Quality Control Test for Solid Dosage Forms.ppt
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Completed forms of the pharmaceutical preparation in which prescribed doses of medication are included. They are designed to: 1- Accurate dose. 2- Protection e.g. coated tablets, sealed ampules. 3- Protection from gastric juice. 4- Masking taste and odour. 5- Placement of drugs within...
Completed forms of the pharmaceutical preparation in which prescribed doses of medication are included. They are designed to: 1- Accurate dose. 2- Protection e.g. coated tablets, sealed ampules. 3- Protection from gastric juice. 4- Masking taste and odour. 5- Placement of drugs within body tissues. 6- Sustained release medication. 7- Controlled release medication. 8- Optimal drug action. 9- Insertion of drugs into body cavities (rectal, vaginal) 10- Use of desired vehicle for insoluble drugs. Solid dosage forms include Tablets Capsules Granules Powders Tablets are solid dosage forms containing one or more active ingredients. They are unit dosage form. They are obtained by single or multiple compression and may be coated or uncoated. They are usually intended for oral applications but sometime they also have some alternative applications such as implants, tablets for injection, irrigation or external use, vaginal tablets etc. Different parameters of tablet appearance are Size and Shape Color Odor Surface Texture PHYSICALTESTS CHEMICAL TESTS 1. Disintegration 2. Weight Variation 3. Hardness 4. Friability 5. Thickness & Diameter Drug Content or Assay CONTENT UNIFORMITY TEST DISSOLUTION TEST Difficulty swallowing tablets and capsules can be a problem for many individuals and can lead to a variety of adverse events and patient noncompliance with treatment regimens. It is estimated that over 16 million people in the United States have some difficulty swallowing, also known as dysphagia. Size and shape of tablets and capsules affect the transit of the product through the pharynx and esophagus and may directly affect a patient’s ability to swallow a particular drug product. Larger tablets and capsules have been shown to have a prolonged esophageal transit time. This can lead to disintegration of the product in the esophagus and/or cause injury to the esophagus, resulting in pain and localized esophagitis and the potential for serious sequelae Researchers specifically compared the transit time of 8 mm diameter round tablets to 11 mm diameter round tablets and 14 mm x 9 mm oval tablets and found the transit times for the 8 mm round tablet to be significantly shorter than for 11 mm round and 14 mm x 9 mm oval tablets (p250 mg >324 mg ±5 % Not more than 2 tablets can deviate from the limit. Not a single unit can deviate twice the limit given in monograph It is the resistance of the tablets against the mechanical shock during packaging, handling and transportation and helpful for checking the lamination and capping Friability is defined as a “percentage of weight loss by tablets due to mechanical action during test. Tablets are weighed before and after testing and friability is percent loss” It is the tendency of tablets to powder, chip, or fragment and this can affect the elegance appearance, consumer acceptance of the tablet, and also add to tablet’s weight variation or content uniformity problems. Significance Check breakability Check drug loss Check capping and hardness Apparatus: (Roche Friabilator) An instrument called friabilator consisting of drum is used to evaluate the ability of the tablet to withstand abrasion in packaging, handling, and shipping. Internal diameter 283-291mm Depth 36-40mm Made of transparent synthetic polymer with internal surface polished. A curved projection with an inside radius b/w 75.5- 85.5mm that extent from middle of the drum to outer wall from where tablets are tumbled. Drum is rotated at 25± 1rpm. Thus at turn, tablets rolls or slide, and fall onto the drum wall or onto each other. Procedure: For tablets weighing upto 0.65g, take a sample of tablets corresponding to weigh approximatelty 6.5 g. For tablets weighing more than 0.65g, take a sample of 10 tablets. Place the tablet on a sieve no. 100 and remove any loose dust with the aid of air pressure or a soft brush. Accurately weigh the tablet samples and place the tablet in the drum. Rotate the drum 100 times (25 rpm for 4 minutes) and remove the tablets. Remove any loose dust from the tablets as before. If no tablets are cracked, split or broken, weigh the tablets to the nearest mg. If tablet size or shape causes irregular tumbling, adjust the drum base so that the base forms an angle of about 10° with the horizontal and the tablets no longer bind together when lying next to each other, which prevents them from falling freely. Effervescent tablets and chewable tablets may have different specifications as far as friability is concerned. In the case of hygroscopic tablets, a humidity-controlled environment is required for testing. A drum with dual scooping projections, or apparatus with more than one drum, for the running of multiple samples at one time, is also permitted. Acceptance