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by

Prof . Renu Cha dh a

Unive rsity I nstitute o f pharm ace utical scien cesPANJA B UNIVERSITYCHANDI GARH-160014

PHARMACEUTICAL COCRYSTALS & THEIR ROLE IN DRUG

DEVELOPMENT

The drug di scovery proc ess i s a l ong and ex pen sive pathway and rich in fail ure.

It starts from the d isease sele ction and id entific ation of th e co-rela ti ve ge ne/targe t and fi nishe s af te r the clin ical tria ls.

Many o f the fai lures are d ue to po or ph armaco kine tic s (PK) , poor effic acy and hig h to xici ty .

PK prope rties inclu de ab sorption, d istri bution , metab olism, e xcre ti on and tox icity.

During last 20 years, by usin g high-throughp ut (co mbinatorial) te chniques a large numb er of poten tial d rug mole cules have bee n syn th esized in non-aqueous solve nts.

However, abo ut 40% of co mmercially availab le drugs and 80-90% of po te ntial d rug candid ates i n R&D pipeli ne have poor solub ility i n water and hence have poo r b ioavailabi lity.

In such scenario, crystal engine ering has proved as a b oon as it produce s vast d iversity o f solid forms of d rug substances with proper balan ce of desirab le properties furnishin g i t into a viable and effective d rug product.

In order to customize physicochemicalpropert ies of solid mater ials modern sol idstate chemistry mainly focus on preparation,ident ificat ion and characterizat ion ofdifferent crystal forms namely polymorphs,solvates, salts,cocrystals etc.

POLYMORPHSPoly morph ism is ch aracteri zed b y the ab ility of a sub stance to e xist in two or mo re cry sta lline ph ases that have d iffere nt arra ngem ents a nd / or con formation s of the mole cule s in the crystal lattice.

Poly morph s h ave si gnifica ntly di ffere nt ph armace utically re levant prope rties. The refore , d iscovery and ch aracteriz ation of polym orphs con stitute a n esse ntial part of ph armac eutical rese arch and de velopm ent.

In rece nt time s, the stud y o f pol ymorph ism ha s assum ed great importan ce be cause of legal and reg ulatory issues in th e p harma ceutica l i ndustry.

The mos t cri ti cal step in ph armac eutica l d evelo pme nt isid entifi cation of d esirab le soli d form of ac ti veph armace utica l ing red ient (A PI) from ind ustrial prod ucti on,mark eting , cli nical , le gal and reg ulatory pe rspecti ve as itreq uires tho rough inf ormati on ab out ex act na tu re ofmate rial in proc ess, stab ility with time , variab il ity ofch emica l and ph ysica l pro pertie s as fun ction of cry stal for metc .In 1998 , Ab bott ha d to stop prod ucti on of its HI V pro teaseinh ibi tor, riton avir (N orvir) , b ecause its man ufac tu ringproc ess was pro duci ng the wrong cry stallin e form of thecom pound .The ne w poly morp hic struc ture of Nor vir, one whi ch ha d no tb een use d in ea rly testing of the d rug, aff ected ho w thesem isolid ca psule d issolved .Pa tients were off ered the d rugin liqu id for m un til the com pany cou ld ref ormula te theprod uct to eli minate the wrong structure.

H yd rogen bonding networ k f or rit onavir f orm I (H yd rogen bonding networ k f or rit onavir f orm I ( like st acks)like st acks)andand for m II ( needle growt h is aligned with hydr ogen bonding)

Form II is less soluble in co mparis ion to Form I

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Projections of aspirinform I (left) and METASTABLE form II (right) Form I of aspirin is commercially availab le.The structures appear identical in projection; the key difference is in th e relative position of th e two layers sh own, and the symmetry elements between them. Th e unit cell for form I is drawn with an acute

angle ( 85°) for direct comparison with the form II unit cell .

The crystal structures of para cetamo l in (a ) f orm I (tricl inic) and (b ) form I I (orthorh omb ic) .Form I I is more solub le and less stable and is comm ercia lly avail able .

