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Premium member Presentation Transcript Pre-formulation studies: Pre-formulation studies Presented by G.Naveen Y12MPH207, M.pharm-1 st year, Pharmaceutics Under the guidance of Dr. A.Seetha Devi Professor & HOD, Department of PharmaceuticsFramework for product development: Framework for product developmentPre-formulation studies: Pre-formulation studies Studies conducted before the formulation of a drug substance into a dosage form It is essential that drug be chemically and physically characterized Provide the type of information (nature of the drug substance). This information provides the framework for the drug’s combination with pharmaceutical ingredients in the fabrication of a dosage form.Pre-consideration : Pre-consideration The amount of drug available. The physicochemical properties of the drug already known. Therapeutic category and anticipated dose of compound. The nature of information, a formulation should have or would like to have.Goals of pre-formulation: Goals of pre-formulation To establish necessary physicochemical parameters of newly identified drug To determine its kinetic profile To establish its physical characteristics To establish its compatibility with common excipientsEstablishment of analytical methods: Establishment of analytical methods First step in Pre-formulation Attribute Test Identity Nuclear magnetic resonance (NMR) Infra red spectroscopy (IR) Ultraviolet spectroscopy (UV) Thin-layer chromatography (TLC) Differential scanning calorimetry (DSC) Optical rotation Purity Moisture (water and solvents), Inorganic elements, Heavy metals, Organic impurities, Differential scanning calorimetry (DSC) Assay Titration, Ultraviolet spectroscopy (UV) High-performance liquid chromatography (HPLC) Quality Appearance, Odour , Solution colour , p H of slurry (saturated solution), Melting pointPrincipal areas: Principal areas 1 2 3Crystallinity and Amorphous solids: Crystallinity and Amorphous solidsPowerPoint Presentation: Reasons: Synthetic production of drug produces polymorphs with different characters Different crystals of drug have different properties Amorphous compounds revert to stable form changing their propertiesAmorphous solids: Amorphous solids Atoms or molecules arranged in random manner Prepared by rapid precipitation, lyophylization , rapid cooling of solid melts Higher thermodynamic energy, high solubility, high dissolution rate Thermodynamic instability makes it unfit for bulk productionCrystallinity : Crystallinity Crystallinity refers to the degree of structural order in a solid The crystal habit describes the overall shape of the crystal in rather general terms A single internal structure of compound have different habits Different crystal habit leading to different properties (From flow to chemical stability)5 types of crystal habits: 5 types of crystal habits Tabular: moderate expansion of two parallel faces Platy: plates Prismatic: columns Acicular: needle-like Bladed: flat acicular Equant : equal axes , equal faces 1 2 3 4 5 6Polymorphism : Polymorphism It is ability of compound to crystallize more than one distinct crystal species Solubility, stability, bioavailability, flow and many physico chemical properties are effected by polymorphism Polymorphs are classified into Enantiotrophs (one polymorph changed into other form by change of conditions) Monotropic ( polymorp unstable at all temperatures and pressure)Polymorph Screening and Stable form Screening: Polymorph Screening and Stable form Screening Recrystallization under various conditions: the crystallinity of the original solid is removed by dissolving in solutions or melting. Crystallinity is then regenerated under a variety of conditions (such as temperature, solvent, supersaturation , additives, etc.) to see whether it results in other crystal forms. Examining the solid–solid transitions induced by heat, humidity, mechanical stresses, etc.High Throughput Crystallization: High Throughput Crystallization Automation in crystallization The advantages of robotic crystallization over conventional manual crystallization are several Examination of various parameters done quickly Rapidity Requires less material ThoroughnessMiniaturization in Crystallization: Miniaturization in Crystallization Reduces the material needed Studies were conducted using capillary tubes Reduced material consumption (5- 50 μ L of solution)Hygroscopicity : Hygroscopicity Moisture interacts with solids via four primary modes: adsorption, absorption, deliquescence, and lattice incorporation Amount of water absorbed by solid can measured by taking specific amount