Criteria: Generally, the test is run once. If obviously cracked, cleaved, or broken tablets are present in the tablet sample after tumbling, the sample fails the test. If the results are difficult to interpret or if the weight loss is greater than the targeted value, the test is repeated twice and the mean of the 3 tests determined. A maximum loss of mass (obtained from a single test or from the mean of 3 tests) not greater than 1.0 per cent is considered acceptable for most products. Not more than 1% USP & BP Not more than 0.8% New Product Formula: 𝑭=𝟏𝟎𝟎 (𝟏−𝑾𝟏/ Wo ) Wo = Weight before test W1 = Weight after test Hardness is synonym for breaking force or resistance to crushing strength. According to USP it is tablet breaking force, and according to BP it is resistance to crushing of tablets. Hardness test ensures mechanical integrity and it defines optimum physical characteristics. Purpose: Hardness test is performed to determine need for pressure adjustments. Hardness can effect disintegration. If tablets have high hardness then disintegration time will be also high and vice versa. It will also serve as guideline in handling, packaging and storage of formulation. Factors Affecting the Hardness: Compression of the tablet and compressive force. Amount of binder. (More binder a more hardness) Method of granulation in preparing the tablet (wet method gives more hardness than direct method, Slugging method gives the best hardness). Particle size Mechanical interlocking Types of hardness testers: Manual or mechanical Strong-Cobb tester Monsanto Hardness tester Pfizer Hardness tester Motor driven Schleuniger Hardness tester Erweka Hardness tester Pharma test hardness tester PROCEDURE i. Stoker-Monsanto Hardness Tester (manual): It is a small potable hardness tester, manufactured by Monsanto chemicals. Select 6 tablets randomly according to USP Place the tablets, diametrically, between the moving and fixed jaw one by one. Gradually increase the force applied to the edge of tablet by moving the screw knob forward until the tablet breaks. The reading is noted from the scale which indicates the pressure required in kg to break the tablet. ii. Erweka hardness tester(mechanical): In this instrument the breaking force is applied by a beam fastened to one end to a pivot. The motor moves a weight along the beam at a constant speed and increase the force against the tablet. When the tablet breaks, a micro switch is activated that stop the motor. An indicator is fastened to the weight shows the breaking strength on a scale in kg. Orientation: Round tablets without scoring: Diametral compression Unique or complex shape: No obvious orientation. In general : Across the diameter or parallel to the longest axis. Scored tablets : Scores perpendicular to platen faces, it is for the strength of matrix Scores parallel to platen faces, it is breaking force required to break tablet at score Units: Kg ( SI unit) Newton ( SI unit) 9.807 Newtons = 1 kilogram. Pound ( lb) 1 kilogram = 2.204 pounds. Kilo pound ( kp) Strong Cobb ( SC) an ad hoc unit of force, 1 Strong-Cobb represented roughly 0.7 kilogram of force or about 7 newtons Acceptance Criteria: Force of about 5-8 kg is considered a minimum requirement for satisfactory tablet. It is important for the tablets and capsules to undergo quality test to make sure all tablets and capsules in the same type are uniform in physiochemical properties (such as diameter, thickness and hardness) to provide the same pharmacological effects and to prevent incorrect dose given to the patients. Devices: Micrometer Screw gauge, Vernier calipers or Digital hardness tester Significance: Proper packaging of solid dosage form, i.e. in blister, strip, bulk or bottle packaging’s. Factors Affecting the thickness & diameter: Following factors are there: Tablet compression or force Amount of material in punch or die Depth and diameter of die Procedure: 1. 10 tablets are selected and then, the test for diameter uniformity and thicknessis carried out by using the apparatus 2. Then the value of the diameter and thickness is taken. The deviation of each is calculated Acceptance criteria The deviation of individual unit from the mean diameter should not exceed ± 5% for tablets with diameter of less than 12.5 and ± 3% for diameter of 12.5 mm or more. DEFINITION: Dissolution is the process by which a solid solute enters in to a solution.i.e, mass transfer from solid surface to liquid phase. In the pharmaceutical industry, it may be defined as “the amount of drug substance that goes into solution per unit time under standardized conditions of liquid/solid interface and temperature. Dissolution process of solid dosage Forms : TABLETS OR CAPSULES DISINTEGRATION DISSOLUTION DRUG IN DISSOLUTION DRUG IN GRANULES OR ABSORPTION SOLUTION BLOOD,OTHER AGGREGATES (IN-VITROOR IN- FLUIDS,AND IN-VIVO VIVO) TISSUES IN-VIVO DISAGGREGATION FINE DISSOLUTION PARTICLES Solid dosage forms may or may not disintegrate when they interact with gastrointestinal fluid following oral administration depending on their design. For disintegrating solid oral dosage forms, disintegration