Pyra zinami de poly morph ic formsPyra zinami de poly morph ic forms

SOLVATESMany p harma ceutica l molec ules incorpo rate stoich iome tric or non-stoich iome tric am ounts of solve nt or water an d a re k nown a s solvates or hy drates respe ctively.

The y are often terme d SOLVATOMORPHS/ PSEUDOPO LYMO RPH S an d th eir physi co-ch emica l prop erties dif fer f rom th ose of o th er polym orphs an d of th e a morph ous form.

Solvate s are of m uch practic al i mportance as the ir prop erties vary wid ely and h ave d iffe rent rates o f uptak e in the b ody lead ing to lo we r or high er b iologic al a ctivity th an de sired . The (a) m ethyl ace tate, (b) DMSO, (c ) 1,4The (a) m ethyl ace tate, (b) DMSO, (c ) 1,4 --d ioxa ne, d ioxa ne,

(d ) DMF , and (e ) an iline solva te s o f (d ) DMF , and (e ) an iline solva te s o f hy droch lorthia zidehy droch lorthia zide

A h exa gonal network fo rmed b y the sulph ame razine (SMZ) A h exa gonal network fo rmed b y the sulph ame razine (SMZ) mol ecule s in the crystal structure of SMZmol ecule s in the crystal structure of SMZ––d ioxa ne ( 1 : 1)d ioxa ne ( 1 : 1)

Vario us Hy dra tes of para cetamol

Amorphous solids consist of disorderedarrangements of molecules and do not possess adistinguishable crystal lattice.

The se are me ta sta ble , h ighe r-en ergy form s tha n the ir crystal line cou nterparts and ten d to rele ase the ir en ergy th rough crystalliza tion.

The y are hygro scopic an d a bsorb mo isture which ac ts as a plasticiz er and prom otes mole cular mob ility, whic h le ads to cry sta llizatio n. Thus hum idity and aqu eous environ ments furth er re duc e the stab ility of amo rphou s solid s.

AMORPHOUS SOLIDS CocrystalsCocrystals, ha ve b een kn own for more than 160 ye ars.

Cocrystal s are crys ta lline mol ecula r co mple xe s tha trely upo n hy drog en-b onde d asse mbli es b etwee nne utral mo lecul es of an ac ti ve ph armac eutica lingre die nt (API) and oth er com pone nts with wel ld efine d stoich iome tr ies

Ph armace utica l coc rystals ha ve gai ned prom inen ce in aflurry of rec ent rese arch rep orts as a me ans ofmod ifyi ng the ph ysicoc hem ical pro pertie s of API switho ut com prom ising the struc tu ral inte grity of APIand thus, possib ly the b ioactivity.

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• The imp act of crys ta l po lymorp hism and solva tion state onph armace utica l pro duct valu e ha s b een illu strated b y costlyprod uct fa ilures and pro tracted pa te nt litig ation ex amp les.Howe ver, d ue to hi gh d egree of sere ndi pity, the con trol andrep roduc ibi lity of the po lymorp hic/ solvatom orph ic form s ha veb een d ifficul t to attain.

• In ad dition , the poly morp hs of ce rta in API s und ergod egrad ation b y sol id-state ph otoch emi cal rea ction whi chd epen ds upo n crystal pac king and arran geme nt of mol ecule s.

• Howe ver, coc rystalli zation inh ib its ph otod egrad atio n b yalter ing the mol ecul ar arran geme nts in the solid state as wasob served in case of carb ama zepin e.

• Also, un like poly morp hs, coc rystals d o no t ha ve same ch emica lcom positi on, thu s introd uc ing gre ater ch ange s in ma te rialprop erties than with poly morph s.

• Furthermore, the solubi lity and dissolution advantagesoffered by metastable polymorph s is often insignificant and isassociated with the risk of phase transformation during thelife cycle of prod uct.

