Review Article www.ijcps.com 15 International Journal of Chemical and Pharmaceutical Sciences 2012, Mar., Vol. 3 (1) Crystal engineering technique – An emerging approach to modify physicochemical properties of active pharmaceutical ingredient Sevukarajan M*, Thamizhvanan K, Sodanapalli Riyaz, Sateesh Babu JM, Naveen Kumar B, Sreekanth Reddy B, Sethu Krishna J, Vivekananda U. Sarada K, Hyndavi N, Hima Bindu R and Roopa Lahari K Department of Pharmaceutics, Sree Vidyanikethan College of Pharmacy, A. Rangampet, Tirupathi. India * Corresponding Author: E-Mail: [email protected]ABSTRACT The rising frequency of drugs which having poor solubility, manufacturability and stability in development offers notable risk of new drug products which having low and variable bioavailability particularly for those drugs administrated by the oral route, with consequences for safety and efficacy. Although, number of strategies exists for enhancing the bioavailability of those drugs, these strategies are greatly dependent on the physical and chemical nature of the molecules being developed. Crystal engineering approach presents a number of routes such as co-crystallization, polymorphism and salt formation to improve physico-chemical properties of drugs, which can be implemented through an in detail knowledge of crystallization processes and the molecular properties of drugs. Various polymorphs usually have different physico-chemical, mechanical and thermal properties that can extremely affect the bioavailability, stability and other characteristics of the active pharmaceutical ingredients. This article covers the concept of crystal engineering approach and discusses the potential advantages, disadvantages and methods of preparation of co-crystals, recent advances in the invention and control of the polymorphs of drug molecules, in terms of the development of the selective nucleation of a particular polymorph. Keywords: Crystal Engineering, Supramolecular Chemistry, Polymorphism and Co-crystals. 1. INTRODUCTION The international pharmaceutical market has extended at an average annual growth rate of 8 percent since 2001 (Figure no 1), with an expected $ 837 billion in sales in 2010). Especially, over the decades, the extent of the pharmaceutical market at a rate of 17 percent in China has developed [1] . During the development of the pharmaceutical industry, crystallization has been engaged more and more extensively for the purification, separation particle formation and co- crystallization of pharmaceutical materials [2]. It is estimated that more than 70% of all solid drugs are produced by crystallization. With regards to this, an understanding of the effect of the crystallization process on the final solid state of a drug is vital for several of the activities of the pharmaceutical industry [3] . Figure No 1: Annual sales amount of pharmaceuticals worldwide since 2001 Crystal form can be critical to the performance of a pharmaceutical dosage form. This is particularly for compounds that have intrinsic barriers such as low aqueous solubility, low dissolution rate in gastrointestinal media, low permeability and first- pass metabolism to drug delivery to site of action. For water insoluble compounds, the nature of its physical form and formulation tends to demonstrate the utmost effect on its bioavailability profile that needs to be administrated orally in high doses [4] . Active pharmaceutical ingredients (APIs) are frequently delivered in the solid-state as part of an approved dosage form (such as tablets, capsules, etc.) to the patient for treatment. Solid state of API or a drug product provides a suitable, convenient, compact and more stable format to store for long period. Studying and controlling the physico-chemical properties of APIs in solid state, both as pure drug and in formulated products, is therefore an important aspect of the drug development process. APIs can be present in a variety of distinct solid crystal forms, including polymorphs, solvates, hydrates, salts and co- crystals showed in figure 2 [5] . Each solid state form of API displays unique physicochemical properties that can profoundly influence the bioavailability, solubility, chemical and physical ISSN: 0976-9390 IJCPS
ABSTRACTThe rising frequency ofdrugswhichhavingpoor solubility,manufacturabilityand stability in
development offers notable risk of new drug productswhich having low and variable bioavailabilityparticularly for thosedrugsadministratedby theoralroute,withconsequences forsafetyandefficacy.Although,numberofstrategiesexistsforenhancingthebioavailabilityofthosedrugs,thesestrategiesaregreatly dependent on the physical and chemical nature of the molecules being developed. Crystalengineering approach presents a number of routes such as co-crystallization, polymorphism and saltformation to improvephysico-chemicalproperties ofdrugs,which canbe implemented through an indetailknowledgeofcrystallizationprocessesandthemolecularpropertiesofdrugs.Variouspolymorphsusuallyhavedifferentphysico-chemical,mechanicalandthermalpropertiesthatcanextremelyaffectthebioavailability, stabilityand other characteristics of the activepharmaceutical ingredients.Thisarticlecoverstheconceptofcrystalengineeringapproachanddiscussesthepotentialadvantages,disadvantagesand methods of preparation of co-crystals, recent advances in the invention and control of thepolymorphsofdrugmolecules, in termsof thedevelopmentof the selectivenucleationof aparticularpolymorph.Keywords:CrystalEngineering,SupramolecularChemistry,PolymorphismandCo-crystals.
