M pharm dissolution

M pharm dissolution

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  DRUG DISSOLUTION
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  Definition- • Dissolutionis a process in which a solid substance solubilizes in a given solvent i.e. mass transfer from the solid surface to the liquid phase. • Rate of dissolution is the amount of drug substance that goes in solution per unit time under standardized conditions of liquid/solid interface, temperature and solvent composition. 2
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  DDrruugg DDiissssoolluuttiioonn PPrroocceessss
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  • Initial mechanical lag • Wetting of dosage form • Penetration of dissolution medium • Disintegration • Deaggregation • Dissolution • Occlusion of some particles 4
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   Intrinsic dissolutionrate (IDR), which is the rate of mass transfer per area of dissolving surface and typically has the units of mg cm-2 min- 1.  IDR should be independent of boundary layer thickness and volume of solvent. Thus IDR measures the intrinsic properties of the drug only as a function of the dissolution medium, e.g. its pH, ionic strength, counters ions etc. 5
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  Where:  m- Amount of dissolved material, kg  t - Time, seconds  A - Surface area of the interface between the dissolving substance and the solvent,m2  D - DDiiffffuussiioonn ccooeeffffiicciieenntt, m2/s  d - Thickness of the boundary layer of the solvent at the surface of the dissolving substance, m  Cs - concentration of the substance on the surface, kg/m3  Cb - concentration of the substance in the bulk of the solvent, kg/m3 6
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   Application:2 7
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  Theories of DrugDissolution I. Diffusion layer model/Film Theory II. Danckwert’s model/Penetration or surface renewal Theory III. Interfacial barrier model/Double barrier or Limited solvation theory.
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  I. Diffusion layermodel/Film Theory :- • It involves two steps :- a. Solution of the solid to form stagnant film or diffusive layer which is saturated with the drug b. Diffusion of the soluble solute from the stagnant layer to the bulk of the solution; this is r.d.s in drug dissolution.
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  • The rateof dissolution is given by Noyes and Whitney: = k (Cs- Cb) dc dt Where, dc/dt= dissolution rate of the drug K= dissolution rate constant Cs= concentration of drug in stagnant layer Cb= concentration of drug in the bulk of the solution at time t
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  Modified Noyes-Whitney’s Equation- dC dt DAKw/o (Cs – Cb ) Vh = Where, D= diffusion coefficient of drug. A= surface area of dissolving solid. Kw/o= water/oil partition coefficient of drug. V= volume of dissolution medium. h= thickness of stagnant layer. (Cs – Cb )= conc. gradient for diffusion of drug.
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  Sink condition ASink conditions describe a dissolution system that is sufficiently dilute so that the dissolution process is not impeded by approach to saturation of the compound of interest. Sink conditions affect the production of the sample but not the condition of the solution upon sampling. In vivo condition, there is no conc. build up in the bulk of the solution and hence no retarding effect on the dissolution rate of the drug i.e. Cs>>Cb and sink condition maintain. 13
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  • Dissolution rateunder sink condition follow zero order dissolution rate. Conc of disslove drug Time Zero order dissolution Under sink condition First order under non sink condition 14
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  For obtaining IVIVCsink condition can be achieved by: 1) Bathing the dissolving solid in fresh solvent from time to time. 2) Increasing the volume of dissolution fluid. 3) Removing the dissolved drug by partitioning it from the aqueous phase of dissolution fluid into the organic phase placed either above or below the dissolution fluid for e.g. hexane or chloroform. 4) Adding a water miscible solvent such as alcohol to the dissolution fluid. 5) By adding selected adsorbents to remove the dissolution drug. • In vitro sink condition is so maintain that Cb always less than 10% of Cs. 15
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   HIXON-CROWELL CUBEROOT RELATIONSHIP • Major assumptions in Noyes-Whitney relationship is that the S.A.(A) term remains constant throughout dissolution process. This is true for some formulations, such as transdermal patches. • However, size of drug particles from tablets, capsules and suspensions will decrease as drug dissolves. • This decrease in size of particles changes the effective S.A. • Thus, Hixon & Crowell modified the eq to represent rate of appearance of solute by weight in solution by multiplying both sides of volume term. W01/3– W1/3 = kt W0 = original mass of drug W = mass of drug remaining to dissolve at time t K = dissolution rate constant 16
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  • This isfirst order dissolution rate process, for which the driving force is concentration gradient. • This is true for in-vitro dissolution which is characterized by non-sink conditions. • The in-vivo dissolution is rapid as sink conditions are maintained by absorption of drug in systemic circulation i.e. Cb=0 and rate of dissolution is maximum.