•Co -crystals offer th e advantage th at API regardless of acidic,basic or ionizab le groups could potentially be co-crystallized . Thisaspect helps complement existing methods by reintroduci ngmolecules th at had limited pharmaceutical profiles based on th ei rnon-ionizable functional groups.

• Thus, pharmaceutical cocrystals provide an alternative tochemi cal modification of drug substance, as well asestablish ed salts, amorphous, solvate and polymorph ic forms,all of which have limitations in their utility.

•APIs wh ich are obtained only in the amorphous form may be crystallized as co-crystals.

• As com pared to oth er cla sses of soli d form s, co crystalsare en dowe d with par ticular scie ntific an d reg ulatoryad vantage s whe n me asure d aga inst the cri te ria ofnove lty, utility, and non -ob viousne ss.

• The d evelo pmen t of ne w coc rystal form s pro videfe rti le gro und for the cre ation of ne w pa te nts andinte llec tu al pro perty and thu s, off er a d istinctcom merci al ad vantage with resp ect to mark et

Coformers

The re are a la rge n umb er o f pote ntial ‘cou nter mol ecule s’ classi fied as GRAS (Gene rally Re gard ed As Safe ) tha t can b e use d in form ation of c o-crystals. The se inc lude vario us f ood ad ditives, pre servative s, ph armace utical ex cipie nts, vitamins, min erals, ami no acid s and oth er bio -mol ecule s, as well as o th er APIs.

Examples of cof ormers

Design of Co-Crystals

In ord er to ge t a d esirab le coc rystal pro duc t of an API ,the first step is to stud y the struc tu re of the targe t APImol ecule and fin d ou t the fu nction al grou ps whi ch can forminterm olec ular intera ction with suitab le cof ormers.A d etailed und erstan din g of the supra mole cular ch emis tryof the fun ctiona l gro ups in API s, whic h may form rob ustsupra mole cular syn thons suc h as ac id ...ac id, ac id...py ridin e,acid ...ami de, ami de...am ide , am ide ...pyr idin e N -ox ide , O-H...O, O-H... N, N -H ...O and N -H ...N is a pre requi site ford esign ing a coc rystal b ecause it fac ilitate s se lection ofapp ropriate con forme rsA goo d cof ormer sho uld b e ab le to form he terom ericinte rmole cular inte raction s with the targe t mol ecul e tha tare more favo urab le than the ho mome ric inte raction s tha tmay ex ist.

Typical hydrogen bonds utilised in cocrystal designing.

Preparation of Co-crystals

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InSolution cocrystal lizationmethod,either a solvent or solvent mixture with similarsolubili ties for both the components are selectedand stoichiometric amounts of the reactants areused (slow evaporat ive method)

ORa solvent with different solubil ities for both thecomponents is selected and non-stoichiometricamounts of the reactants are used (reactioncrystallization method) .

Solvent drop gr inding methods (Green chemistryapproach) involves cogrinding the components instoichiometric ratio under ambient conditions, withaddition of small amounts of suitable solvent toaccelerate thecocrystal lization.

Twin-screw extrusion is another mechanochemicalmethod in which two parallel screws are rotated inthe same or opposing directions facili tating themixing and movement of mater ial. It is acontinuous and scalable process making it ideal forindustrial purposes.Hot melt extrusion for cocrystal formation is athermal microscopic method which allows the meltprofile of a two-component system to be mappedand ascertain if a molecular complex or cocrystalphase is present versus systems with simpleeutecticprofiles .Ultrasound assisted slurry crystall izat ion havealso been used in screening and preparation ofcocrystals.

Preparation ofcocrystal by solvent free twin screwextrusion.

Characterization of Co-crystals The DSC records an accurate value ofcocrystal melting onset temperature whi leTGA determines the onset temperature ofcocrystal decomposition and loss of a volati lecomponent by recording sample mass lossdur ing heat ing. Quantitation of the mass lossin the case of volati le coformersconfirms thestoichiometry.