1.INTRODUCTION The internationalpharmaceuticalmarkethasextendedatanaverageannualgrowthrateof8 percent since 2001 (Figure no 1), with anexpected$837billioninsalesin2010).Especially,overthedecades,theextentofthepharmaceuticalmarket at a rate of 17 percent in China hasdeveloped [1]. During the development of thepharmaceutical industry, crystallizationhasbeenengaged more and more extensively for thepurification,separationparticleformationandco-crystallizationofpharmaceuticalmaterials[2]. It isestimated thatmore than70% ofall soliddrugsare produced by crystallization.With regards tothis, an understanding of the effect of thecrystallizationprocessonthefinalsolidstateofadrug is vital for several of the activities of thepharmaceuticalindustry[3].Figure No 1: Annual sales amount ofpharmaceuticalsworldwidesince2001
Crystalformcanbecriticaltotheperformanceofapharmaceuticaldosageform.Thisisparticularlyforcompoundsthathaveintrinsicbarrierssuchaslow aqueous solubility, low dissolution rate ingastrointestinalmedia,lowpermeabilityandfirst-passmetabolismtodrugdeliverytositeofaction.Forwater insolublecompounds, thenatureof itsphysical form and formulation tends todemonstrate the utmost effect on itsbioavailability profile that needs to beadministratedorallyinhighdoses[4].
Activepharmaceutical ingredients (APIs)are frequentlydelivered in thesolid-stateaspartof an approved dosage form (such as tablets,capsules, etc.) to thepatient for treatment. SolidstateofAPIoradrugproductprovidesasuitable,convenient, compact and more stable format tostoreforlongperiod.Studyingandcontrollingthephysico-chemicalpropertiesofAPIsinsolidstate,bothaspuredrugand in formulatedproducts, istherefore an important aspect of the drugdevelopment process. APIs can be present in avariety of distinct solid crystal forms, includingpolymorphs, solvates, hydrates, salts and co-crystals showed in figure 2 [5] . Each solid stateform of API displays unique physicochemicalproperties that can profoundly influence thebioavailability, solubility, chemical and physical
Over the decade, Advances in crystalengineering and supramolecular chemistryreported from Indiahighlighted thecategoriesofnew intermolecular interactions, designedsupramolecular architectures, multi-componenthost–guest systems, cocrystals, networkstructures,andpolymorphs.
Thisarticledescribescrystalengineering,supramolecular chemistry, co-crystals,polymorphs;mechanismofformation,methodsofpreparation and application of co-crystals andpolymorphs to alter physicochemicalcharacteristicsofAPIsalongwiththecasestudies.The intellectual property suggestions of creatingco-crystalsby crystalengineeringarealsohighlyrelevant.2.Supramolecularchemistry
Supramolecular chemistry is animportant, interdisciplinary branch of scienceencompassing ideas of physical and biologicalprocesses, defined as ‘chemistry beyond themolecule’, i.e. the chemistry of molecularaggregates assembled via non-covalentinteractions [7,8].The term ‘synthon’was initiallyestablishedtoexplainsyntheticorganicstructuralfeatures. The term ‘supramolecular synthon’establishedbyDesiraju[9]isdefinedas:‘structuralunitswithinsupermoleculeswhichcanbeformedand/or assembled by known conceivablesynthetic operations involving intermolecularinteraction’.
In biological processes, supramolecularchemistry is nothing but non-covalentmolecularbinding recognized by Paul Ehlrich and EmilFischer’s lock-and-key principle through conceptof complementarity and selectivity. Anelectropositive hydrogen bond donor movetowardsanelectronegativeacceptor,cation…anionelectrostatic interaction in metal complexes andsalts, and strikes in one part of themolecule fitinto hollows of another portion (hydrophobicinteractions).While the fundamental recognitionprocesses that guide aggregation ofsupramolecular are administrated by the sameprinciples and forces, the chemical systemsstudied are generally classified into two majorclasses (figure 1): in general molecularrecognition in solution is referred to assupramolecular chemistry, and periodicarrangementofsupermolecules in the solid stateascrystalengineering[10-12].3.Crystalengineeringapproach
Crystal engineering defined as ‘theunderstanding of noncovalent intermolecularinteractionsbetweenthemoleculesinthecontextof crystal packing and the utilization of suchintermolecular interactions in the design of newsolids with desired physical and chemicalproperties’. Inaddition, it isrecognized that it ‘isappropriate increasingly evident that thedirectionality, predictability, and specificity ofintermolecularhydrogenbondscanbeutilizedtoassemble supramolecular structures withcontrolleddimensionality’[13].
Through the concept of supramolecularsynthons, this Crystal engineering approachwasbrought into the root of organic chemistry, [14]which are repeating periodic arrangement ofstructural units in crystal structures that arebasedonhydrogenbondpatternsandothernon-covalent interaction, able to direct the rationaldesign of supramolecular architectures.Whitesides [15, 16] provide an interpretation ofphysicalorganic chemistry tocrystalengineeringas ‘the study of molecular and crystal structurecorrelation in a family of compounds’.Supramolecular chemistry has developed basedon Lehn's analogy that ‘supermolecules are tomolecules and the intermolecular bond, whatmoleculesaretoatomsandthecovalentbond’[17].By connecting atoms with covalent bonds,moleculesarebuilt;byconnectingmoleculeswithintermolecularinteractionssolid-statecrystalsarebuilt. In 1962, the basics of crystal engineeringweredescribedbyvonHippel indetailunder theterm ‘molecular engineering’ [18].Modern crystalengineering originally commence astopochemistry for understanding the productdistribution and regioselectivity in solid-statemolecular reactions, [19]. This approach has builtrapidly, predominantly with the introduction ofmodern crystallographic techniques followed bythe development of area detector technology.Crystal engineering technique now coversmanyaspects of intermolecular interactions in solid-state compounds,predictionof structure, controland rationalization, in addition to the novelmolecular building blocks synthesis andpreparationof crystallinematerials,andperhapspacked up into the components of analysis andsynthesis [20].Within theconceptofacrystalasasolid state supramolecularentity lies certainkeyideas mainstream to the crystal engineeringactivity.
