Slide 1

Presented byKritika NayakNIPERAPHD2015PE01Co-Crystal

Flow of PresentationIntroductionAdvantagesPreparation MethodsCharacterization TechniquesMarketed FormulationsReference2

Similarity between Co-Crystal and Eutectic Mixture3Non-Covalent DerivativesMade up of two or more components but at end, homogenousBoth lack long range order ( Co-Crystal has short range order)

Difference between Co-Crystal and Eutectic mixtureCo-CrystalEutectic Mixture4Enthalpy advantage outweighs Entropy LossNecessarily CrystallinePrimary supramolecular growth units should be at least 3 molecules long for co-crystal to form When NCD with crystal packing shape compatibility found Entropy Gain outweighs Enthalpy lossNot necessaryPrimary supramolecular growth unit is restricted to finite heterodimerWhen NCD but without packing shape compatibilityNCD = Non-covalent derivative

5Contains two eutectic points and a region of cocrystal at the maximum between the two eutectic points. This results in a typical W-shaped phase diagramDSC thermal data for eutectic mixtures results in a classic V shape where the minimum point of the V represents the molar ratio and temperature at the eutectic point

6

Typical DSC Thermogram of Co-crystalTypical DSC Thermogram of Eutectic mixture

Spring Parachute Effect

7

8Drug absorbed when it is in supersaturated solution formSupersaturation leads to higher absorptionSupersaturation leads to Precipitation (Recrystallization) of drugAs supersaturation disappear, drug absorption decreasedThis is called Spring Effect

9Precipitation inhibitors are used to delay precipitationLeads to longer supersaturation, thus prolonged absorption of drugDrug absorption decreases with time but very slowlyThis is called Parachute Effect

10Precipitation inhibitors: Polymers (PVP,HPC, HPMC, PEG etc)They did by hampering nucleation and crystal growthSurfactants (SDS, labrafil etc) by micellar formationSome increases drug solubility, enhance dissolution rate

11

Co-crystalNo Proper Definition, Persist in knowledge but ill studiedBy FDA Draft guidiline 2011, these are Solids that are crystalline materials composed of two or more molecules in the same crystal latticeSometimes named as molecular complexNonionic supramolecular complexCrystalline material comprised of API with co-crystal formers (solid at room temperature)12

Multiple component crystalline solid formed in a stoichiometric ratio between two compounds that are crystalline solids under ambient conditionsThe first known co-crystal Quinhydrone, was studied by Friedrich Whler in 1844 Can be divided intoAnhydrates of co-crystalHydrates (Solvates) of co-crystalAnhydrates of co-crystals of saltsHydrates (Solvates) of co-crystal of salts

13

14

AdvantagesStable crystalline form as compared to amorphous formGive increased solubility; thus increased bioavailabilityTechnique can be used for purification 15

16

Co-crystal coformersMost important for co-crystal formationIts structure dictate structure of co-crystalAlso dictate solubilityDiffer from Excipient

Example: ascorbic acid, gallic acid, nicotinamide, citric acid, aglutamic acid, histidine, urea, saccharine, glycine, tyrosine, valine17

Difference between Excipient and Co-crystal coformerExcipientCo-crystal coformerSupposed to be chemically inertDo not become the part of the crystal structureInvolved in final dosage formParticipate in intermolecular interactionBecome part of co-crystal structureThey need further processing steps to be in final dosage form18

SolventsAlso important componentCo-crystal formation depend upon selection of solventSolubility of drug and co-former is considered while selection of solventExample: ethanol, methanol, acetonitrile and others organic solvents19

Method of Co-crystal preparationSOLUTION METHODSEvaporative co-crystallizationCooling crystallizationGRINDING METHODNeat/Dry grinding methodLiquid assisted grinding methodANTISOLVENT METHODSLURRY CONVERSION METHODSUPERCRITICAL FLUID TECHNOLOGY

20

Steps involved in PreparationSelection of APISelection of co-formerEmpirical and theoretical guidanceCo-crystal screeningCo-crystal characterizationCo-crystal performance21

Synthon: Part/constituent of API and Coformer involved in intermolecular interactionSynthons exist in two distinct categories: Supramolecular Homo- synthons that are composed of identical complementary functional groups such as carboxylic acid dimers (aspirin)Supramolecular Hetero- synthons composed of different but complementary functional groups such as acidweakly basic nitrogen (aspirinmeloxicam) and acidamide (aspirincarbamazepine)22

23

Flowchart for choosing Co-crystal candidate24

Evaluation MethodsPXRD (Powder X-rays diffraction study)IR- SpectroscopicScanning Electron MicroscopePercentage YieldDetermination Of Melting PointSolubility AnalysisCompatibility Studies (IR Spectroscopy)In vitro drug release studies25

Marketed formulationPharmaceutical co-crystals of carbamazepine (Tegretol)Pharmaceutical co-crystals of fluoxetine hydrochloride (Prozac)Pharmaceutical co-crystals of itraconazole (Sporanox)Pharmaceutical co-crystals of sildenafil (Viagra) Co-crystal of melamine and cyanuric acid26

Co-crystals of theophyllineCo-crystals of aceclofenacCo-crystal of 5-nitrouracilCo-crystals of indomethacin27

ReferenceAlsenz, J., et. al. 2012. The Impact of Solubility and Dissolution Assessment on Formulation Strategy and implications for oral drug disposition. Encyclopedia of Drug Metabolism and Interactions. 1-53.Aitipamula, S., et. al. 2012. Polymorphs, salts and co-crystals: Whats in the name?. Cryst. Growth & Design. 12. 2147-2152.Schultheiss, N., et. al. 2009. Cocrystals: Pharmaceutical cocrystals and their physicochemical properties. Cryst. Growth and Design. 9. 2950-2967.Zalte, A., et. al. 2014. Cocrystals: An Emerging Approach to Modify Physicochemical Properties of Drugs. Am. J. Pharm. Tech Res. 4. 179-189.28