DS C endot her ms of Agomela tinec oc r ys ta l ( 2) wit h g lyc o lic a cid. Thes ing le endotherm a t a tem per a tur ediff erent fr om the m elt ing poin ts of thepur e c om ponent s is indic at ive of ahom ogeneous c oc r ys ta l pha s e

Powd er x-ray d iffrac to metry (P XRD ) give s a un ique‘fing erpr int’ d iffrac ti on pa tte rn ch aracter istic of apar tic ular sol id form and d oes no t req uire the growth ofhig h-qua lity sing le crys ta ls to ob tain the d ata. Infavo urabl e circu mstanc es, struc ture solu tion foll owed b yRietveld t ref ineme nt me thod s ca n give the ful l 3D crys ta lstructure from powd er d ata.

PXRD traces of pure starting components (Nevirapine andGlutaric acid)and th eircocrystal product (NVGLT) obtai ned byth e liquidassi sted grinding method.

FT-IR spectroscopy help in determining th e nature of interactionsinvolved in formation of supramolecular synthons th at differentiatebetween cocrystals and salts, especi ally whena carboxylic acid is usedas a coformer.Broad stretch es near 2450 and 1950 cm-1 are characteristics ofneutral intermolecular O-H.....N hydrogen bonds th at can only comeabout ifth e two reagents formheteromericsupramolecular synthons

FT-IR spectra ofcocrystal ofoxcarbazepine withsuccinic acid (OXCBZ-SUC) .The shifting of IRbands of both th e drugand coformer uponcocrystallization can beclearly seen.

SCX RD prov ide s com ple te struc tural pro of of co crystals .It prov ide s a cle ar d istincti on b etween salts andcoc rystals b ased on C-O d istance s, since a carb ox ylanio n po ssesses two sim ilar C -O valu es, whe reas a ne utralcarb ox yl gro up po sseses two d istincti vely d iffere nt C -Ovalue s; com plex es with C -O < 0 .03 are salts, whi lecom plex es with C-O > 0.08 are coc rystals.

Thre e-d imensi onal pac king diag ram of 1:1 coc rystal of Fl uconaz ole with glutaric acid a s d etermin ed by SCXRD

Solid -state nuc lear mag netic reso nance (ss NMR) ha sgre at po te ntial in ch aracte rizatio n of coc rystalsb ecause of its ab ility to sele ctive ly d etect hy drog enb ondi ng whi ch play s a criti cal role in the ir form ation .In this tec hniq ue, NMR sh ifts for hy droge n b ondi ngpro to ns are hig hly d eshie lde d, cove ring a ne arly 10ppm rang e.

Solid-state 13C NMRspectra of niclosamidecocrystals withnicotinamide andisonicotinamide (NCL NCTand NCL INA) . Thechange in carbonyl peakshiftindicates a newsolidphase.

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Stabi li ty StudiesThe stabi lity of different co-crystals is

determined under various stress condit ions likehydrolysis, oxidat ion, photodecompositionaccording to ICH guidelines for stress test ing.

Evaluation of Co-crystalsThe final step in the study of cocrystals include

studies (solubil ity, intr insic dissolution anddissolut ion tests)

The cocrystals showing improved solubil ity/dissolut ion are further subjected tobioavai labili ty/ pharmacokinet ic studies in orderto measure the rate and extent of the activedrugthat reaches the systemic circulation.

ExamplesN

H

H 2N O

O

HC 1

C2

C 3

C 4N 5

C 6

C 7

C 8

C 9C 1 0

C 11

C 1 4

C 1 5

C 1 2

C 1 3

C 1 6

N1 8O 1 7

Cocrystals and s olvate of Oxcarbazep ine

Ox carb azep ine (OXCBZ) isantic onvulsa nt d rug use d in thetreatme nt of ep ilepsy .

Carbo xamide mo iety, the prin cipa l fun ctiona l un it inOXCBZ, is expec ted to form mul tipoin t N-hy drog en bond inte ractio n with th e co -cry stal fo rmersha ving com plem entary fun ctiona l grou ps.