Crystallizationprocess isconcernedwiththeprogress frommeltof thecrystallinestateorsupersaturationsolution.Withinthisfieldprimaryconcerns include the influence of crystallizationconditions,thedevelopmentofcrystalnuclei.Itissurroundedbytheconceptofthegrowthunitthat
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adiscretelinkwiththesupramolecularconceptofa synthon is accomplished. This supramolecularsynthons are spatial arrangements ofintermolecular interactions; therefore, generallytheobjectiveofcrystalengineeringistorecognizeanddesign synthonsbetweenmolecules thatarestrong enough to be interchanged betweennetwork structures. This ensures simplificationeventually leading to the predictability of one-,two-andthree-dimensionalpatternsproducedbyintermolecular interactions. The CambridgeStructural Database investigation [21] possiblyutilized to recognize stable hydrogen bondingmotifs [22] with the objective that the strongestmotifswillremain intactcrossafamilyofrelatedstructures. Amides and carboxylic acids containfunctional groupswhich are self-complementaryand capable of producing supramolecularhomosynthons,howevertheyarecomplementarywith each other and can also interact throughformation of a supramolecular heterosynthon(Fig.4).Thismotifhasbeenconsideredforintheframework of crystal engineering [23, 24] and thecarboxylic acids interaction with heterocyclicbasesispossiblythemostextensivelystudiedtypeofsynthons[25–29].4.Polymorphism Discovery and control ofPolymorph is afundamental problem in pharmaceutical science.Polymorphismreferstoacompoundthatcanexistin two or more crystalline forms wherein themolecules have different arrangements (packingpolymorphism) and/or conformations(conformational polymorphism) in the crystallattice [30].Polymorphism is established tobe anextensivephenomenon formostpharmaceuticals[31]. A variety of polymorphs of a drugmoleculemay have different physical and chemicalproperties such as stability, solubility, meltingpoint, bioavailability, etc [32]. Stavudine, athymidine nucleoside is reverse transcriptaseinhibitorwhich act against of the HIV has beenexited in two polymorphic forms I (packingpolymorphism) and form II (con-formationalpolymorphism[33].PolymorphformIhasahighermeltingpointat170.1°C,whilepolymorphformIIhas a lower melting point at 166.6°C.Furthermore,thesolubilityofpolymorphformIislesserthanthatofpolymorphformII.
The investigation of polymorphism is amost importantactivity in thepracticeof crystalengineering today. This subject possibly studiedthrough the crystallization of various forms ofcrystal and the measurement of theirphysicochemical properties by analyticaltechniques such as single crystal X-ray
crystallography,powderX-raydiffraction,infraredand Raman spectroscopy, differential scanningcalorimetry and modern and exotic techniquessuchasterahertzspectroscopy.Fromthepointofviewofthepharmaceuticalindustryitisessentialtobe able to identify very small amounts of onepolymorph in the presence of a large excessamount of another. Polymorphism may also beinvestigatedthroughcomputationalmethods.Anycrystal structure is linked with energystabilization with deference to its isolatedmolecules.This is the energy that shouldbeputinto a crystal in order to separate it into itsconstituentmolecules; it isalsocalledtheheatofsublimation[34].
Themost effective and commonmethodfor preparing drug polymorphs is crystallizationfromsolutionsormelts[35,36].Thetypicalmethodsfor preparing drug polymorphs and solvates areEquilibrium and non-equilibrium crystallization[35–38] (Table 1). Equilibrium crystallizationMethods from solution are depended onisothermal or constant-concentration solventevaporation from a solution in equilibriumwithcrystals of a given polymorph.Methods of Non-equilibrium crystallization are carried out atsignificantsupersautrationconditionsinamethodowing to rapid variable-temperaturecrystallization, solvent exchange, and drying bysprayingorsublimation.
Key factors that affect the drugpolymorphism from crystallization process aredegreeofsupersaturation,temperature,pressure,solution composition, pH of solution, nature ofsolvent and stirring rate [54].The factors such astemperature and pressure play a critical role inselection of preparation conditions of a certaindrugpolymorphsastheydefinetheconditionsoftheir stability,metastability, and solubility [35, 36].Thetypeofthesolventdoesnotaffectdirectlythefree-energy difference of the drug polymorphs.However,choiceofsolventcanaffectthekineticsbecause of a selective influence on the rate ofnucleation and growth of crystals of a certaincrystallinemodification.
Operating conditions of crystallizationcan affect in the final crystalline forms.Consequently, a full understanding of thenucleation, crystal growth and phasetransformation in the crystallization sequence(Fig.5)isvitalforthecontrolofthepolymorphicform. It isrecognized that thenucleationprocessistheprincipalstepinthecontrolofpolymorphiccrystallization[3].
Figure No 5: Schematic representation ofpolymorphic crystallization sequence.Modifiedfromreference[3]
4.1.Controlofsupersaturation Three of the possible competitivenucleation types of a dimorphic system wereshown in figures no 6. For example, the rate ofnucleationofpolymorphIcanbehigherthanthatof polymorph II inwhole supersaturation levels
(Fig. 6(a)), at high supersaturation levels (Fig.6(b)), or at both low and high supersaturationlevels (Fig. 6(c)). Taking this into consideration,by careful controlof the levelof supersaturationthedesiredpolymorphcanbeselectivelyobtainedinsomepolymorphicsystems.Forexample,atlowinitial supersaturation (σ) less than 1.5 at thetemperatureof20°C,themetastableαpolymorphof phenylbutazone nucleates, while the stable δpolymorphoccursatσ≥5.0[55].
