dissolution techniques

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sumit kumar, i.s.f college of pharmacy, moga

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Presented by: Sumit kumar mittal M.Pharma (2 nd sem ) Department of QUALITY ASSURANCE I.S.F. College of Pharmacy( Moga ) DISSOLUTION TECHNOLOGY

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Definition Process involved in dissolution of solid dosage form Mathematics of dissolution Factors affecting the rate of Dissolution Design of Dissolution Apparatus Apparatus used for Novel/Special doasage form Data Presentation and Interpretation In Vitro-In Vivo Correlation Methods of Dissolution Enhancement Conclusion References CONTENTS

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WHAT IS MEANT BY “DISSOLUTION”? A process in witch a solid substance is solubilised in a given solvent that is mass transfer from solid surface to liquid phase. It is a process by which drug released from solid dosage form and immediately goes into molecular solution.

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Process involved in dissolution of solid dosage form: 1. Initial mechanical lag 2.Wetting of the dosage form 3. Penetration of the dissolution medium 4.Disintegration 5. Deaggregation of the dosage form and dislodgement of the granules. 6. Dissolution 7.Occlution of the same particles of the drug

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Mathematics of dissolution Dissolution rate of the drug given by Noyes and Whitney as follows: dC / dT =k(Cs-c)………………….(1) When C is small (C<0.15Cs) dC / dT =KCs……………………….(2) Eq. 2 is commonly referred to a sink condition, which implies exist during the process of dissolution Modified Noyes-Whitney equation: dC / dT =DA Kw /o(Cs-C) Vh

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Factors affecting the rate of Dissolution Factors related to physiological properties of the drug Factors related to drug product formulation Effect of processing factors on the dissolution rate Factors related to dissolution test parameter Miscellaneous factors

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Factors related to physiological properties of the drug a. Effect of solubility on dissolution: The modified Noyes and Whitney’s equation shows that the aqueous solubility of the drug is the major factor that determines it’s dissolution rate. b. Effect of particle size on dissolution : The dissolution rate is directly proportional to the surface area of the drug. Higher dissolution rate may be achieved through the reduction of the particle size. If drug is hydrophobic , reduction of particle size may be lead to decrease effective surface area and hence a slower rate of dissolution .

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Cont…… c. Effect of solid phase characteristics of drug on dissolution: Amorphicity and crystallinity , the two important solid phase characteristics of the drug affect their dissolution profile. d. Effect of polymorphism on dissolution: The polymorphism and the state of hydration, solvation and/or Complexation markedly influence dissolution characteristics of the drug by change in solubility characteristics of the drug. Eg . Tolbutamide , chloramphenicol .

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Effect of granulation agent and binders: The hydrophilic binder show better dissolution profile with hydrophobic drug like phenacetin , by imparting hydrophilic properties to the granules surface. Large amount of strong binders increase hardness decrease disintegration and dissolution rate of the drug. PEG6000 was found to be a deleterious binder for Phenobarbital as it forms a poorly soluble complex with the drug. Factors related to drug product formulation

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Cont…… b. Effect of disintegrant and diluents: The type and amount of disintegrating agent implied in the formulation significantly control the overall rate of dissolution of dosage form. Efect of lubricant: The nature, quality and quantity of lubricant added can affect the dissolution rate.

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3. Effect of processing factors on the dissolution rate Method of granulation: Wet granulation has been shown to improve the dissolution rate of poorly soluble drugs by imparting hydrophilic properties to the surface of granules. The use of fillers and diluents such as starch, spray dried lactose, and microcrystalline cellulose tends to increase the hydrophilicity of active ingredients and thus improve dissolution.