Thi s mot ivated to explo re the pote ntia l of OXCBZ toco-cry stalli ze with an aim to e nhan ce its solu bil ity an dd issolution prof ile an d in turn its ora l ab sorptio n.

The multicomponent compounds of OXCBZ have been identified with only three coformers:solvated co-crystal of OXCBZ with succinic acid SUC (OXCBZ-SUC) and its desolvated co-crystal form (OXCBZ-SUC(desolv)), co-crystal with saccharin SAC (OXCBZ-SAC) andsolvate with acetic acid AA (OXCBZ-AA).

Methods of preparationOXCBZ-SUC an d OXCBZ-AA were pre pare d bysoluti on me thodOXCBZ-SUC(desol v) was pre pare d by desolva tion ofcom poun d OXCBZ-SUC by ke epin g it at a co nstanttem pera ture of 150 C for 3 ho ursOXCBZ-SAC was pre pare d by fa st eva pora tionme thod

CharacterizationThe mu lticom pone nt form s were ch aracte rize d insoli d state by DSC, TGA, HSM, opt ical mi crosco py,PXRD, FTI R a nd SS-NMR. Comple te structu redeterm inatio n fo r OX CBZ-SUC was pe rforme d bySCX RD .

Optical micrographs of OXCBZ and its multicomponent forms

OXCBZ, cof ormersand the irmuti comp onen tform s.DSCthe rmogram s of

Differential Scanning calorimetry

TGA curves of (a) OXCBZ-SUC and (b) OXCBZ-AA.

Thermogravimetric Analysis Hot stage microscopy

Hot stag e mi croscop y mi crogra phs of OXCBZ-SUCexhib iting the va rious eve nts oc curing as thetem pera ture incre ase d from 24 to 240 C.

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XRPD pa tternsof OXCBZ an ditsmul ticomp one ntform s.

X-Ray Powder Dif frac tion 13C Solid state NMR SpectroscopyIn 13C SS -NMR s pec tr umof OXCBZ-SA C, m ains pec tr al per t ur bat ionsappear in the amidecar bonof both OXCBZ andSA C, and in C22 which isadjacent to the –SO 2

group of SAC. Theses hif ts indic ate that theamide group of OX CBZ ism os t likely in terac tingwit h both the amidecar bonyl as well as –SO 2

of SA Cin OXCBZ-SA C.The 13C r es onanceschar act er is tics of AAm olecule (C23 and C24)can be s een c learly ins pec tr um of OXCBZ-AA .

13 C CP/MAS s sNMR s pect ra of OXCBZ, SAC, OX CBZ-SA C and OXCBZ-AA .

ORTEP vie w of anasym metric un it ofOXCBZ-SUC withatom ic num be ringsch eme .

Crystal Structure Analysis• OXCBZ-SUC was ob taine d fromthe solu tion as cry stals ofsuitab le size , whe reas, OXCBZ-SAC and OXCBZ-AA cou ld onlyb e ob taine d as fin e cry stallinepowd ers.• Thus, the sing le crysta l x-raycrys ta llogra phy ha s b eenpe rforme d only on OXCBZ-SUC.• OXCBZ-SUC crys ta llize s in amon oclin ic spa ce grou p withthe sing le uni t ce ll con sisting ofeig ht mo lecul es of OXCBZ, fou rmol ecule s of SUC and fou rmol ecule s of ch loroform

The layered structure of OXCBZ-SUC in wh ich OXCBZ molecules areconnected to SUC molecule by O- and N- hydrogenbonds. Interaction between CHCl3 molecule hydrogen and keto oxygenof OXCBZmolecule of adjacent layersare also observed.

(a )Pa cking in spa ce fil ling mo de alo ng th ecry stallog raph ic c-ax is sh owing CHCl3 mol ecule sfitte d in void s betwee n lay ers (gree n = OX CBZ,b lue = SUC, red = CHCl3).

