Solid dispersions as a formulation strategy for …

1 1 Solid dispersions as a formulationstrategy for poorly soluble compoundsG. Van den MooterUniversity of Leuven, Belgium20thAnnual Symposium of the Finish Society of Physical PharmacyVithi, Finland 28-29 January 20092 Outline- Introduction: 1. General view on the solubility problem2. formulation strategies for class II compounds- Rationale for using Solid dispersions - Physical structure of Solid dispersions - Carriers in the formulation of Solid dispersions - Analysis of the physical structure- Preparation of Solid dispersions - Advantages and disadvantages of Solid dispersions3 Introduction:general view on the solubility problemOral deliveryis preferred route for drug administrationCandidates for oral drug delivery:adequate solubility / dissolution propertiesadequate absorption through the gutmetabolic stability and no effluxHigh number of all development candidates fail due to biopharmaceutical reasonsPoor physicochemical properties (solubility/dissolution)account for the majority of these failures (ca.)

2 40%)BCS classification: (Amidon et al.,1995)Class I: high permeability and solubilityClass II: high permeability but low solubilityClass III: low permeability but high solubilityClass IV: low permeability and low solubility4 The bioavailability of class I compounds is determined only by delivery of the drug solution to the intestineFormulation independentThe bioavailability of class II compounds is limited by drug solubility/dissolutionFormulation dependentThe bioavailability of class III compounds is limited by intestinal permeability Dependent on barrier propertiesThe bioavailability of class IV compounds is limited both by solubility /dissolution and intestinal permeabilityFormulation and barrier properties dependentIntroduction:general view on the solubility problem5 Micronisation, nano-sizing(nanosuspensions)Complexation Co-solvent approachSurfactant based strategies(micelles, emulsions, S(M)EDDS,liposomes)pH adjustmentMicronisation, nano-sizingComplexationSurfactant based strategies(S(M)(N)EDDS, wetting agents)SaltsAdsorption formsSolid dispersions ( amorphoussystems)Liquid systems(semi) Solid systemsIntroduction: formulation strategies for class II compounds6050100150200250020406080100 Crystalline itraconazoleGlassy itraconazolePVPVA 64 Eudragit E100 HPMC E5% dissolvedTime (minutes) Solid dispersionsIn vitro dissolution of itraconazolein SGFI ntroduction: formulation strategies for class II compoundsSix et al, J.

3 Pharm. Sci, 2004 Dissolution properties Different carriers: different dissolution behavior30% drug loading7 Introduction: formulation strategies for class II compoundsSolid dispersions020406080100120020406080100 Percentage dissolvedTime (minutes)0 1020304050607080020406080100120140160180 200220240260280300 HPMCC oncentration (ng/ml)Time (hours)0 1020304050607080050100150200250300 Eudragit E100 Concentration (ng/ml)Time (hours)0 1020304050607080020406080100120140160180 200220240260280300 SporanoxConcentration (ng/ml)Time (hours)Itraconazolein vitro dissolution (SGF)Itraconazolein 8 human volunteersSix et al, Eur. J. Pharm. Sci, 2005 HPMC (ME)SporanoxEudragit E100 (ME)In vitro in vivo40% drug loading8 Rationale for using Solid dispersionsLattice energySolvatation/hydratationSolubility processHigh lattice energyPoor solvatationReaggregationAmorphous materialsProtective materialsCrystallinematerial9 Amorphous materials ? Thermodynamically metastablerelaxation, nucleation, crystallizationliquidSolidTH, VSupercooled liquidAmorphous(glass)TmTgstructuralrela xationPURE DRUGS ?

