OO

O

NHO2N

216

5 4 3






References






































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of





Quinine

Cocrystal

Rela

tive i

nten

sity

250

450

650

850

1050

1250

1450

1650

1850






Quinidine

CocrystalRe

lativ

e int

ensit

y



















Quinidine

Cocrystal

Rela

tive i

nten

sity

600 800 1000 1200 1400 1600 1800Energy (cmminus1)





4 Conclusions



Quinidine

Cocrystal

Rela

tive i

nten

sity

250

450

650

850

1050

1250

1450

1650

1850




NH OO

O

NHO2N

216

5 4 3






References






































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of













Quinidine

Cocrystal

Rela

tive i

nten

sity

600 800 1000 1200 1400 1600 1800Energy (cmminus1)





4 Conclusions



Quinidine

Cocrystal

Rela

tive i

nten

sity

250

450

650

850

1050

1250

1450

1650

1850




NH OO

O

NHO2N

216

5 4 3






References






































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


Quinidine

Cocrystal

Rela

tive i

nten

sity

250

450

650

850

1050

1250

1450

1650

1850




NH OO

O

NHO2N

216

5 4 3






References






































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of



















































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of















Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of










Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of

Documents

Research Article Vibrational Spectroscopic Study of the …downloads.hindawi.com/journals/jspec/2015/340460.pdf · Research Article Vibrational Spectroscopic Study of the Cocrystal