(b )Spac e fil ling mode re presen ting the void in whi chCHCl3 mol ecule fits in.

Powder Diss olution Studies

Dissolution profiles for pure commercial sample of OXCBZ incomparison with OXCBZ-SUC(desolv), OXCBZ-SAC and OXCBZ-AAin 0.1NHCl at 37 C.

This stud y sh owedtha t the co-crys ta lliza tion ofOXCBZ with SACimp roved its max imu msolub il ity b y ~ 3 .5fold s.

Both OXCBZ-AA andOXCBZ-SUC(d esolv)reve rted b ack to thefre e b ase form ofOXCBZ upo n slurry ingin aqu eous me dium

Paramete r Value

SOXCBZ (M ) 5.0 7× 10-4± (6 .05 × 10 -6)

SSAC (M ) 14 1.3 9 × 10 -4± (1 63 .77 × 10 -6)

Ksp (M 2) 5.8 7 × 10 -6 ± (0 .42 × 10-7)

K11 (M -1) 22 .64 ± 2.3 6°

(kJ .mol -1) -0.5 8 ± 0.0 1

The solub il ity va lues of rea ctants an d sp, 11 an dfor co-cry stal OXCBZ-SAC ha s al so been determ inedin 0.1N HCl at 37 C.

Dose-Response studies in mice

Dose-dependent effect of OXCBZ-SACwas determined by performing MES test inmice. Equivalent amounts of both OXCBZand co-crystal OXCBZ-SAC were givenorally to sufficient numb er of animals invarious dosesand th e abolition of hind limbextension was observed.Th e ED50 value for OXCBZ-SAC followingoral administration was found to be lower(9.02 mg/kg)as compared to pure OXCBZ(15.67 mg/kg). This lowering of th e doseprovides an evidence th at co-crystal basedenhanced solubility of th e drug resulted initsbetter oral absorptionin mice.

Dos e-r es pons e graph forco-crys tal O XCBZ-SAC incom par ison wit h pur ecom mer cial s am ple ofOXCBZ in m ice.

Renu Chadha, Anupam Saini, D haramv ir Singh Jain and Palot h Venugopalan. Preparation and Solid -Stat e Char ac terizat ion of Three N ov el Multic omponent So lid Forms of O xcar bazepine: Impr ov em ent in So lubility t hr ough Saccharin Cocr ys tal. Cryst al Growth and Des ign . (8), 4211–4224, 2012.

• Lamotrig ine is an ticon vulsan t d rug use d in th etrea tmen t of ep ilepsy an d b ipolar d isorde rs.

• The lam otrig ine (L TG) framewor k is co mprise d up offou r ac idic am ino hy drog en bond donors a long with twobasic hy drog en bond ac cepto rs i .e . am ino -py ridin enitro gen ato ms giv ing rise to a va riety of hy dro genbondi ng d onor/ ac cepto r site s fo r an ap proac hin gcof ormer to b ind , thu s ma king it a pote ntia l targ et forboth co-cry stal an d salt form ation .

Cocrystals/ salts of Lamotrigine

Lamotrigine

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The multicomponent forms of Lamotr igine (LTG)have been prepared with:nicotinamide NCT (LTG-NCT), acetamide ACT (LTG-ACT), sacchar in SAC (LTG-SAC), 4-hydroxy-benzoic acid 4-HBA (LTG-HBA), acetic acid AA (LTG-AA-1) and (LTG-AA-2), propionic acid PA (LTG-PA), glutar ic acid GA (LTG-GA) and 1,4-dioxane (LTG-Dioxane) Most of these coformers have been selectedbased upon their pKa value with an intent ion toobtain intermolecular hydrogen bonded complexeswith LTG.