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  • Under sinkconditions, if the volume and surface area of the solid are kept constant, then dC dt = K • This represents that the dissolution rate is constant under sink conditions and follows zero order kinetics.
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  II. Danckwert’s model/Penetrationor surface renewal Theory :- • Dankwert takes into account the eddies or packets that are present in the agitated fluid which reach the solid-liquid interface, absorb the solute by diffusion and carry it into the bulk of solution. • These packets get continuously replaced by new ones and expose to new solid surface each time, thus the theory is called as surface renewal theory.
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  • The Danckwert’smodel is expressed by equation dC dt = dm V = A (Cs-Cb). γ D dt Where, m = mass of solid dissolved Gamma (γ) = rate of surface renewal
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  III. Interfacial barriermodel/Double barrier or Limited solvation theory :- • The concept of this theory is explained by following equation- G = Ki (Cs - Cb) Where, G = dissolution rate per unit area, Ki = effective interfacial transport constant.
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  3) Interfacial layermodel S Film boundary Bulk solution Cs C Stagnant layer In this model it is assumed that the reaction at solid surface is not instantaneous i.e. the reaction at solid surface and its diffusion across the interface is slower than diffusion across liquid film. therefore the rate of solubility of solid in liquid film becomes the rate limiting than the diffusion of dissolved molecules equation : dm/dt = Ki (Cs – C ) K = effective interfacial transport rate constant
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  Biopharmaceutical Classification System High Solubility (Dose Vol. NMT 250 mL) Low Solubility (Dose Vol. >250 mL) High Permeability (Fract. Abs. NLT 90%) CLASS І e.g. Propranolol metoprolol CLASS II e.g. piroxicam, naproxen Low Permeability (Fract. Abs. <90%) CLASS III e.g. ranitidine cimetidine CLASS IV e.g. furosemide hydrochlorothiazide
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  Drug release mechanismin CDDS Slow zero order release Slow first order release Initial rapid release followed by slow zero order release Initial rapid release followed by slow first order release
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  • Zero orderkinetics • First order kinetics • Hixoncrowell cube-root model • Higuchi model • Korsmeyer peppas model
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  • The equationfor zero order kinetics is Qt=Qo+Kot Qo=initial amount of drug Qt=cumulative drug released at t Ko=zero order release constant t= time in hours • It describes the system where the drug release rate is independent of its concentration of the dissolved substance.
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  • A graphis plotted between the time taken on x axis and cumulative percentage of drug release on y axis and it gives straight line Time(hours) Cummulative %of drug release
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  • First orderrelease equation is logQt=logQo + Kt/2.303 Qt=cumulative amount of drug released at time t Qo= initial amount of drug K= first order rate constant t= time in hours • Here the drug release rate depends on concentration ( unimolecular reaction)
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  • A graphis plotted between time taken on x- axis and log cumulative percentage of drug release on y- axis will give a straight line Time(hours) Log % of drug release
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  • THE HIXSON-CROWELLRELEASE EQUATION IS ∛Qo-∛Qt=KHCt Qo=initial amount of drug Qt= cumulative amount of drug released at time t KHC= hixson crowell release constant t= time in hours • It describes the drug releases by dissolution and with the change in surface area and diameter of particle.