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4. Factors related to dissolution test parameter a. Vibration : the excessive vibration of the dissolution apparatus considerably increases dissolution rate. B. Vessel design and construction: Minor changes in vessel shape may considerably alter the dissolution rates determined by the paddle method Glass vessels with an inside bottom flatter then specified gave a high bias in dissolution rates and those with an inside bottom of steeper curvature gave a low bias. Plastic vessels provide more perfect hemispheres then glass vessels

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Cont…… c. Temperature control: Drug solubility is temperature dependent, crae full temperature control during the dissolution process is very important… The dissolution fluid should be maintained at 37-*0.5’C as even slight temperature variation may have a significant effect on tablet dissolution. d. Dissolution medium: Surface tension of the dissolution medium: PH of the dissolution medium Viscosity of the dissolution medium Deaeration of the dissolution medium

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5. Miscellaneous factors: Adsorption: The adsorption has an influence of the dissolution rate of a slightly soluble solid. Adsorption isotherms can be employed to calculate the approximate amount of absorbent required to increase the slower dissolution rate. Sorption: The sorption from the atmosphere into tablets containing microcrystalline cellulose is very rapid. The relative density of the tablets was found to decrease, resulting in increases disintegration time with increase in water sorption rate constant. humidity: Moisture has shown to influence the dissolution rate of many drugs from solid dosage form.

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Design of Dissolution apparatus The ideal features of a dissolution apparatus are: Must be simply desinged Must be enough sensitive Uniform hydrodynamic flow is essential An easy means of introducing the dosage form Provide minimum mechanical abrasion to the dosage form The medium must be maintained at a fixed temperature Samples should be easily withdrawn

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TYPES OF DISSOLUTION APPARATUS USP dissolution apparatus (official) Apparatus 1: rotating basket type Apparatus 2: paddle type Apparatus 3: reciprocating type Apparatus 4: flow through cell Apparatus 5:padle over disc Apparatus 6:rotating cylinder Apparatus 7:reciprocating disc USP dissolution apparatus (non-official) Rotating bottle method Diffusion cell Peristalisis method Interinsic dissolution method

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IP dissolution apparatus apparatus 1: paddle type apparatus 2: basket type BP dissolution apparatus apparatus 1: basket type apparatus 2: paddle type apparatus 3: flow through cell

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USP APPARATUS 1: BASKET TYPE Design: vessel:-made up of borosilicate glass -semi-hemispherical bottom - capacity- 1000ml b) shaft:- stainless steel 316 -rotates smoothly without significance c) basket:- stainless steel 316 -gold coating upto 0.0001 inch d)water bath: maintained at 37 +/- 0.5*C use: capsules, tablets, f loting doasge form

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APPARATUS 2: PADDLE TYPE Design: vessel:- b) shaft:- the blade passes through shaft so that bottom of blade fuses with bottom of shaft. c) stirring elements:- made of tefflon - for laboratory purpose -stainless stell 316 d)water bath: maintained at 37 -0.5*C e) sinkers: platinum wire used to prevent capsule/tablet from floating

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APPARATUS 3: Reciprocating cylinder Design: vessel:-cylindrical flat bottom glass vessel Agitation type: reciprocating generally 5-35 rpm c) Volume of dissolution fluid: 200-250 ml d)water bath: maintained at 37 + 0.5*C Use: Extended release

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APPARATUS 4: flow through cell Design: reservoir:-for dissolution medium b) pump:- forces dissolution medium through cell -holding a sample - laminar flow is maintained -peristaltic/centrifugal pumps are not recommended c)water bath: Maintained at 37 -0.5*C Major advantage : - to maintain sink condition - large volume dissolution media is used.

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flow through cell

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APPARATUS 5: PADDLE FLOW DISK Design: vessel:- shaft:- stirring elements:- Sample holder:- disk assembly that hold the product in such a way that release surface is parallel with paddle. - paddle is directly attached over disk assembly. - samples are drawn away b/w the surface of medium and top of paddle blade e)volume:- 900ml f) temperature:32*C

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APPARATUS 6: ROTATING CYLINDER Design: vessel:-in place of basket cylinder is use. shaft:-stainless steel 316 Sample :- mounted to cuprophan (inner porous cellulosic material)an entire system is adhere to cylinder - dosage unit is place in cylinder and release from outside. d)water bath: Maintained at 32 -0.5*C Use: Transdermal patches cannot be cut into small size.