usually plays a vital role in the dissolution process since it determines to a large extent the area of contact between the solid and liquid. Figure 1: Schematic diagram of the dissolution process MECHANISM OF DISSOLUTION AND FACTORS AFFECTING DISSOLUTION Mechanism of Dissolution Dissolution test determines the cumulative amount of drug that goes into solution as a function of time Steps involved liberation of the solute or drug from the formulation matrix (disintegration) dissolution of the drug (solubilization of the drug particles) in the liquid medium The overall rate of dissolution depends on the slower of these two steps Mechanism of dissolution First Step Cohesive properties of the formulated solid dosage form drug play a key role disintegration and erosion Semi- solid or liquid formulations, the dispersion of lipids or partitioning of the drug from the lipid phase is the key factor If the first step of dissolution is rate-limiting, then the rate of dissolution is considered to be disintegration controlled Mechanism of dissolution Second Step Solubilization of the drug particles depends on the physicochemical properties of the drug such as its chemical form (e.g., salt, free acid, free base) and physical attributes Theories of Drug Dissolution 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. 75 I. Diffusion layer model/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. 76 77 The rate of dissolution is given by Noyes and Whitney: dc = k (Cs- Cb) 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 78 Modified Noyes-Whitney’s Equation - dC = DAKw/o (Cs – Cb ) dt 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. 79 This is first 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. 80 Under sink conditions, if the volume and surface area of the solid are kept constant, then = K dC dt This represents that the dissolution rate is constant under sink conditions and follows zero order kinetics. 81 Dissolution rate under non-sink and sink conditions. zero order dissolution Conc. of dissolved drug under sink condition first order dissolution under non-sink condition Time 82 Hixon-Crowell’s cubic root law of dissolution takes into account the particle size decrease and change in surface area, W01/3 – W1/3 = Kt Where, W0=original mass of the drug W=mass of drug remaining to dissolve at time t Kt=dissolution rate constant. 83 Danckwert II. model/Penetration or 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. 84 85 The Danckwert’s model is expressed by equation dC dm A (Cs-Cb). γD V dt = = dt Where, m = mass of solid dissolved Gamma (γ) = rate of surface renewal V= kinematic viscosity, D=diffusion coefficient 86 III. Interfacial barrier model/Double barrier or Limited solvation theory Based on solvation mechanism, and it is function of solubility rather than diffusion When considering dissolution of the crystal have different interfacial barrier , given by the following equation G = Ki (Cs - Cb) Where, G = dissolution rate per unit area, Ki = effective interfacial transport constant. model can be extended to both the diffusion layer model and danckwert’s model 87 FACTORS INFLUENCING DISSOLUTION AND DISSOLUTION STUDIES I. Physicochemical Properties of Drug II. Factors related with formulation III. Processing Factors of Formulation IV. Factors Relating Dissolution Apparatus V. Factors relating Dissolution test parameters 1. PHYSICOCHEMICAL PROPERTIES OF DRUG 1)DRUG SOLUBILITY Solubility of drug plays a prime role in controlling its dissolution from dosage form. Minimum aqueous solubility of 1% is required to avoid potential solubility limited absorption problems. The drug might be considered ‘poorly soluble’ when its dissolution rate is slower than the time it takes to transfer past its absorption sites, resulting in incomplete bioavailability. This generally is the case for drugs where aqueous solubility is less than 100 mg/ml 2) 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. For poorly soluble drugs and many hydrophobic drugs, reduction in the particle sizes of about 3–5 mm is frequently employed as a successful strategy for enhancing drug dissolution rate. It is important to note that for some drugs too much reduction in the particle size can lead to exposure of surface charges, which can retard the drug dissolution rate. Micronization of sparingly soluble drug to reduce particle size is by no means a guarantee of better dissolution and bioavailability. 3)SALT FORMATION 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 Pencillin- G, sulfa drugs, phenytoin, barbiturates etc. 4)SOLVATES AND HYDRATES: A solvate is a molecular complex that has incorporated the crystallizing solvent molecules into specific sites within the crystal lattice. If the solvent is water, it is called a hydrate. Anhydrous compounds are highly soluble than hydrate compounds.eg: anhydrous and hydrate forms of ampicillin. 