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  • A linearplot of cube root initial concentration minus cube root of percent remaining vs time gives straight line . • And release is dissolution rate controlled. • slope gives K value Time (hours) ∛Qo-∛Qt
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  • Higuchi equationis Q=[Dt/Ƭ (2A-tCs)Cst]1/2 or Q=Kt1/2 Q=cumulative drug release at time t D= diffusion coefficient of drug in in matrix Cs=solubility of drug in polymeric matrix Ƭ= tortuosity of capillary system A=total amount of drug in unit volume matrix K= higuchi release constant • Higuchi equation suggest s that the drug release is by diffusion
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  • A graphis plotted with square root of time taken on x-axis and cumulative % of drug release on y- axis • It gives a straight line, slope gives K value √Time ( hours) cumulative % of drug release
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  • Korsmeyer –peppasequation is F=Mt/M∞ = Ktn F= fraction of drug released at time t Mt=amount of drug released at time t M∞=amount of drug released at infinite time K= kinetic constant t= time in hours n= diffusion or release exponent • n is estimated from linear regression of (Mt/M∞) vs time(t) • If n= 0.45 then indicate fickian diffusion • If o.45<n<0.89 then indicates anomalous diffusion or non-fickian diffusion • If n= 0.89 then indicates case-2relaxtaion or super case transport-2
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  • A graphis plotted between log time taken on x-axis and log of cumulative percentage of drug release at y-axis it gives a straight line. Log time cumulative % of drug release
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  Classification • Thereare basically three general categories of dissolution apparatus : 1. Beaker methods 2. Open flow-through compartment system 3. Dialysis concept
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  1. BEAKER METHODS
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  to accessing therapeuticefficacy. Monitoring batch to batch consistency. High cost of in vitro dissolution test. Assessment of bioequivalence. Requirement for regulatory approval for product marketing and is a vital component of the quality control program. 40
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  Design: Vessel:- Made up of borosilicate glass  semi hemispherical bottom  Capacity: 1000ml Shaft:-  Stainless steel 316  Rotates smoothly without significance wooble Basket:-  Stainless steel 316  Gold coatings up to 0.0001 inch Water bath:- Maintained at 37± 0.5˚c 42
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  • Dosage formcontained within basket • Dissolution should occur within Basket • pH change by media exchange • Uses: Capsules, tablets, delayed release, suppositories, floating dosage forms. 43
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  • • Drugproduct – Solids (mostly floating) • Monodisperse (tablets) • Polydisperse (encapsulated beads) • Agitation – Rotating stirrer – Usual speed: 50 to 100 rpm • Disadvantage – Formulation may clog to 40 mesh screen 44
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  • Dosage formshould remain at the bottom centre of the vessel • Sinkers used for floaters • Useful for : • – Tablets • – Capsules • pH change by media addition 46
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  • • Drugproduct – Solids (mostly non floating) • Monodisperse (tablets) • Polydisperse (encapsulated beads) • • Agitation – Rotating stirrer – Usual speed: 25 to 100 rpm • Standard volume: 900/1000 ml • Advantages: 1. Easy to use and robust 2. Ph change possible 3. Can be easily adapted to apparatus 5 • Disadvantages – Floating dosage forms require sinker – Positioning of tablet 47
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  48
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  Design: 1.vessel: cylindricalflat bottom glass vessel. 2.Agitation type: -reciprocating -generally 5-35 rpm 3. Volume of dissolution fluids: 200-250 ml 4. Water bath: maintain at 37±0.5˚c 5. Use: extended release 49
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  The assembly consistsof a set of cylindrical, flat-bottomed glass vessels; a set of glass reciprocating cylinders; )stainless steel fittings (type 316 or equivalent) and screens that are made of suitable nonsorbing and nonreactive aterial(polypropelene) and that are designed to fit the tops and bottoms of the reciprocating cylinders; and a motor and drive assembly to reciprocate the cylinders vertically inside the vessels 50
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  • The vesselsare partially immersed in a suitable water bath of any convenient size that permits holding the temperature at 37 ± 0.5 during the test. • The dosage unit is placed in reciprocating cylinder & the cylinder is allowed to move in upward and downward direction constantly. Release of drug into solvent within the cylinder measured. • Useful for: Tablets, Beads, controlled release formulations • Standard volume: 200-250 ml/station • Advantages: 1) Easy to change the pH-profiles 2) Hydrodynamics can be directly influenced by varying the dip rate. • Disadvantages: 1) small volume (max. 250 ml) 2) Little experience 3) Limited data 51