FigureNo6:SchematicgraphicoftheeffectofsupersaturationlevelSonthenucleationratesJ of polymorphs I and II. Modified fromreference[3]
Polymorphism-EquilibriumCrystallizationMethods
Method Principle Examples Reference
ByEquilibriumcrystallizationfromthemeltofdrug
Slowisothermalcrystallizationofdrug Pramocaine
Chloramphenicol-palmitate
39,40
Isothermalevaporationofsolvent Slow isothermal evaporation of solvent from asolutioninequilibrium
ExchangeofSolvent Depended on rapid isothermal reduction of drugsolubility in solution by addition of solvent thatdiminishesthesolubilityofthedrugintheresultingsolution
sulfamethoxydiazine,
diflunisal
histidine
IbuprofenSodium
47-49
Spraydrying BASED on generating the vital degree of drugsupersaturation in a solution dispersed in a gas-heat-transferstreambecauseofsolventevaporation
Phenobarbital
50
Sprayingfromsupercriticalsolvents It involves generating the required degree of drugsupersaturation in a supercritical solution upondispersionbecauseofsolventevaporation
Tolbutamide,
Barbital
44,51
Sublimationdryingmethod Based on solvent sublimation from a preliminarilyfrozendrugsolution
4.2.Controloftemperatureinnucleation One of the predominant and generallyconsideredasoperational factors isTemperaturethataffectnucleation,growthandtransformationof polymorphs. The effect of temperature onnucleation has both thermodynamic and kineticinferences, predominantly for enantiotropicpolymorphs [2]suchasdeliberateoradventitiousseeds but sometime possibly overshadowed byotherfactors.4.3.Selectionofsolvent The selective adsorption of solventmoleculeson crystal faces followedby inhibitionof nucleation and growth of particularpolymorphicformsiscreditedbytheselectivityofsolvent upon polymorphs [2], the solvent-soluteinteractions, etc [56]. A solvent molecule willestablish hydrogen bonding with the solutemolecule, with its stronger ability to donate oraccept hydrogen bonding than the solutemolecule, which consequently will result inselective nucleation [57]. For instance, twopolymorphs ofdrug sulfathiazole (IIand III) canbe obtained in water, two other polymorphicFormsIandIVarecrystallizedfromacetone,evenasn-propanolgivesonlyformI[58].4.4.Seedingtechnique During the nucleation phase, Addingseeds of the preferred form are frequentlyeffectivetocontroltheproductcrystalpolymorph.Positively the success of this method issignificantly dependent upon the “polymorphicrecognition” (notmerelymolecular recognition),which otherwise may effect in the cross-nucleation between polymorphs. For instance,when the alpha polymorph seeds alone wereadded, the same polymorph of D-mannitolproduced, while the seeding of the deltapolymorph yielded the alpha polymorph in newgrowthatsmallundercooling[59].4.5.Usageofadditives Occasionally,additionofadditivescausesan impressive outcome of crystallization [60].Forthe period of polymorphic crystallization,structurally similar or related additives mayimpudence pre-nucleation aggregation processesand/or selectively bind the faces of a growingcrystal.Byuseoftailor-madeadditives,thedesignof crystal growth accelerators or inhibitors ispossible when the crystal structures ofpolymorphs are already known [61]. ThemetastablepolymorphVofflufenamicacid(FFA)can experience a rapid interface mediatedpolymorphictransformation.4.6.Polymertemplatingtechnique
Heterogeneousnucleationhappensmuchmore rapidly when the surface introduced canreducethefreeenergyfornucleation.Asaresult,heterogeneous nucleation depends on specificinteractions such as static forces, hydrophobicinteractions, etc between the solute and thesurface.Anumberofdifferentmaterialshavebeenutilized such as certain polymers includingpoly(vinylchloride), poly(2,3,5-tribromostyrene),chlorinated polyethylene,poly(tetrafluoroethylene), isotacticpolypropyleneand nylons. For now, other polymers such aspolycarbonate, ethylcellulose,poly(vinyl acetate),etc.,[62].4.7.Usageofmicroporousmembranes Recently, Microporous membranes havebeenapplied in the crystallizationprocesses.Forthe separationandpurificationofboth inorganicandorganicmaterials,Membranecrystallizationisbeingregardedasapromisingtechniquewhichiscoupled by membrane separation andcrystallization[63].5. Resent case studies of pharmaceuticalpolymorphs:
The followingare thefewcasestudiesofpharmaceutical polymorphs of drugs whichstructures are prepared and solved by crystalengineeringapproach.5.1.PolymorphsofTolbutamide
The anti-diabeticdrugTolbutamide (TB)crystallizes in four polymorphic forms (Forms I-IV),whicharedifferintheircrystalpackingmodeand in molecular conformation but which arehaving similar hydrogen bonding synthon (ureatape motif). The first three polymorphs weresolvedfromsinglecrystalX-raydataandFormIVwas solved using conventional powder X-raydiffraction(PXRD)data.ThermodynamicstabilityrelationshipsofpolymorphicpairswereevaluatedbyDSCandgraphicallyvisualized in a schematicenergy-temperaturediagram.Form II is found tobethethermodynamicallymorestablepolymorphand beyond which Form I(H) is the stablepolymorph[44].5.2.PolymorphsofPyrazinamide
Pure pyrazinamide polymorphs α, δ, γandmixturesof theβ formwithoneof theotherpolymorphswerealsopreparedbycrystallizationfromdifferentsolvents,alsoby lyophilizationandsublimation. These forms were completelycharacterized and clearly distinguishingpolymorphsencompassingadimericpirazinamideunit, α, β, and δ, andwhere the dimer does notexist, the γ one. The thermal analysis study ofpolymorphsdemonstratedanattractiveschemeofsolid phase interconversion. Solid-solid