of sample and exposed to controlled humid conditions of humidity chamber, Gravimetry , MicrocalorimetryParticle size characterization: Particle size characterizationDifferent methods: Different methods Method Measured parameters Light microscopy Size, shape, roughness, size range Polarized light microscopy Crystallinity Scanning electron microscopy Size, shape, roughness, size range Sieving Size, size distribution Light diffraction particle size Quantitative size, distribution, spanPowerPoint Presentation: Method Min, micron Max, micron PSD Shape Texture Grams Crystallinity Microscopy Light 1 1000 Yes Yes Yes < 0.1 No Polarized 1 1000 Yes Yes Yes < 0.1 Yes S E M 0.02 1000 May be Yes Yes < 0.1 No Dynamic image analysis 1 10000 Yes Yes No 2-5 No Light scattering Laser—wet 0.02 2000 Yes No No 1-2 No Laser—dry 0.02 2000 Yes No No 1-2 No Other Sieving 25-50 2000 Yes No No 3-5 NoLight Microscopy: Light Microscopy The sample is usually mounted in a medium that has sufficient contrast to the sample, and in which the sample is insoluble The particles should all be in the same plane, be adequately separated from each other, and should represent the size and distribution of the entire sample population Particle shape parametersPolarized microscopy: Polarized microscopyScanning electron microscopy (SEM): Scanning electron microscopy (SEM) Requires more time-consuming sample preparation than optical microscopy Fine beam of electrons scan across the prepared sample in a series of parallel tracks The electrons interact with the sample, and produce several different signals which can be detected and displayed on the screen of a cathode ray tubeLight diffraction: Light diffractionDynamic image analysis: Dynamic image analysisSieving: Sieving Simple method that is used for determining the particle size distribution of a powder Most suitable for powders whose average particle size is greater than 25–50 microns API is not usually evaluated by sieving due to the particle size limitations, as well as the more irregular particle shapes Used for formulations or excipients since larger quantities are neededMechanical sieving: Mechanical sieving Tapping also helps to de-agglomerate samples with electrostatic, hygroscopic or other adhesion problems log–log plot (sieve size versus cumulative percent)Sonic sieving: Sonic sieving For material-sparing sieving, a sonic sifter using 3-inch sieves Sieving combines two motions Vertically oscillating air column to lift particles and carry them back against mesh openings at several thousand pulses per minute, Repetitive tapping pulse to help reduce sieve blinding. Sieve series are arranged in increasing order of sieve number or decreasing order of sieve aperture sizeParticle size by Andreasen apparatus: Particle size by Andreasen apparatus Stokes's law d st = √18 η o h/( ρ s - ρ 0 ) gt h is the distance of fall in time t d st is the mean diameter of the particles based on the velocity of sedimentation ρ s is the density of the particles ρ 0 that of the dispersion medium g is the acceleration due to gravity η 0 is the viscosity of the medium.Air Permeability Method (surface area): Air Permeability Method (surface area)Determination of particle volume by Coulter counter : Determination of particle volume by Coulter counterSolubility : SolubilityPowerPoint Presentation: Most important physico -chemical property The determination of drug solubility and ways to alter it are essential components of pharmaceutical development The bioavailability of an orally administered drug depends primarily on its solubility in the gastrointestinal tract and its permeability across cell membranes.PowerPoint Presentation: Solubility should ideally be measured at two temperatures: 4°C to ensure physical stability and extend short-term storage and chemical stability until more definitive data are available. The maximum density of water occurs at 4°C.This leads to a minimum aqueous solubility. 37°C to support biopharmaceutical evaluationBasic Concepts of Solubility and Dissolution: Basic Concepts of Solubility and Dissolution A true solution is a homogenous mixture of two or more components on a molecular level. Formation of solution Solute is placed in solvent Solute molecules start to break away from the surface and pass into the solvent system Detached solute molecules are free to move randomly throughout the solvent bulk forming a uniform solution Some of these solute molecules strike the bulk solute surface and redeposit on it Once sufficient solute molecules have populated the solvent bulk, the rate of molecules leaving becomes equal to the rate of redeposition (dynamic equilibrium)PowerPoint