4 ?Rationale for using Solid dispersionsAmorphous materials: structural relaxation10 Pure amorphous drugs can be used rarely (stability) formulation of amorphous drugs in protective environment/matrixsolid state physical stability no precipitation following dissolutionSolid dispersion : A dispersion of one or more active ingredients in aninert carrierormatrix at solidstateprepared by the melting (fusion), solvent ormelting-solvent method (Chiou & Riegelman, 1971) A product formed by converting a fluid drug-carriercombination to the solidstate (Corrigan, 1985)No physical mixturesMechano-chemical processing?Drug particle size? Solid state?Physical structureRationale for using Solid dispersions11 Physical structure of Solid dispersionsEutectic systemsL; 1PS; 2PL+SL+STdrugTcarrier% carrierETwo phases in the Solid stateParticle size reductionSolubilizing effect of carrierCrystalline material12 Physical structure of Solid dispersionsMolecular dispersion : crystalline carrierSubstitutional Solid solution: carrier molecules are replaced withdrug molecules one phase systemsxyzxyz+Molecular isomorphism !

5 !drug13 Physical structure of Solid dispersionsMolecular dispersion : crystalline carrierInterstitial Solid solution: interstitial positioning of drug molecules in the carrier latticeone phase systemsxyzxyz+Size of guest molecules !!drug14 Physical structure of Solid dispersionsMolecular dispersion : crystalline carrierL; 1P + ; 2PL+ L+ TaTb% bE Solid state solubility:continuousdiscontinousTwo phases in the Solid state: + (b in aand a in b)Particle size reduction at molecular level: Solid solutionS15 Physical structure of Solid dispersionsMolecular dispersion : amorphous (glassy) carrier >> glass solutions+Amorphous Solid solution (1P; interstitial )carrierdrugHydrophilic polymers16 Physical structure of Solid dispersionsPartial molecular dispersion +Phase separation (P>1)Clusters:amorphous orcrystallineMolecular dispersionComplex phases:nanocrystalline domainscarrierdrug17- high Tg- supersaturation potential- screening studies from DMSO, DMF,..in aqueous carrier solutions- possibility of interactions with drug- Solid state solubility (miscibility) of drug in the carrier(molecular dispersion ) - phase behavior studies ( one Tg )films- theoretical models ( Flory-Huggins)- solubility in monomers ( NMP)- ternary phase diagrams- solubility in water (organic solvents depending on manufacturing process)- manufacturing processSelection criteria for polymeric carriersPolymeric carriers for Solid dispersions18 Neutral cellulose derivatives (HPMC, HPC.)

6 Acidic cellulose derivatives (HPMC-phtalate, HPMC-acetate-succinate,..)PVP (K25, K30)PVPVA64 PEG sp-(meth)acrylates ( Eudragit E100)Kollicoat IRGelucire 44/14 TPGSM annitol, urea, citric acidCombination of carriers (polymer-polymer; polymer-surfactant) SE- Solid dispersion Type of carriersCarriers for Solid dispersions19 Solid dispersions on the marketSporanox (itraconazole)Intelence (etravirine)Prograf (tacrolimus)Crestor (rosuvastatin)Gris-PEG (griseofulvin)Cesamet (nabilone)Solufen (ibuprofen)NOT SO MANY !!! Unknown = unloved Physical stability ?? 20 Physical structureManufacturingProcessingMaterial sIn vitroIn vivodissolutionDrug: molecular dispersionsolid state solubilitycrystalline / amorphous suspensionagglomerates / aggregatespolymorphic modificationsmixed / combined systems (P>1)chemical / physical interaction with carrierStabilitySolid dispersions on the market21 Analysis of the physical structure of soliddispersionsThermal analysis (DSC): characteristics of pure solidamorphous: Tgcrystalline: melting transitionXRD: crystallinity, unit cel parametersThermal analysis (DSC): characteristics of pure polymerThermal analysis (DSC): mixing/phase behaviourIR/Raman/ss-NMR: interactionsXRD: amorphous arangement(disordered nanocrystalline ortrue amorphous)More recently: Imaging techniques( TA, nano-TA; (E)SEM;TEM; AFM)Inverse GCsurface propertiescomplex phasesMobility in amorphous systems:thermal analysis (DSC); ss-NMR.