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endothermicphasetransitionsgivingrisetotheγform are observed for the three polymorphshaving pyrazinamide dimeric units, being the γpolymorph the stable phase for temperaturevalueshigherthan∼145C[52].5.3.PolymorphsofCaffeine Polymorphic solid-state transition ofcaffeine anhydrate from form I (stable at hightemperatures) to form II (stable at roomtemperature) were investigated. The surfacephenomenaduringthissolid-statetransitionwereobserved by an atomic force microscope (AFM.The transitionkineticswaswellexplainedby thepenetration model in which the transitiondeveloped as the form II structure propagatedinward from the crystal surface. The activationenergy of this polymorphic transition wasdeterminedtobe73.8kJ/mol[64].5.4.Polymorphsofaspirin
All elastic stiffness coefficients, thethermal expansion coefficients and a reliable,internallyconsistentdatasetofacetylsalicylicacidhave been presented. The elastic stiffnesscoefficientspresentamacroscopicdemonstrationof the anisotropy of the bonding in the crystal.They semiquantitatively predict the elasticbehavior of form I and also describe the elasticbehavior of form II. Thisweakens the argumentthat form IIcan’tbegrownbecauseof instabilitywithrespecttoasmalldistortion.Theexplanationof the diffraction patterns initially assumed torepresent form II as being due to a domainstructurecomposedof form Iand form II isverycredible[65].5.5.Polymorphsofefavirenz
Polymorph, a solvate,and two cocrystalsof the anti-HIV drug efavirenz have beenprepared, isolated,and structurally characterizedby crystal engineering technique. Systematictemperature dependent investigation on singlecrystals of the nonsolvated form (I) disclose aninteresting transformation of single-crystal tosingle-crystal from an orthorhombic P21212structure to a monoclinic P21 structure with aassociatedincreaseofZʹfrom3to6oncooling.Asimilar transformation was observed in thecyclohexanesolvate.AlowenergyrotationbarrierforthecyclopropylgroupcouldberesponsiblefortheaforementionedhighZʹstructures,asrevealedby DFT calculations. Formation of cocrystals ofefavirenz seems to be a mostly unpredictablematter. In the cocrystalwith 4,4ʹ -bipyridyl, thesynthonsaremoreeasilypredictable[43].5.6.PolymorphsofIbuprofenSodium
IbuprofensodiumPolymorphshavebeeneffectively micronized with a semicontinuous
supercritical antisolvent (SAS) process. Productanalyses shows that SAS processing does notcause any contamination or degradation of theproduct.Inaddition,ithasbeenexposedthatwithansufficientselectionoftheprecipitationrateandsupersaturation during the precipitation, whichcan be restricted bymanagement of parameterssuchastemperatureandratioofCO2/solution, itis achievable to selectively produce eithercrystalline particles with rod crystal habit andparticle sizes of1-5µm, or amorphous sphericalparticleswithparticlesizesofabout500nm[49].5.7.PolymorphsofFurosemide(Lasix)
X-raycrystalstructureoffourpolymorphoffurosemideisreportedintheliteratureandhasbeen characterized. Molecular conformation andhydrogen bonding motifs information on X-raycrystalstructuresofforms2and3offurosemidewere reported, which present their accurateclassification as conformational and synthonpolymorphs. Phase transformations demonstratethat metastable form 2 changes to form 1 ingrinding and slurry crystallization experiments.The stability of thermodynamic form 1 isdemonstratedbyitsmoreefficientcrystalpackingandhigherdensity.Areproducibleprocedure forgrowing crystals of form 3 is still awaited. Thethermodynamicpolymorphof furosemide form1having twometastable conformers in the crystalstructureprovidesas areminder that there isnosubstitute for crystallization experiments andstabilitytestingofdrugpolymorphs[66].6.Co-crystalapproach Analternativeapproachavailable for theenhancement of drug solubility, dissolution andbioavailability, is co-crystals through theapplication of crystal engineering of co-crystals,historically referred to as molecular complexes.The physicochemical properties and the bulkmaterialpropertiesoftheAPIcanbemodified,atthesametimeasmaintainingtheintrinsicactivityof the drug molecule. Pharmaceutical co-crystallization is emerging as an attractivealternative to polymorphs, salts and solvates inthe modification of an active pharmaceuticalingredient (API)duringdosage formdesign.Theintellectual property implications of creating co-crystalsarealsohighlyrelevant. This approach of co-crystalinvolvestheexpansionofasupramolecularlibraryof co-crystallizing agents. A hierarchy of guestfunctional groups is classifiedwithin the libraryaccording to a specific role to a crystal packingarrangement, which is dependent on the hostmoleculefunctionalities.Theseareobtainedfrominvestigation of structure property relationshipspresent in the Cambridge Structural Database