Methods of preparationLTG-nico ti namid e mono hyd rate (L TG -NCT): Solution m ethod with rapi d evapora ti onLTG-Ace ta mid e (LTG-ACT) : Reaction crystall ization m ethodLTG-Sacch arin (L TG -SAC), LTG-4-hy drox y be nzoic acid (LTG-HBA) , L TG-ace tic a cid (L TG -AA-1, LTG-AA-2), LTG-prop ionic aci d (LTG-PA) , L TG-glutari c acid (LTG-GA) and LTG-1,4-d ioxa ne (L TG-d ioxa ne) : Solution m ethod with slow evapo ration

Optical micrographs of LTG and its multicomponent forms

DSC the rmogra ms ofLTG fre e b ase andits mu ti comp onen tform s.

Differential Scanning calorimetry

TGA curves of compounds LTG-NCT, LTG-ACT, acetamide, LTG-AA-1, LTG-AA-2, LTG-PA, LTG-GA and LTG-dioxan.

Thermogravimetric Analysis

Hot stage microscopy

Hot sta ge microsco py mic rograph s of (A) Cocrystal LTG-ACT and (B) Salt so lvate LTG-AA-1 .

XRPD pa tternsof LTG fre ebase an d itsmul ticomp one ntform s.

X-Ray Powder Dif frac tion

Scheme re prese nting all the fou r h yd rogen bond ing m otifs.

Crystal Structure Analysis• The crystal structure ofLTG is built fromhydrogenbonded dimeri c uni ts of th edrug molecule showing twodominant supramolecularsynthon motifs,aminopyridine dimerhomosynthon (moti f1)

amine -aromati c nitrogensynthon (moti f2) .

•Th e LTG dimerhomosynth on is conservedin all th e complexes exceptin LTG-SAC .

Pa cking d iag ram of 2 (sh owing hyd roge n bo ndin g and C l…Cl inte ractio n).

LTG-ACT (1:1) cocrystal

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Basic sup ramo lecu lar un it sh owing 4-HBA d imer an d LTGd imer with vario us wea k inte raction s

LTG-HBA (1:1) salt

LTG d imers sa ndwic hed be tween a cetic a cid l aye rs

LTG-AA-1 (1:3) salt solvate LTG-AA-2 (1:1) salt

The p ackin g d iagram of sa lt L TG-AA-2 showing the form ation o f a ladde r type n etwork.

LTG-PA (1:1) salt

(a )The octameric unit of LTG-PA con necte d thro ughN-H…O hy drog en bonds .

(b ) The arra ngem ent of mol ecule s aro und 41 scre w ax isin LTG-PA.

LTG-GA (1:1 ) salt isobutanolate monohydrate

An inte rwoven thre e d imensi onal ne two rk of LTG-GA.(L TG ca tions invo lved in d imer-GA -d imer sh eets- b lue,LTG ca tions invo lved in LTG-GA-LTG corru gate d she ets-gre en, GA d ianio ns- red , isobuta nol mol ecul es- pin k,wate r mol ecule s- ye llow).

LTG-dioxane (1:1) solvate

The ad jacen t co rrugate d lay ers pre sent in an inve rtedpos ition to ea ch oth er, form ing void s in whi ch d ioxanemol ecule s are pre sent in LTG-Dioxane .(L TG mo lecul es- b lue an d gre en, 1,4-d ioxanemol ecule s- ye llow an d red ).

Compar isonCompar ison ofof thethe ex per imen tallyex per imen tally d eterm inedd eterm ineden th alpyen th alpy ofof solu tionsolu tion ofof mul ticomp one ntmul ticomp one nt form sform s withwiththe irthe ir calc ulate dcalc ulate d mol armol ar en thalp yen thalp y ofof solu tionsolu tion sh owsh ow tha ttha tthe sethe se form sform s b ehaveb ehave moremore en dothe rmic allyen dothe rmic ally whe nwhe ncom paredcom pared toto thethe calc ulatedcalc ulated value svalue s..

TheThe d rivingd riving fo rcefo rce forfor thethe form ationform ation ofof the sethe semul ticomp one ntsmul ticomp one nts isis pre sumab lypre sumab ly thethe introd uc tionintrod uc tion ofofad ditio nalad ditio nal stab iliz ationstab iliz ation b yb y hy droge nhy droge n b ondi ngb ondi ng andand alsoalsoofof Coulomb icCoulomb ic intera ctionsintera ctions inin thethe saltssalts..