Presentation: The concentration of the solute in the solvent at which this equilibrium is reached is defined as the thermodynamic solubility The rate at which the equilibrium is achieved is the dissolution rate. Thus, solubility is an equilibrium concept, while dissolution is a kinetic phenomenon and dependent on the experimental conditions, including temperatureNoyes –Whitney equation: Noyes –Whitney equation The dissolution rate of a solute in a solvent is directly proportional to its solubility dM / dt is the rate of mass transfer D is the diffusion coefficient (cm 2 /sec) A is the surface area of the drug (cm 2 ) h is the static boundary layer (cm) Cs is the saturation solubility of the drug Ct is the concentration of the drug at time ( t )Intrinsic solubility (C0): Intrinsic solubility (C 0 ) The fundamental solubility when completely unionized. The solubility value obtained in acid for a weak acid or alkali for a weak base can be assumed to be the intrinsic solubility (C 0 )Effect of drug: solvent ratio on solubility when the drug is impure: Effect of drug: solvent ratio on solubility when the drug is impurePartition coefficient : Partition coefficient The octanol – water partition coefficient is the ratio of the activities of the solute in octanol ( a o ) and that in water (a w ). For dilute solutions where the activity coefficient is close to unity S o and S w are the solubilities of the liquid solute in octanol and waterMethods determining K: Methods determining K Shake-Flask Method Potentiometric Titration Chromatographic Hydrophobicity IndexChromatographic Hydrophobicity Index: Chromatographic Hydrophobicity Index In reversed-phase liquid chromatography, the lipophilicity of compounds governs their retention. Fast gradient reversed-phase retention time to a Chromatographic Hydrophobicity Index (CHI) using a set of test compounds to calibrate the HPLC system CHI can serve as an alternative to logKPotentiometric Titration: Potentiometric Titration Preacidied solution of a weak acid is alkalimetrically titrated to some appropriately high pH Partition solvent ( Octanol ) is then added, and the dual-solvent mixture is acidimetrically titrated back to the starting pH Analysis of the two titration curves will yield two pKas : pKa and poKa ( poKa is the apparent constant derived from the octanol -containing segment of data)PowerPoint Presentation: For an acid PHA = (10 +( poKa−pKa ) − 1)/r For a base, PB = (10 −(poKa−pKa) − 1)/r r = volume of the organic phase/volume of the aqueous phaseThe General Solubility Equation: The General Solubility Equation log 10 ( S w ) = - A log 10 (K ow ) + B A and B are solute specific constants log 10 ( S w ) = log 10 (S o ) - log 10 (K ow ) For solutes that are completely miscible with octanol log 10 ( S w ) = 0.5- log 10 ( K ow )pKa from solubility data: p Ka from solubility data Henderson- Hasselbalch equations for weak bases and acids To determine p Ka by following changes in solubility To predict solubility at any pH, provided that the intrinsic solubility (C 0 ) and p Ka are known To facilitate the selection of suitable salt-forming compounds and predict the solubility and pH properties of the salts.PowerPoint Presentation: Factors effecting pKa Buffer, temperature, ionic strength, co solvent Methods Spectroscopy Potentiometry Phase equilibrium methodPotentiometric titration: Potentiometric titrationSpectrophotometry: Spectrophotometry Determination of the ratio of molecular species (neutral molecule) to ionized species in a series of nonabsorbing buffer solutions “Analytical wavelength,” is chosen at which the greatest difference between the absorbances of the two species is observedPowerPoint Presentation: For acids, pKa = pH+ log A I − A/A− A M pKa = pH+ log A− A I /A M − A For bases, pKa = pH+ log A− A M /A I − A pKa = pH+ log A M − A/A− A IPhase Equilibria: Phase Equilibria Calculated from the pH-solubility profile For bases, pKa = pH+ log (S T /[B] s − 1) For acids, pKa = pH− log (S T /[A] s − 1)Solubility Enhancement by pH Control and Salt Formation: Solubility Enhancement by p H Control and Salt Formation pH-solubility of free acid or its saltSolubilization Using Complexation: Solubilization Using Complexation Complexation may be defined as reversible non-covalent interaction between m molecules of drug with n molecules of a ligand species The equilibrium constant K m:nPhase solubility diagrams: Phase solubility diagrams Phase solubility diagrams 2 types Type A phase diagrams (wherein the complex is soluble and does not precipitate irrespective of the ligand concentration) Type B phase diagrams (wherein the complex