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(CSD) which contains classes of known crystalstructures [29]. Generally in the pharmaceuticalindustry,Chemists and engineers trytofind todeliver crystalline forms of their activecompounds, principally due to the inherentstability of crystalline materials and the well-established impactofcrystallizationprocessesonisolationandpurificationofchemicalsubstances[4]. Increasing interest is now receiving to theimpactofpropertiesofmaterialondrugdiscoveryanddevelopment[67].Thetaskofpharmaceuticalindustry is to hastily advance developmentprograms through good confidence with theintentionthatformulationproblemsareunlikelyto occur and to maximize a compoundspotentialasatherapeutic.Thesolidformwhichispreferredusually the thermodynamicallymoststablecrystallineformofthecompound[68,69].Onthe other hand, the stable crystal form of theparentcompoundmayshowinsufficientsolubilityand/or dissolution rate which resulting in poororalabsorption,mainlyforpoorlyaqueoussolublecompounds. In this case, alternative solid formsmaybeexplored. Preparation of salt formsforionizable compounds using pharmaceuticallyacceptableacidsandbasesisaordinarystrategytoimprovebioavailability[4]. A major tool is the hydrogen bondwhich is accountable for the majority ofdirectedintermolecularinteractionsinmolecularsolids. Co-crystals aremulti-component crystalsdepend on hydrogen bonding interactionslackingthetransferofhydrogenionstoformsalts.Pharmaceuticalco-crystalscanbedefinedas multi-component crystalline materialscomprisedofanAPIandoneormoreuniqueco-crystal formers, which are solids underambientconditions. Fornonionizable compounds, co-crystalsenhance pharmaceutical properties bymodification of solubility, dissolution rate,chemical stability,mechanicalbehavior,moistureuptake and bioavailability [70]. Recently,Pharmaceuticalco-crystallizationhasonlygainedwidespread attention as a tool of changing thephysicochemical properties of drugs, for thereason that co-crystal formationmay probablybe employedwith all drugs, including acidic,basicand non ionizablemolecules and a largenumber of probable ‘countermolecules’whichpossibly considered to be non toxic possiblyrising the scope of the pharmaceutical co-crystallization over the salt forms. To saltselection, an correlation can be drawn inwhichpKapointofviewareusedtoselectacid-basepairsthatcanbeconvertedtosaltcompounds.ChemistryexhibitsthatapKadifferencebetweenan acid and a base of at least two units is
necessitated to form a salt that is stable inwater [71]. In addition, it is significant toremember that salt formation is usuallydirectedatasingleacidicandbasicfunctionalgroup. On the contrary co-crystals canconcurrently address multiple functional groupsin asingleAPI. Aswell space isnot limited tobinary combinations that is acid-base pairs astertiaryandquaternaryco-crystalsarerealisticone[72,73]. The key difference between solvatesand co-crystals is the physical state of theindividualcomponents[74].Atroomtemperature,Ifonecomponentisliquidthenthecrystalsareassignedsolvates,whileifbothcomponentsaresolids at room temperature then the crystalsare called as co-crystals. Though, Co-crystalshave a propensity to be a product of morerational design and are more stable,predominantlyastheco-crystallizingagentsaresolidsatroomtemperature. The key remunerationsassociatedwithapproach of co-crystallization to alter theproperties of pharmaceutical solids are thetheoreticalabilityofalltypesofdrugmoleculesto form co-crystals includingweakly ionizableand non-ionizable, and the existence ofnumerous,potentialcounter-molecules, includingpreservatives, food additives, pharmaceuticalexcipientsaswellasotherdrugs, for co-crystalsynthesis. Major advantage for thepharmaceutical industry is co-crystal synthesiswhichmay offer is an opportunity toaddressintellectual property (IP) issues by extendingthelifecyclesofoldAPIs[75].7.Advantagesofcocrystalapproach Co-crystals having several advantagessuch as no necessitate to make or breakcovalent bonds, as compared to amorphoussolids it is stable crystalline form, theoreticalability of all types of drug molecules such asweakly ionizable/non-ionizable to form co-crystals, the existence of numerous potentialcounter-molecules such as food preservatives,pharmaceutical excipients, additives, and otherAPIs,theonlysolidformthatisdesignableviacrystal engineering patentable expanding IPportfoliosand canbeproducedusingsolid-statesynthesis green technologies high yield, nosolventorby-products[4].8. General design approaches for co-crystallization Like to salt screening, Co-crystalscreening is a process which is predominantlysuited to high-throughput technologies [74]. Apharmaceutically acceptable non-toxic
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coformer(s) should be chosen after selection ofAPI for co-crystallization so as to result in apharmaceuticallyacceptableproduct.Thisrestrictthe coformers to those thathavebeen approvedfor consumption by humans, for examplepharmaceutical excipients and compoundsclassifiedas generally recognized as safe (GRAS)foruseasfoodadditives(asclassifiedbytheU.S.DepartmentofHealthandHumanServices). For each additive, The List of FoodAdditives Status provides data on limitations toutilize and permitted tolerances. For completeinformation on a substance's utilize andlimitations,referencetothespecificregulationforeach substance is recommended. The majorityGRASsubstanceshavenoquantitative limitationsas to their levels in foodproducts,although theirusemustbe conventional togoodmanufacturingpractices. Even though GRAS substances aregenerallyrecognizedassafe in foods, their levelsand utilization can be limited in pharmaceuticalproducts.