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APPARATUS 7: RECIPROCATING DISK Design: vessel:-flat bottom cylindrical vessel - volume of dissolution medium 50-200ml shaft:- Sample :- placed on disk shaped holders. Agitation : reciprocation - reciprocating frequency 30 cycles/ min. d)water bath: Maintained at 32 -0.5*C Use: Transdermal patches

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Data presentation and interpretation The USP 28 assesses dissolution in a three stage series of tests with the amount of drug dissolved after a specified time being expressed as a percentage of the normal content of the dosage form. The time at which the sample is to be tested is specified in the monograph, as is the so called Q- value, the minimum percentage dissolved at that time. In the first stage(S1), six units are tested and the pass criteria are the amount of drug dissolved from each unit at the specified time should be no less then Q *5%. Failure at S1 requires a second stag test (S2) to be performed on an additional six units.

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To pass the test at 2 nd stage, the average content dissolved from the combined two stages( ie ..12 units) should be equal to or greater than Q with no unit being less then Q-15%. Failure leads to stage 3 where a further 12 units are tested. The average of the total of the 24 units thus tested should be equal to or greater then Q. no more than two units should be less than Q-15% and no unit should be less than Q-25%. In the delayed- release products there is a similar three-tiered approach for both the acid-dissolution and buffer-dissolution stages. For extented -release the levels are denoted as L1, L2 and L3.

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In Vitro-In Vivo correlation The in vitro in vivo correlation (IVIVC) is a scientific approach to describe the relationship b/w an in vitro property of a dosage form ( e.g , the rate (or) extended of drug release)and a relevent in vivo response ( e.g , plasma drug concentration (or) amount of drug absorbed). Need of IVIVC To serve as a surrogate for in vivo bioavailability and to support bio waivers. To reduce the number of human studies during the formulation development

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Conti…. Correlation levels: three correlation levels have been defined in the IVIVC FDA guidance. Level IN Vitro In vivo A Dissolution Curve Input (absorption curves) B Statistical moments: MDT Statistical moments: MRT, MAT, etc. C Disintegration time, time to have 10, 50, 90 % dissolved, dissolution rate, dissolution efficiency Cmax , Tmax , Ka, Time to have 10, 50, 90 % aborbed , AUC (total or cumulative)

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Biopharmaceutics classification system (BCS): Class I: High solubility-High permeability Class II: Low solubility-High permeability Class III: High solubility-Low permeability Class IV: Low solubility-Low permeability

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Conti…. For class II- drugs , according to the biopharmaceutics classification system the dissolution rate is the limiting factor for the drug absorption rate. Also for class IV-drugs the dissolution rate can be the limiting factor. An enhancement in dissolution rate is important to attain suitable blood-levels of these drugs

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METHODS OF DISSOLUTION ENHANCEMENT 1. PHYSICAL MODIFICATION Particle size reduction Micronization Nanosuspention Sonocrystallisation Spray drying B. Modification of the crystal habit Polymorphs Pseudopolymorphs C. Drug dispersion in carriers Solid dispersion Solid solution Eutectic mixtures

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D. Complexation Molecular Encapsulation with Cyclodextrins E. Solubilization by surfactants : Surfactants Microemulsion II. Chemical Modifications Salt formation Alteration of pH of drug microenvironment III. Other techniques Co solvency Co-crystallization Hydrotrophy Solubilizing agent Nanotechnology approches

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Calibiration of Dissolution Apparatus Different types of calibiration are: Chemical Calibration Physical Calibration Chemical Calibration: Requirement for the analyst to perform apparatus suitability test using USP Calibration tablets. USP Calibration tablets come with certification identification appropriate range and reference standard. USP Prednisone Tablets 10 mg (disintegrating type)

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Physical Calibration: Following parameters should be checked: Paddle shaft centering Paddle height Rotation per minute (RPM) Temperature of the vessels dissolution medium 2, 5 clock test Clock test Wobbling of the shaft

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References: United State Pharmacopeia Indian Pharmacopeia British Pharmacopeia William. L and Wilkins. Remington the science and practice of pharmacy 21 st ed., vol1.p.672-88 http:/www.pharmscitech.org

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Thank you