TheThe b reaki ngb reaki ng ofof the sethe se hy drog enhy drog en b onds ,b onds , whic hwhic h isis ananen dothe rmicen dothe rmic proc essproc ess isis res ponsib leres ponsib le fo rfo r the irthe ir h ighe rh ighe ren dothe rmicen dothe rmic en thal pyen thal py ofof solu tionsolu tion tha ntha n thethe ca lculate dca lculate dvalue svalue s..

Th er mody namic cy cle represen tin g en th alpies of solu ti on .

Molar enthalpy of solution of LTG free base, coformers and th eirmulticomponent forms in phosph ate buffer pH 7.0at37 °C and th e valuesof rH.

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•A significant increase (almost50 ti mes) in th e solubility of LTG hasbeen observedin case of compound LTG-AA-1.

•Th e pH of each sample solution has been found to decrease in eachcase exceptLTG-ACTin contrastwith LTGfreebase.

Equil ibr ium solubil ity Studies in water

Solubility andpotentialconversion ofmulticomponentforms insolubilitystudiesperformed inwater at 25

C.

Powder dissolution studies of LTG free base and its multicomponentformsat various time pointsin 0.1N HCl at 37 C.

•

Powder Dissolut ion Studies in Acidic Medium•Except for LTG-NCT,LTG-ACT and LTG-AA-1,th e concentration ofdrug ach ieved in all oth ercompounds after 6 hrsof dissolution study wasfound to be lower th anth at of free base LTGsample.•Th e FT-IR analysis ofsolid resid ues remainingafter th e experimentshowed th at all th esamples converted toLTG hydroch loride saltinth e HClmedium.

Crystal Packing-Solubility Relationship

• Break ing of mo ti f 1 incre ased the con centra tion in water,while b reaki ng of mo tif 2 b ut re te ntion of mo ti f 1resu lted in imp roved con centra tions of LTG in ac idicme dium .• The mul ticomp one nt form s LTG-NCT and LTG-AA-1retai ned moti f 1 b ut sho we d b reaki ng of mo ti f 2 andex hib ited a h ighe r solub il ity tha n pure LTG in ac idicme dium .• Compou nd LTG-ACT sh owed b reaki ng of motif 2 b utcon tained mo tif 3 inste ad of 1 and ex hi bite d solu bil ityalm ost com parab le to pure LTG in acid ic me dium .• In LTG-SAC, LTG -HBA, LTG-AA-2, LTG -PA, LTG -GAand LTG-Dioxane , mo tif 1 is b roken whic h acc ounts forthe ir hig her solub ility in water than the fre e b ase LTG.

•ED50 values determined in micefollowing oral administrationshowed compounds LTG-NCT,LTG-SAC and LTG-AA-1 to beeffective evenat a lower dose of2.5 mg/kg wh ile LTG-HBA andLTG-PA achieved simi lar potencyat a dose of 5.0 mg/kg ascompared to LTG-ACT and LTGfree base wh ich abolished th eHLEonly at a dose of 7.5mg/kgandabove. ED50 values (mg/kg) of LTG in pure commercial

sample and itsmulticomponent forms.Multicomponent Solids of Lamotr ig ine with some selec ted coformers and their

charact erizat ion by thermoanalytical, spectr os cop ic and X-ray dif fr act ionmethods. Cryst al Eng ineer ing & Comm un icat ions , 2011, 13, 6271 -84

Renu Chadha, Anupam Sain i, Sadhika Khu llar, Dhar amv ir Singh Jain , SanjayMandal, and T N Gur u Row. Crystal Str uct ur es and physic ochemical Pr oper tiesof Four New Lamotrig ine Multicomponent Forms. Crystal Growth and Design .3 (2), 858-870, 2013.