Where there isnopharmaceuticalmodeluse and where the intended additive has nopharmacopoeialmonograph,GRASstatusdoesnotassuranceitsuseasco-crystalformingagent.Stillwhereprecedentsexist, theadditionofadditivesis limited to levels established to be safe inexistingpharmaceuticalproducts.Forinstancethemaximumadditive levelofmalicacid (whichhasbeen co-crystallized with the anti-fungal drugitraconazole) inhardcandy is<7% [76].Anumberof co-crystals have been formed with co-crystallizing agents classified as GRAS. Though,the required therapeutic level needs to bebalancedwith theactivedrug level for a feasibleapplication in drug development and so, exceptthe resulting stoichiometric amount of co-crystalagent is less than the permitted additive level,their pharmaceutical applications will not berealized.Co-crystallizationbetweentwodrugshasalso been proposed as a foundation for bothcompounds to be pharmaceutically acceptable.This possibly will require the use of sub-therapeutic amounts of drug substances such asaspirinoracetaminophen[73],orthedrugstohavesimilarlevelsoftherapeuticactiveconcentration. The majority of co-crystallizationresearch has infrequently involved usingpharmaceutically acceptable conformers andconditions.Theformationofparacetamoladductswithhydrogen-bondacceptorshasbeenreported[77]. Though the co-crystallisation agents usedwere not GRAS substances, andmorpholine andpiperazinedihydrochlorideasthesalt(s)ofoneormore fatty acids, are only permitted as foodadditivesattheapplicablelevel[78].
9.Co-crystalsdesign The crystal engineering trialscharacteristically involves the CambridgeStructuralDatabase (CSD) investigation followedby the experimental work. Co-crystals designbased on the principals of supramolecularsynthesis; it affords a powerful approach forproactivediscoveryofnovelpharmaceuticalsolidforms.Co-crystalscontainsmultiple componentsin given stoichiometric ratio, where differentmoleculargroupsinteractbyhydrogenbondingand by non-hydrogen bonding.The utilizationof rules of hydrogen bonding, synthons andgraphsetspossiblywillsupportintheanalysisand design of co-crystal systems. as a generalthough,predictionof whether co-crystallizationwill occur is notyet probable andbe repliedempirically at present. Formation of Co-crystalpossibly modernized by consideration of thehydrogen bond donors and acceptors of thematerials that are to be co-crystallized.subsequent the broad examination of superiorpacking preferences and patterns of hydrogenbondinanumberoforganiccrystals,Etterandco-workersprojectedtherulestofacilitatethedeliberatedesignofhydrogen-bondedsolids[4].
a. Allgoodprotondonorsandacceptorsareusedinhydrogenbonding.
b. Six-membered ring intramolecularhydrogen bonds form in preference tointermolecularhydrogenbonds.
c. The best proton donor and acceptorremainingafterintramolecularhydrogen-bond formationwill form intermolecularhydrogenbonds tooneanother (butnotallacceptorswillnecessarilyinteractwithdonors).
These observations help to address theissue of competing hydrogen bond assembliesobservedwhen using a particular cocrystallisingagent. A comprehensive thoughtful of thesupramolecular chemistry of the functionalgroups present in a given molecule is thequalificationfordesigningthe co-crystals as itassists the selection of the appropriate co-crystal former. Supramoecular synthons thatcanhappeningeneralfunctionalgroupsoastodesign new co-crystals and certain functionalgroups such as carboxylic acids, alcoholsandamides are mainly agreeable to formation ofsupramolecular heterosynthon [34]. The stronghydrogenbond contains (O-H---O), (O-H---N) (N-H---O),and(-N-H---N).Theweakhydrogenbondsinvolvesthe–C-H---OandC-H---O=C[15]. Co-crystallizationofcis-itraconazolewithaseriesof1,4-dicarboxylicacidsaccomplishedof
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extended(anti-)conformationswereobserved[29].Interaction between succinic acid and thestrongest base position of itraconazole thoughwas not present in the co-crystal structure. Co-crystals might not be formed from maleic acidwith Z regiochemistryabout theC=Cbond (withpKa=1.9),orfrom1,3-or1,5-dicarboxylicacids.Asaresultinthiscasestructuralfitemergestobefar more significant than acid-base strengthcomplimentarily for successful co-crystallisation.Intherelativehumiditystabilitystudiesofaseriesof caffeine/carboxylic acid co-crystals [79] it wasestablish that the oxalic acidwhich is strongestacid guest molecule produced the caffeine co-crystal of most stable, at the same time as theweakest acid (glutaric acid) produced the leaststable cocrystal. Though, a polymorph of theglutaric acid/caffeine co-crystal showedintermediate stability; sopKa alonemustnotbethe only factor dictating co-crystal stability. Theexerciseofhydrogenbondingrules,synthonsandgraphsetsmaysupportinthedesignandanalysisofco-crystalsystems.10.Methodsofpreparationofco-crystals In the literature, formation of Co-crystaldescribed shows the disreputably difficultsituation thesesystems presentwith regard topreparation it hasbeen recognized to take 6months to prepare a single co-crystal ofappropriate quality for single X-raydiffractionanalysis[80]. This is partially as such aheteromericsystemwillonlyform ifthenon-covalentforcesbetweentwoormoremoleculesarestrongerthanbetweenthemoleculesinthecorresponding homomeric crystals. Co-crystaldesign strategiesare stillbeing researchedandthemechanismofformationisfarfrombeingunderstood.Co-crystalscanbepreparedby solidand solventbased techniques.The solvent-basedtechniques involve solvent evaporation, slurryconversion, cooling crystallization andprecipitation.Thesolidbasedtechniquesinvolvenet grinding, solvent-assisted grinding andsonication(appliedtobothtodryorwetsolidmixtures)80oto85°[80].10.1.Co-crystallizationfromSolution The two components must have similarsolubilityforsolutionco-crystallization;otherwisethe component which has least soluble willprecipitateoutentirely.Ontheotherhandsimilarsolubility of two components alone will notpromisesuccess.Ithasbeen recommended thatit possibly useful to believe polymorphiccompounds, which exist in more than onecrystalline form as co-crystallizingcomponents.If a molecular compound exists in numerouspolymorphic forms it has showed a structural