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  Apparatus 3 –Reciprocating cylinder 52
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  USP APPARATUS 4- FLOW THROUGH CELL 54
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  • The assemblyconsists of a reservoir and a pump for the Dissolution Medium; a flow-through cell; a water bath that maintains the Dissolution Medium at 37 ± 0.5 • The pump forces the Dissolution Medium upwards through the flow-through cell. • Assemble the filter head, and fix the parts together by means of a suitable clamping device. • Introduce by the pump the Dissolution Medium warmed to 37 ± 0.5 through the bottom of the cell to obtain the flow rate specified in the individual monograph. • Collect the elute by fractions at each of the times stated. • Perform the analysis as directed in the individual monograph 55
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  Tablets 12 mmTablets 22,6 mm Powders / Granules Implants Suppositories / Soft gelatine capsules • Useful for: Low solubility drugs, Micro particulates, Implants, Suppositories, Controlledrelease formulations • Variations: (A) Open system & (B) Closed system • Advantages: • 1. Easy to change media pH2. PH-profile possible • 3. Sink conditions • Disadvantages: • 1. Deaeration necessary • 2. High volumes of media • 3. Labor intensive 56
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  APPARATUS 4 –FLOW-THROUGH CELL 57
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  Design 1. Vessel: 2. Shaft: 3. Stirring elements 4. Sample holder: - Disk assembly that hold the product in such a way that release surface is parallel with paddle. 5. Paddle is directly attached over disk assembly. 6. Samples are drawn away b/w the surface of medium and top of paddle blade. 7. Volume; 900ml 8. Temperature; 32˚c 58
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  USP APPARATUS 5- PADDLE OVER DISK 59
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  • Use thepaddle and vessel assembly from Apparatus 2 with the addition of a stainless steel disk assembly designed for holding the transdermal system at the bottom of the vessel. • The disk assembly holds the system flat and is positioned such that the release surface is parallel with the bottom of the paddle blade • The vessel may be covered during the test to minimize evaporation. Useful for: Transdermal patches • Standard volume: 900 ml • Disadvantages: Disk assembly restricts the patch size. Borosilicate Glass 17 mesh is standard (others available) Accommodates patches of up to 90mm 60
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  Design; 1. Vessel:in place of basket cylinder is used. 2. Cylinder : stainless steel 316. 3.Sample: - mounted to cuprophan(inner porous cellulosic material) an entire system is adhere to cylinder. -Dosage unit is place in cylinder and released from outside. 4. Water bath : maintain at 32±.0.5˚c Use : transdermal patches can not be cut into small size. 61
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  USP APPARATUS 6- CYLINDER 62
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  • Use thevessel assembly from Apparatus 1 except to replace the basket and shaft with a stainless steel cylinder stirring element • The temperature is maintained at 32°C ± 0.5°C • The dosage unit is placed on the cylinder with release side out • The dosage unit is placed on the cylinder at the beginning of each test, to the exterior of the cylinder such that the long axis of the system fits around the circumference of the cylinder & removes trapped air bubbles. • Place the cylinder in the apparatus, and immediately rotate at the rate specified in the individual monograph. 63
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  USP APPARATUS 7– RECIPROCATING HOLDER 65
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  • The assemblyconsists of a set of volumetrically calibrated solution containers made of glass or other suitable inert material, a motor and drive assembly to reciprocate the system vertically • The temperature is maintained at 32°C ± 0.5°C • • The dosage unit is placed on the cylinder with release side out The solution containers are partially immersed in a suitable water bath of any convenient size that permits maintaining the temperature, inside the containers at 32 ± 0.5 For Coated tablet drug delivery system attach each system to be tested to a suitable Sample holder 66
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  •For Transdermal drugdelivery system attach the system to a suitable sized sample holder with a suitable O-ring such that the back of the system is adjacent to and centered on the bottom of the disk-shaped sample holder or centered around the circumference of the cylindrical-shaped sample holder. Trim the excess substrate with a sharp blade. 67
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  Advantages of theBeaker Methods The basket method is the most widely used procedure which confines the solid dosage form to a limited area which is essential for better reproducibility. It is advantageous for capsules as they tend to float at the surface thus minimizing the area exposed to the dissolution fluid.