precipitates when the ligand concentration reaches a critical value)A phase diagrams: A phase diagramsB phase diagrams: B phase diagramsSolubilization by Cosolvents: Solubilization by Cosolvents Cosolvents are partly polar, due to the presence of hydrogen bond donors, Cosolvents are partly polar, due to the presence of hydrogen bond donors The presence of cosolvents in aqueous medium leads to reduction in properties (surface tension, dielectric constant, and solubility parameter) that are reflective of solvent polarity The addition of cosolvent can lead to increase or decrease in solubility, depending on the polarity of the drug candidatePowerPoint Presentation: Equation describing the solubilization by a cosolvent S mix is the solubility in the mixed solvent f c as the fractional cosolvent volume S w is the solubility in water σ is defined as the solubilizing power of the cosolventPowerPoint Presentation: In form of y = mx +c, slope = σ and given by K ow is the octanol – water partition coefficient S and T are characteristic constants of particular cosolventDisadvantages of cosolvancy: Disadvantages of cosolvancy Toxicity especially at high concentrations of cosolvant Dilution may lead to precipitation of drugSolubilization by Surfactants: Solubilization by Surfactants Surfactants are amphiphilic molecules that self associate in solution and form aggregated structures known as micelles Micellization occurs only above the critical micellar concentration (CMC) At surfactant concentrations above the CMC the total solubility of the drug P T is the total surfactant concentration drug, and k is a proportionality constantMethods determining solubility: Methods determining solubility Whether to determine Thermodynamic equilibrium solubility or a Kinetic dissolution rate Mainly consists of 2 parts Saturating the solvent with the solute Measuring the amount of solute present per unit of the solvent at that saturation state by analytical techniques like UV, GravimetryPermeability : PermeabilityPowerPoint Presentation: The effective permeability coefficient ( P eff ) C in and C out are the inlet and outlet concentration of the compound in the perfusate Q in is the flow rate of perfusion medium entering in the intestinal segment 2π rL is the mass transfer surface area within the intestinal segment that is assumed to be the area of a cylinder, with length L and radius r.Classification : Classification Effective Permeability ( P eff ) (cm/s) Classification Comments ≤0.1× 10 −6 Low Will have permeability problems 0.1–1× 10 −6 Moderate May have permeability problems ≥1× 10 −6 High No permeability problemCaco -2 cell cultured well or cup: Caco -2 cell cultured well or cupCaco-2 Measurement: Caco-2 Measurement Epithelia Voltohmmeter , from which transepithelial electrical resistance (TER) for integrity Aliquot samples are taken from the receiver chamber over a period of 120 min and are analyzed by HPLC The experiments are performed in both apical to basolateral (A→ B) and basolateral to apical (B→A) directions under nongradient pH conditions (pH 7.4 on both sides) and pH-gradient conditions (pH 5.5 apically, pH 7.4 basolaterally )PowerPoint Presentation: Metoprolol , Propranolol , and Atenolol are commonly used as controls in permeability measurement ( Metoprolol is generally used in the manual method and Propranolol in the automated method). If the apparent permeability coeffcient (P app ) of drug , in the apical (A) to basolateral (B) direction, is higher than that of Metoprolol , the drug may have good permeability. If P app of (B →A)/(A → B) is higher than 1, the drug may have efflux in the Caco-2 system.Everted Gut Sac Technique: Everted Gut Sac TechniqueIn Situ Method (Rat jejunal perfusion): In Situ Method (Rat jejunal perfusion)Ussing Chamber: Ussing Chamber Krebs–Ringer bicarbonate buffer (KRB) with a mixture of O 2 :CO 2 (95:5).Intestinal Perfusion in Man: Intestinal Perfusion in ManFranz diffusion cell: Franz diffusion cellBiopharmaceutical Classification System: Biopharmaceutical Classification SystemMelting point: Melting pointTechniques: Techniques Capillary melting Hot stage microscopy Differential scanning calorimetry or thermal analysis.Capillary melting: Capillary meltingHot stage microscopy: Hot stage microscopyDifferential scanning calorimetry and thermal analysis: Differential scanning calorimetry and thermal analysisSalt Screening and Selection: Salt Screening and SelectionPotential pharmaceutical salts: Potential pharmaceutical salts Basic drugs (Anions) Acidic drugs ( Cation ) Hydrochloride Sulphate Mesylate Maleate Phosphate Salicylate Tartrate Lactate Citrate Succinate Acetate