flexibilityandisnotlockedintoasingletypeofcrystalline lattice or packingmode. Therefore,thepossibility of conveying such acomponentinto a different packing arrangement incoexistencewith anothermolecule is improved.Obviouslypolymorphismalonedoesnotpromisethe functionality of a molecule to act as a co-crystallizingagent,atthesametimeastheabilityof a molecule to contribute in intermolecularinteractionsclearlyplaysacriticalrole[29]. Co-crystal from Small-scale preparationhas been described. Scale-up crystallization wascarried out in a water-jacketed glasscrystallization vessel and temperature wascontrolled by a circulating water bath. Teflonbladeandoverheadstirrerwithaglassshaftwereattachedtovesselportsandalsoarefluxcolumn,digital thermometerwere attached. TheAPI andco-crystal formerwere added to this vessel andweredissolved inethanol/methanolmixtureandheatedto700Cunderrefluxfor1hour.Toinduceprecipitation of co-crystal, temperature wasdecreasedatarateof100Cinastirred,unseededsystem. Literate to improve solids recoverydecreasetheadditionaltemperature[81].10.2.Co-crystallizationbyGrinding: Theproductacquiredwhenpreparingco-crystals from grinding is usually consistentwiththatobtainedfromsolution.Thismayspecifythatpatterns of hydrogen-bond connectivity are notidiosyncratic or determined by non-specific anduncontrollableeffectsofsolventorcrystallizationconditions.Howevertherearesomeomissions.atthesametimeasmanyco-crystalmaterialscanbeprepared from both solution co-crystallizationand solid-state grinding, some can only beprepared by solid-state grinding.For instance,in the co-crystallizationof 2,4,6-trinitrobenzoicacid and indole-3-acetic acid,different crystalformswereprepared from solutionas comparedwith grinding co-crystallization. Disappointmentin co-crystals formation by grinding co-crystallizationpossiblyduetoan incapability togeneratesuitableco-crystalarrangementsratherthan due to the stability of the initialphases.Whilst formation of co-crystal has beensuccessfulfromsolutionbutnotfromgrinding,maybe of solvent inclusion in stabilizing thesupramolecularstructure.Eventhoughformationof co-crystalby solid-state grinding has beenestablished for a moment and a late 19thcenturyreportisfrequentlycitedastheinitialreference to such a procedure, the currenttechnique of liquidassistantgrinding hasbeenshowntoimprovethekineticsandfacilitateco-crystal formation and as lead to increasedattentionofsolid-stategrindingasamethodforco-crystallization[29].
Solvate formation suppressed by using solvent mixtures, that they reduce thesolubilitydifferencesbetweendifferentcompoundsascomparedtopuresolvents.
84
Caffeine
MaleicAcid
GlutaricAcid
Reported1:1and2:1cocrystalstogetherwithanewpolymorphofmaleicacidandrationalize this behavior through measurement of the binary and ternary phasediagrams.
thephasediagram ofcaffeine-glutaricacid-acetonitrile in the temperature rangeof10-350C was charted using ATR-FTIR and has laid the foundation for furthercocrystallizationprocessdevelopmentofthemodelsystem.
The sulfamethazinemolecules form a dimer through the intermolecular hydrogenbonding(O…H-N),andtwointermolecularhydrogenbonds(O…H-NandN…H-N)keepthetheophyllineattachedthedimer.
88
Acetaminophen
2,4-pyridinedicarboxylic
Acid
Red colored cocrystal discovered by screening using the solution-mediated phasetransformationtechnique.
89
10.3.Co-crystallizationbySlurryconversion Experimentations in slurry conversionwerecarriedoutindifferentorganicsolventsandwater.100 to200mlofSolventwas added andthe resulting suspensionwas stirred at roomtemperature for few days.After few days, thesolventwasdecantedandthesolidproductwasdried under aflowofnitrogen forfewminutes.The remaining solids were then characterizedusingPXRDanalysis.10.4. Co-crystallization by addition ofantisolvent Thisisoneoftheprecipitationmethodsfor co-crystallization of the co-crystal formeranddrug.Inthismethod,solventsincludebuffers(pH) and organic solvents. For instancepreparationofaceclofenac-chitosanco-crystals,inwhich solution of chitosan was prepared bysoaking chitosan in glacial acetic acid for fewhours.Byusinghighdispersionhomogenizer thedrug was dispersed in chitosan solution. Thisdispersionwasaddedtodistilledwaterorsodiumcitratesolutiontoprecipitatechitosanondrug[82].11.CONCLUSION
Thedesign ofnew crystal form ofdrugswith application of crystal engineering is anevolving subject. Ability to design new crystalstructureswilldependmostlyonsupramolecularchemistryandonviewingacrystalstructurewithinteractions of various types and strengths.Crystal engineering approach involvesidentification of interactions or supramolecularsynthons that will covers an entire family ofstructureswith the object of identifying a set ofnewcrystalformsofAPI.
The development of new molecularcomplexes,co-crystalandpolymorphsofdrugsbycrystal engineering is becoming progressivelymore important as an alternative to saltformation,mainlyforneutralorweakly ionizablecompounds. Even though lack of priority inmarketedproductsandconcernsaboutthesafetyand toxicityofco-crystal formingagents, there israising interest and activity in this area, whichaims to increase the understanding of crystalengineeringapproach.
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