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  Limitation of theBeaker Methods Clogging of the basket screen by gummy particles. Tendency of the light particles to float. Sensitivity of the apparatus to variables such as vibration, eccentricity, etc. Rapid corrosion of the SS mesh in presence of HCl. Sensitivity of the apparatus to any slight changes in the paddle orientation. Non-reproducible position of the tablets at the bottom of the flask.
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  2. OPEN FLOW-THROUGH COMPARTMENT SYSTEM The dosage form is contained in a small vertical glass column with built in filter through which a continuous flow of the dissolution medium is circulated upward at a specific rate from an outside reservoir using a peristaltic or centrifugal pump. Dissolution fluid is collected in a separate reservoir. E.g. lipid filled soft Gelatin capsule
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  Advantages No stirringand drug particles are exposed to homogeneous, laminar flow that can be precisely controlled. All the problems of wobbling, shaft eccentricity, vibration, stirrer position don’t exist. There is no physical abrasion of solids. Perfect sink conditions can be maintained.
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  Disadvantages Tendency ofthe filter to clog because of the unidirectional flow. Different types of pumps, such as peristaltic and centrifugal, have been shown to give different dissolution results. Temperature control is also much more difficult to achieve in column type flow through system than in the conventional stirred vessel type.
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  3. DIALYSIS SYSTEM Here, dialysis membrane used as a selective barrier between fresh solvent compartment and the cell compartment containing dosage form. It can be used in case of very poorly soluble rugs and dosage form such as ointments, creams and suspensions.
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  THE ROTATING FILTERMETHOD It consists of a magnetically driven rotating filter assembly and a 12 mesh wire cloth basket. The sample is withdrawn through the spinning filter for analysis.
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  ROTATING FLASK DISSOLUTION METHOD This consists of a spherical flask made of glass and supported by a horizontal glass shaft that is fused to its sides. The shaft is connected to a constant speed driving motor. The flask is placed in a constant temperature water bath and rotates about its horizontal axis.