Potassium Sodium Lithium Calcium Magnesium Diethanolamine Zinc Choline AluminiumPowerPoint Presentation: The solubility of an organic molecule is frequently enhanced more by an ionized functional group Salt form of a drug is usually more soluble than the non-ionized form in an aqueous medium A salt form also can impact other physico -chemical properties of the drug substance, such as hygroscopicity , chemical stability, crystal form, and mechanical properties. Salt form has profound impact on biopharmaceutical and pharmaceutical properties Appropriate choice of the most desirable salt form is a critical step in the development process.pH-Solubility Profiles and the Role of pKa: p H -Solubility Profiles and the Role of p Ka BH + H 2 O B + H 3 O + K’ a = apparent dissociation constant of HB + S T = [BH + ] + [B] S T = sum of the individual concentrations respective species K’ apH-solubility profile of an ideal basic compound: p H -solubility profile of an ideal basic compound The pH-solubility profile of an acidic drug is the mirror image of the profile of a basic drugPrediction of Salt Solubility (In Situ Salt Screening): Prediction of Salt Solubility (In Situ Salt Screening) X p = X – S . V X p (The amount of the compound precipitated) X (mg) is the amount of solid base added S (mg/ mL ) is the solubility in the acid solution which is determined from solubility studies V ( mL ) is the volume of the solution.PowerPoint Presentation: Concentration of the acid remaining in solution, [A S ] [A] is the concentration of the acid used MW is the compound’s molecular weightPowerPoint Presentation: Knowing the ionization constant of the acid, p Ka ’ and the pH of the saturated solution The concentration of the acid in its ionized form, [A ionized ],PowerPoint Presentation: The molar concentration of the compound in solution is The K SP of the salt can then be calculated byPowerPoint Presentation: Finally, the solubility of the salt, S salt (mg/ mL ) MW s is the molecular weight of the respective salt form of the drugSolubility and Dissolution Rate of Salts: Solubility and Dissolution Rate of Salts Noyes–Whitney equation D is the diffusion coefficient h is the thickness of the diffusion layer at the solid liquid interface A is the surface area of drug exposed to the dissolution media V is the volume of the dissolution media C s – C is concentration gradiationDissolution of Salts in GI Fluids: Dissolution of Salts in GI Fluids Factors that may affect the extent of solubilization include Hydrophobicity (log P) Molecular weight of the drug Specific interactions between drug and bile salts Common ions, such as Cl – and Na + Supersaturation in the intestinal fluidBehavior of salt of basic drug: Behavior of salt of basic drugBehavior of salt of acidic drug: Behavior of salt of acidic drugIn vitro dissolution method: In vitro dissolution method Intrinsic dissolution rate The rate of diffusion is directly proportional to the saturated concentration of the drug in solution υ is the kinematic viscosity ω is the angular velocity of a rotating disc of drugPowerPoint Presentation: By maintaining the dissolution fluid viscosity and rotational speed of the sample constant, the dissolution rate (dc/ dt ) from a constant surface area (A) will be constant and related solely to solubility. Under sink conditions (Cs >>>C) gives Intrinsic dissolution rate (IDR) is given byDissolution apparatus: Dissolution apparatusMeasurement of intrinsic dissolution rate: Measurement of intrinsic dissolution rate A compressed disc of material can be made by slow compression of 500 mg of drug in a 13 mm IR disc punch and die set to a high compaction pressure greater than 500 MPa (to ensure zero porosity) and a long dwell time (to improve compaction). The metal surfaces in contact should be prelubricated with stearic acid (5% w/v in chloroform)PowerPoint Presentation: The compressed disc is fixed to the holder of the rotating basket apparatus using a low-melting paraffin wax and successively dipped so that the top and sides of the disc are coated. The lower circular face should be cleared of residual wax using a scalpel and carefully scraped to remove any stearic acid transferred from the punch face.Conditions maintained: Conditions maintained 100 rpm speed 20 mm from the bottom of a 1 L flat-bottomed dissolution flask containing 1 L of fluid 37°C temperaturePowerPoint Presentation: Each compressed candidate should be measured in 0.05 M HCl (gastric) and phosphate buffer pH 7 (intestinal), and distilled water The amount of drug release is then monitored, usually by UV spectrometry, with time. The slope of the line of amount