7 Rheology22 Mixing and phase behaviorVolume additivityTotal miscibilityInteractions =Not:Water, solvents,Interactions (H, dipolar,..)Gordon-Taylor equation:TgwTgKwTgwKw=++112 212 TgwTgKwTgKwTgwKwKw=++++1112 223 31223 Binary:Ternary:Six et al, J. Therm. Anal. Calor. 2002 Six et al, Pharm. Res. 20033103153203253303350 20406080100 Percentage itraconazoleTg (K)Itraconazole/Eudragit E100 Hot melt extrudatesAnalysis of the physical structure of soliddispersions23 ONCH3CH3CH2CH2 OHNC lloperamideCH2 CHCOOH()npolyacrylic acidHHONC lfragment 2 Intermolecular interactions1300140015001600170018001900 2000edcba20 %% Transmissionwave number (cm-1) COOHCOO -TgcalcTgexpWeuts et al, Eur. J. Pharm. Sci 2005 Analysis of the physical structure of soliddispersions24 Preparation of Solid dispersionsSolvent based methods-Spray drying-Bead coating- (Film casting, rotavapor)Mechanical methods- Dry mixing (pressure)Heat based methods-Hot melt extrusion- Melt compression- Melt compounding- Melt granulation25 Preparation of Solid dispersions Dissolve the drug and the carrier in a common solvent and remove the solvent Rate of solvent removal largely determines the physical structure ( maintenance of chaos entropic contribution)(film casting spray drying !)

8 !)Thermally instable drugs and carriersEnvironmental and toxicological issues Residual solventsDown stream processing: capsules, tablets,..Solvent based manufacturing methods26 Preparation of Solid dispersionsSpray drying- Solution- Atomisation of solution- Mixing of spray with gas- Evaporation of solvent- Separation of particles from gas- Collection of particlesBuchi Mini Spray Dryer27 Preparation of Solid dispersionsSpray dryingPro-C-epT Micro Spray Dryer28 Preparation of Solid dispersionsSpray dryingFeed rateNozzleAtomisation pressureDrying (air, nitrogen) rateInlet temperatureOutlet temperatureCondenser outlet temperature29 Preparation of Solid dispersionsBead coating, layeringCore (bead, pellet)Coating ( Solid dispersion )Protective : Sporanox capsules:HPMC/Itraconazole/PEG 2000030 Preparation of Solid dispersions Apply heat and / or shear forces to a physical mixtureof drug and carrier, followed by cooling Physical structure is mainly determined by the intrinsic miscibility , the amount of heat applied (processing temperature), shear forces (mixing) and rate of coolingNo or less environmental and toxicological issuesThermally stable drugs and carriersDown stream processing: capsules, tablets.

9 Heat based manufacturing methods31 Preparation of Solid dispersionsHot melt extrusion32 Preparation of Solid dispersionsHot melt extrusion33 Preparation of Solid dispersionsHot melt extrusion Twin screw extruders: Micro-scale equipment Approximately 5g of product Batch mode Vendor: Haake, DSM34 Preparation of Solid dispersionsHot melt extrusion combined with super- or subcritical CO2 Temporary plasticizer Foaming agent increased surface areaProcessing of thermolabile drugs35 Preparation of Solid dispersionsHot melt extrusion combined with super- or subcritical CO2 Ethylcellulose with CO2injection in Leistritz twin screw extruder(Verreck et al., J. Supercritical Fluids, 2006)130 C/40bar130 C/60bar100 C/100bar36 Preparation of Solid dispersionsHot melt extrusion combined with super- or subcritical CO2 Processing of thermolabile drugs: p-ASA in ethylcellulose matrix(Verreck et al, Int. J. Pharm. 2006)37 Advantages and disadvantages of soliddispersionsAdvantages- Processing equipment available at small and large scale- Thermolabile products- Relatively high drug doses are possible- Most carriers can act as Solid solvent- Carriers (mainly surface active agents) can maintain supersaturation in GI tract- Down stream processing is Understanding the physics of amorphous materials- Understanding the physical structure of Solid dispersions - Understanding the relationship between physical structure and drug release- Stability issues; residual solvents- Prediction of shelf life of amorphous materials?

10 - Increasing number of drugs with low solubility in organic solvents- Few new carriers (>> combination!!).