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  ROTATING AND STATICDISK METHODS The compound is compressed into non disintegrating disc Mounted – One surface is exposed to medium Assumption – Surface area remains constant Used to determine the intrinsic dissolution rate
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  Types of dosageform Release method Solid oral dosage forms(conventional) Basket,paddle,reciprocating cylinder, or flow through cell Oral suspension Paddle Orally disintegrating tablets Paddle Chewable tablets Basket,paddle,reciprocating cylinder Transdermal-patches Paddle over disk Suppositories Paddle, modified basket, or dual chamber flow through cell 80
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  FACTORS AFFECTING DISSOLUTION RATE4 Factors related to Physicochemical Properties of Drug Factors related to Drug Product Formulation Processing Factor Factors Relating Dissolution Apparatus Factors Relating Dissolution Test Parameters Miscellaneous factors 81
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  FACTORS RELATED TOPHYSICOCHEMICAL PROPERTIES OF DRUG 1) DRUG SOLUBILITY • Solubility of drug plays a prime role in controlling its dissolution from dosage form. Aqueous solubility of drug is a major factor that determines its dissolution rate. Minimum aqueous solubility of 1% is required to avoid potential solubility limited absorption problems. • Studies of 45 compound of different chemical classes and a wide range of solubility revealed that initial dissolution rate of these substances is directly proportional to their respective solubility. • Ex. Poorly soluble drug :griseofulvin, spironolactone hydrophilic drug :neomycin 82
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  2 ) SALTFORMATION • It is one of the common approaches used to increase drug solubility and dissolution rate. It has always been assumed that sodium salts dissolve faster than their corresponding insoluble acids. Eg.sodium and potassium salts of Peniciilin G, sulfa drugs, phenytoin, barbiturates etc. • While in case of Phenobarbital dissolution of sodium salt was slower than that of weak acid. Same is the case for weak base drug, strong acid salts, such as hydrochlorides and sulphates of weak bases such as epinephrine, tetracycline are commonly used due to high solubility. However, free bases of chlortetracycline, methacycline were more soluble than corresponding hydrochloride salt at gastric pH values, due to common ion suppression. 83
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  3) PARTICLE SIZE There is a direct relationship between surface area of drug and its dissolution rate. Since, surface area increases with decrease in particle size, higher dissolution rates may be achieved through reduction of particle size. • Micronization of sparingly soluble drug to reduce particle size is by no means a guarantee of better dissolution and bioavailability. • Micronization of hydrophobic powders can lead to aggregation and floatation. when powder is dispersed into dissolution medium. So, mere increase in S.A. of drug does not always guarantee an equivalent increase in dissolution rate. Rather, it is increase in the “effective” S.A., or area exposed to dissolution medium and not the absolute S.A. that is directly proportional to dissolution rate. 84
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  • Hydrophobic drugslike phenacetin, aspirin shows decrease in dissoln. rate as they tend to adsorb air at the surface and inhibit their wettability. Problem eliminated by evacuating surface from adsorbed air or by use of surfactants. So these drugs in-vivo exhibit excellent wetting due to presence of natural surfactants such as bile salts • Eg. therapeutic conc. of griseofulvin was reduced to half by micronization 85
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  • 4) SOLIDSTATE CHARACTERISTICS • Solid phase characteristics of drug, such as amorphicity, crystallinity, state of hydration and polymorphic structures have significant influence on dissolution rate. • Anhydrous forms dissolve faster than hydrated form because they are thermodynamically more active than hydrates. Eg. Ampicillin anhydrate faster dissolution rate than trihydrate. • Amorphous forms of drug tend to dissolve faster than crystalline materials. E.g.Novobiocin suspension, Griseofulvin. 86
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  • Where inthe dissolution rate of amorphous erythromycin estolate is markedly lower than the crystalline form of erythromycin estolate. • Metastable(high activation energy)polymorphic form have better dissolution than stable form 87
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  5) Co precipitationor Complexation Co precipitation as well as complexation are use for enhancing the dissolution rate of drug due to, Formation energetic amorphous drug phase or Drug being molecularly dispersed or Formation of co accervates e.g.1) Hydroflumethiazide – PVP co precipitate has four times more solubility than crystalline drug. 2) Dissolution rate of sulfathiazole could be significantly increased by co precipitating the drug with povidone 88