released Vs time gives the IDRSimulated dissolution fluids: Simulated dissolution fluids FaSSIF (Simulating Fasted state intestinal fluid) FeSSIF (Simulating fed-state intestinal fluid) FaSSIF FeSSIF KH 2 PO 4 0.39% (w/w) Acetic acid - 0.865% (w/w) Na taurocholate 3 mM 15 mM Lecithin 0.75 mM 3.75 mM KCl 0.77% 1.52% (w/w) p H 6.5 5.0γ-Scintigraphy: γ - Scintigraphy Radionuclides Indium ( 111 In) Iodine ( 131 I) Chromium ( 51 Cr) Erbium ( 170 Er) Ytterbium ( 175 Yb) Barium ( 138 Ba) Samarium ( 153 Sm)Potential Disadvantages of Salts: Potential Disadvantages of Salts Common ion effect for compounds with poor solubility, such as an HCl salt; Poor chemical stability in gastric fluid Poor solid-state stability at the microenvironment p H of the salt Precipitation of free acid/base form on the solid surface that reduces the dissolution rate of salts.Powder characterization: Powder characterizationTrue Density: True Density Average mass of the particles divided by the solid volume There are three basic methods for determining true density: Gas pycnometry or displacement; Liquid displacement; and Flotation in a liquidGas pycnometry: Gas pycnometry Easy, reproducible and reliable, non-destructive Material can be reused after testing is complete ρ = ω / V s ω is the weight of the sample V s is the powder volume True density is used to calculate solid fractionBulk Density: Bulk Density Bulk density is the mass per unit volume of a loose powder bed Bulk Density(g/ mL ) = M/V o M mass in grams V o untapped apparent volume in milliliters The unit volume includes the spaces between the particles, and the envelope volumes of the particles themselves depend on a number of powder properties, including particle shape , particle size distribution, inter- particle friction, and cohesionMethod I—Measurement in a Graduated Cylinder: Method I—Measurement in a Graduated Cylinder Pass a quantity of material sufficient to complete the test (approx. 100 g ) through a 1.00-mm (No. 18) Into a dry 250-mL cylinder introduce, without compacting Carefully level the powder without compacting Read the unsettled apparent volume, V o Calculate the bulk density, in g per mL , by the formula: (M) / (Vo)Method II—Measurement in a Volumeter (Scott Volumeter): Method II—Measurement in a Volumeter (Scott Volumeter ) Allow an excess of powder to flow through the apparatus into the sample receiving cup until it overflows Carefully scrape excess powder from the top of the cup Remove any material from the sides of the cup Determine the weight, M V o is the volume, in mL , of the cup Calculate the bulk density, in g per mL , by the formula: (M ) / (Vo)Tapped Density: Tapped Density Tapped density of a powder is the ratio of the mass of the powder to the volume occupied by the powder after it has been tapped for a defined period of time Tapped Density(g/ mL ) = M/ V fTapped density apparatus: Method 1 Method 2 Fixed drop of 14 ± 2 mm Fixed drop of 14 ± 3 mm 300 drops per minute 250 drops per minute is used Tapped density apparatusMeasuring tapped density: Measuring tapped density Into a dry 250-mL glass graduated cylinder (readable to 2 mL ) weighing 220 ± 44 g and mounted on a holder weighing 450 ± 10 g introduce, without compacting, approximately 100 g of test sample, M Tap the cylinder 500 times initially and measure the tapped volume, V a Repeat the tapping an additional 750 times and measure the tapped volume, V b If the difference between the two volumes is less than 2%, V b is the final tapped volume, V f Repeat in increments of 1250 taps, as needed, until the difference between succeeding measurements is less than 2%Compressibility Index: Compressibility Index Measure of the relative importance of inter-particulate interactions CI(% ) = 100( V 0 -V f )/V o V o = untapped apparent volume V f = tapped apparent volume Hausner ratio Hausner Ratio=V o /V fPowerPoint Presentation: Flow character Compressibility index Hausner ratio Excellent ≤10 1.00–1.11 Good 11-15 1.12–1.18 Fair 15-20 1.19–1.25 Passable 21-25 1.26–1.34 Poor 26-31 1.35–1.45 Very poor 32-37 1.46–1.59 Very, very poor >38 >1.60Angle of Repose: Angle of Repose Angle of repose is a characteristic related to inter-particulate friction or resistance to movement between particles It is the constant, three-dimensional angle (relative to the horizontal base) assumed by a cone-like pile of material formed by any of several different methods (funnel, open cylinder)Relation between angle of repose and flow: Relation between angle of repose and flow Angle of repose (degrees) Type of flow <20 Excellent 20-30 Good 30-34 Passable >40 Very poorIdealized cohesive strength test: Idealized cohesive strength testShear cell analysis method: Shear cell analysis method Shear cell methods allow the assessment of flow properties as a function of consolidation load and time, as well as powder–hopper material interactions Most common type - Jenike shear cell Jenike Direct Test Method generates Mohr’s circle to plot the shear stress ( τ ) versus the consolidation pressure ( σ ); Effective yield locus; Flow function.Jenike shear cell: Jenike shear cellMohr stress circles: Mohr stress circlesJenike yield locus: Jenike yield locus The line gives the stress conditions needed to produce flow for the powder when compacted to a fixed bulk density. If the material is cohesive, the yield locus does not produce a straight line, and it does not pass through the origin. Intercept OT is the tensile strength of the consolidated specimen, and OC is the cohesion of the specimen, that is, the shear stress needed to initiate movement of the material when it is not subjected to normal forceNumerical characterization of flowability: Numerical characterization of flowability ff c = σ 1 / σ c Unconfined yield strength = σ c Consolidation stress = σ 1 ff c < 1 - not flowing 1 < ff c < 2 - very cohesive 2 < ff c < - 4 cohesive 4 < ff c < 10 - easy-flowing 10 < ff c - free-flowingAvalanching Behavior: Avalanching BehaviorCompact (mechanical property) characterization: Compact (mechanical property) characterizationStress–strain curve: Stress–strain curveSolid fraction ( SF ) of a compact: Solid fraction ( SF ) of a compact SF = Wt/ ρ true ν ν = Tablet volume Wt = Tablet weight The relationship between the solid fraction and porosity ( ε ) ε = 1 /SFQuasi-static Testing: Quasi-static Testing Methods for characterizing the elastic, plastic, and brittle properties of compacts These tests measures of tableting performance Material required for testing varies from 1 to 100 grams 3 steps: Test Specimen Preparation Tensile Strength Determination Tableting Indices DeterminationTensile Strength Determination (static testing): Tensile Strength Determination (static testing) 1)Square compacts using triaxial compression are prepared free of defects in a split die 2) Split die permits triaxial decompression such that the pressure applied to all three axes is essentially equal during the decompression processTensile Strength Determination(Dynamic testing): Tensile Strength Determination(Dynamic testing) Powder is compressed into square or circular compacts transversely ( like tablets) Conventional hardness testing of tablets can result in a measurement of tensile strengthPendulum Impact Device: Pendulum Impact Device Flat-faced, square tablets of the test substance are compressed at different compression pressures, and then subjected to impact with a stainless steel ball The rebound height of the ball and the chordal radius of the dent are carefully measured, and used to calculate the permanent deformation pressureTableting Indices: Tableting Indices Relative measures of properties that reflect the performance of materials during processing They are: Bonding index Brittle fracture index Viscoelastic indexBonding index: Bonding index BI = σ T /H σ T is the tensile strength of the compact at a given solid fraction H is the permanent deformation pressure (i.e., hardness) of a compact at the same solid fraction A bonding index in excess of 0.01 (range 0.001 to 0.06) is typically desiredBrittle fracture index: Brittle fracture index BFI = 0.5[( σ T /σ T0 )-1] σ T = tensile strength of a compact σ To = tensile strength of a compact with small hole (stress concentrator) Brittle index Nature Very brittle compacts 1 Non brittle Materials range 0 to 1Visco-elastic index: Visco -elastic index If a material is very viscoelastic , substantial stress relaxation with time Some of the stresses developed during compaction will have a chance to be relieved Ratio of the dynamic to quasi-static indentation hardness VE = H d / H qs = BI qs / BI d (H = hardness BI= bonding index )Application of Quasi-static Testing: Application of Quasi-static Testing Fundamental understanding of critical mechanical properties of the active ingredient and excipients ; Identification of mechanical property deficiencies and attributes; Selection of excipients that can overcome deficiencies of active ingredient Identification of lot-to-lot variations in materials; Identification of potential manufacturing problems associated with tableting processDynamic Testing: Dynamic Testing Studying the mechanical properties of solids under dynamic conditions Equipment used: Hydraulic press Eccentric (single station) tablet press Rotary tablet press Compaction