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  FACTORS RELATED TODRUG PRODUCT 1)DILUENTS • Studies of starch on dissolution rate of salicylic acid tablet by dry double compression process shows three times increase in dissolution rate when the starch content increase from the 5 – 20 %. • Here starch particles form a layer on the outer surface of hydrophobic drug particles resulting in imparting hydrophilic character to granules & thus increase in effective surface area & rate of dissolution 89 FACTORS RELATED TO DRUG PRODUCT FORMULATION
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  10 20 3040 50 Time in min. 100 80 60 40 20 Amt of dissolved mg 10% starch 5% starch The dissolution rate is not only affected by nature of the diluent but also affected by excipient dilution (drug/excipient ratio). 90
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  2)DISINTEGRANTS • Disintegratingagent added before & after the granulation affects the dissolution rate. • Studies of various disintegrating agents on Phenobarbital tablet showed that when copagel (low viscosity grade of Na CMC) added before granulation decreased dissolution rate but if added after did not had any effect on dissolution rate. • Microcrystalline cellulose is a very good disintegrating agent but at high compression force, it may retard drug dissolution. • Starch is not only an excellent diluent but also superior disintegrant due to its hydrophilicity and swelling property. 91
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  3)BINDERS AND GRANULATINGAGENTS • The hydrophilic binder increase dissolution rate of poorly wettable drug. • Large amt. of binder increase hardness & decrease disintegration /dissolution rate of tablet. • Non aqueous binders such as ethyl cellulose also retard the drug dissolution. 92
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  • Phenobarbital tabletgranulated with gelatin solution provide a faster dissolution rate in human gastric juice than those prepared using Na –carboxymethyl cellulose or polyethylene glycol 6000 as binder. • In Phenobarbital tablet, faster dissolution rate was observed with 10% gelatin whereas decrease in dissolution rate with 20% gelatin. This was due to higher concentration which formed a thick film around tablet. • Water soluble granulating agent Plasdone gives faster dissolution rate compared to gelatin. 93
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  4) Lubricants •Lubricants are hydrophobic in nature (several metallic stearate & waxes) which inhibit wettability, penetration of water into tablet so decrease in disintegration and dissolution. • The use of soluble lubricants like SLS and Carbowaxes which promote drug dissolution. 94
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  5)SURFACTANTS • Theyenhance the dissolution rate of poorly soluble drug. This is due to lowering of interfacial tension, increasing effective surface area, which in turn results in faster dissolution rate. • E.g. Non-ionic surfactant Polysorbate 80 increase dissolution rate of phenacetin granules. 95
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  6)WATER-SOLUBLE DYES •Dissolution rate of single crystal of sulphathiazole was found to decrease significantly in presence of FD&C Blue No.1. • The inhibiting effect was related to preferential adsorption of dye molecules on primary dissolution sources of crystal surfaces. They inhibit the micellar solubilization effect of bile salts on drug. • Riboflavin tablet decrease when used FD & C Red no.3 dye in film coat 96
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  7)Effect of coatingcomponent on tablet dissolution • Coating ingredient especially shellac & CAP etc. Also have significant effect on the dissolution rate of coated tablet. Tablets with MC coating were found to exhibit lower dissolution profiles than those coated with HPMC at 37ºC. 97
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  PROCESSING FACTORS 1)METHOD OF GRANULATION • Granulation process in general enhances dissolution rate of poorly soluble drug. • Wet granulation is traditionally considered superior. But exception is the dissolution profile of sodium salicylate tablets prepared by both wet granulation and direct compression where the dissolution was found more complete and rapid in latter case. • A newer technology called as APOC “Agglomerative Phase of Comminution” was found to produce mechanically stronger tablets with higher dissolution rates than those made by wet granulation. A possible mechanism is increased internal surface area of granules produced by APOC method. 98
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  2)COMPRESSION FORCE •The compression process influence density, porosity, hardness, disintegration time & dissolution of tablet. 1. tighter bonding 2 . higher compression force cause deformation crushing or fracture of drug particle or convert a spherical granules into disc Shaped particle 3.& 4. both condition 99
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  3) DRUG EXCIPIENTINTERACTION • These interactions occur during any unit operation such as mixing, milling ,blending, drying, and/or granulating result change in dissolution. • The dissolution of prednisolone found to depend on the length of mixing time with Mg-stearate • Similarly as increase in mixing time of formulation containing 97 to 99% microcrystalline cellulose or another slightly swelling disintegrant result in enhance dissolution rate. 100