simulator Compaction emulator commonly usedPowerPoint Presentation: Compaction simulator Compaction emulator( Presster )Heckel plot: Heckel plot Compaction pressure versus tablet porosity (compressibility) “ in die ” Heckel plot or “ out of die ” constructed Out of die measurements is that they represent the “final product ” after decompression and ejectionAthy–Heckel equation: Athy–Heckel equation Change in solid fraction (i.e., relative density) with compaction pressure is proportional to the porosity of the compact d ρ r / dP α ε ( ε =1- ρ r ) Integrating yeilds In[1/1- ρ r ] = k P + A k is a measure of the plasticity of the material k =1/3y y = yeild strength(is a measure of the deformability)PowerPoint Presentation: Theoretical Heckel plot Heckel plots of pharmaceutical powdersApplication of Dynamic Testing: Application of Dynamic Testing Properties can be determined under dynamic conditions representing those in a production environment Small quantities are typically required Compactibility : tensile strength and solid fraction Tabletability : tensile strength and compression pressure Compressability : compaction pressure and solid fraction or porosity Manufacturability : tablet crushing force and compression forceExcipient compatibility: Excipient compatibilityPowerPoint Presentation: The selection of excipients is vital in the design of a quality drug product Excipients and their concentration in a formulation are selected based not only on their functionality, but also on the compatibility between the drug and excipientsPowerPoint Presentation: An incompatibility in dosage form can result in any of the following changes: Change in color/appearance; Loss in mechanical properties (e.g., tablet hardness) Changes to dissolution performance; Physical form conversion Loss through sublimation Decrease in potency Increase in degradation productsMethod : Method Drug Excipient 50% mixture Interaction No interaction TLC Recommended excipient No Yes Significant breakdown? Alternative excipient DSCDrug Stability and Product Stability Studies: Drug Stability and Product Stability StudiesPowerPoint Presentation: Drug degradation occurs by four main processes Hydrolysis Oxidation Photolysis Trace metal catalysisAccelerated stability testing: Accelerated stability testing All medicinal products decompose with time As time factor is limited accelerated stress conditions selected Objectives of accelerated tests: Rapid detection of deterioration in different initial formulations of the same product The prediction of shelf-life (time in which product will remain satisfactory when stored under expected or directed storage conditions) The provision of a rapid means of quality controlFor drug substances: For drug substances Study Storage condition Minimum time period covered by data at submission Long term 25°C ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH 12 months Intermediate 30°C ± 2°C/65% RH ± 5% RH 6 months Accelerated 40°C ± 2°C/75% RH ± 5% RH 6 monthsFor drug products: For drug products Study Storage condition Minimum time period covered by data at submission Long term 25°C ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH 12 months Intermediate 30°C ± 2°C/65% RH ± 5% RH 6 months Accelerated 40°C ± 2°C/75% RH ± 5% RH 6 monthsDetermining water loss for liquids stored in semi permeable containers: Determining water loss for liquids stored in semi permeable containers Alternative relative humidity Reference relative humidity Ratio of water loss rates at a given temperature 60% RH 25% RH 1.9 60% RH 40% RH 1.5 65% RH 35% RH 1.9 75% RH 25% RH 3.0Solid-state Thermal Degradation Studies: Solid-state Thermal Degradation Studies Isothermal microcalorimetry Reactivity of solids with water (20% by weight added water to solid, 50–60°C) Detect most complex reactions, such as Milliard reaction Dynamic moisture sorption gravimetric analysis and thermal gravimetric analysis Hydrate formation at the selected temperaturesOxidative Degradation Studies: Oxidative Degradation Studies Azobisisobutyronitrile (AIBN) + Drug molar ratios - 0.2 to 1.0 Temperature – 40 0 C Hydrogen peroxide concentration range of 0.3% to 30% Fe +3 and Cu +2 EDTA complexes Rose Bengal dyePhoto degradation Studies: Photo degradation Studies Test chambers equipped with an ICH Type I light source, xenon arc lamp Samples packaged in clear glass containers or packaging amber colored bottles wrapped in aluminum foil After exposure ( hrs to 1 day) assayedReferences : ReferencesPowerPoint Presentation: Thank you You do not have the permission to view this presentation. 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