5) pH EFFECT: The solubility of a weak acidic drug or weak basic drug is influenced by the pH of the fluid. Therefore, differences are expected in the solubility and the dissolution rate of such drugs in different regions of the GIT. Rate of dissolution is increases while increasing the pH solution. Ex: Pencillin , Aspirin alkaline buffered tablets dissolution The solubility of weak acids and bases depends on their ionization constants, pKa as well as the pH of the dissolution medium. Intrinsic solubility can be defined as the solubility of a compound in its free acid or base form. For weak acids this is approximated by the solubility at pH values greater than one unit below its pKa. As the pH of the fluid increases, the solubility of the weak acid increases owing to the contribution from the ionized species. At pH values greater than pH = pKa + 1, a linear relationship between the logarithm of the solubility and the pH is observed, until the limiting solubility of the ionized form is reached Weak Acid Weak Base 6) ADSORBENTS: The concurrent administration of drugs and medicinal products containing solids adsorbents (eg:antidiarrhoeal mixtures) may result in the adsorbents interfering with the absorption of such drugs from the GIT.eg: Promazine adsorbs on to attapulgite decreases absorption. 7)CO-PRECIPITATION: Dissolution rate of sulfathiazole could be significantly increased by co-precipitating the drug with povidone. 8)POLYMORPHISM AND AMORPHISM: When a substance exists in more than one crystalline form, the different forms are designated as polymorphs and the phenomenon as Polymorphism. Stable polymorphs has lower energy state, higher M.P. and least aqueous solubility. Metastable polymorphs has higher energy state, lower M.P. and higher aqueous solubility. Generally, the metastable form is preferred because it exhibits the faster dissolution rate. There are a number of methods available for obtaining the metastable form that include recrystallization from different solvents, melting or rapid cooling. Polymorphism has been shown to influence solubility and, therefore, dissolution rate and bioavailability of drugs. Enhanced dissolution rate as a result of the right polymorph selection, however, does not always translate into improved bioavailability 9)COMPLEXATION: Complexation of a drug in GIT fluids may alter the rate and the extent of absorption.eg: streptomycin, tetracyclines. Eg: -Diakylamides -prednisone FACTORS RELATED TO DRUG PRODUCT FORMULATION 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 100 Amt of dissolved 80 mg 60 40 10% starch 20 5% starch 10 20 30 40 50 Time in min. The dissolution rate is not only affected by nature of the diluent but also affected by excipient dilution (drug/excipient ratio). E.g. in quinazoline comp. dissolution rate increases as the excipient /drug ratio increases from 3:1 to 7:1 to 2)DISINTEGRANTS Disintegrating agent added before & after the granulation affects the 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. 3)BINDERS AND GRANULATING AGENTS 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 100 retard the drug dissolution. Phenobarbital tablet granulated 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. Water soluble granulating agent Plasdone gives faster dissolution rate compared to gelatin. 101 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. 102 5) SURFACTANTS They enhance 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. 7) EFFECT OF COATING 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. 103 7) EFFECT OF Solubility Enhancer Cyclodextrins: The renewed interest of the past 25 years in cyclodextrins has provided an additional avenue for improving the solubility of poorly soluble drugs. Cyclodextrins are torus-shaped oligosaccharides composed of glucose molecules, which can form inclusion complexes by accepting a guest molecule into the central cavity. A positive feature of cyclodextrin complexes is that they are stable in aqueous solution. The earlier natural cyclodextrins included a-, b- and g-cyclodextrins containing 6, 7 and 8 glucose units, respectively PROCESSING FACTORS OF FORMULATION 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. 106 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 107 3.& 4. both condition 3) DRUG EXCIPIENT INTERACTION 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 4) STORAGE CONDITIONS Dissolution rate of hydrochlorothiazide tablets granulated with acacia exhibited decrease in dissolution rate during 1 yr of aging at R.T For tablets granulated with PVP there was no change at elevated temperature but slight decrease at R.T. 108 FACTORS RELATING DISSOLUTION APPARATUS 1) AGITATION Relationship between intensity of agitation and rate of dissolution varies considerably according to type of agitation used, the degree of laminar and turbulent flow in system, the shape and design of stirrer and physicochemical properties of solid. Speed of agitation generates a flow that continuously changes the liq/solid interface between solvent and drug. In order to prevent turbulence and sustain a reproducible laminar flow, which is essential for obtaining reliable results, agitation should be maintained at a relatively low rate. Thus, in general relatively low agitation should be applied. 109 2) STIRRING ELEMENT ALIGNMENT The USP / NF XV states that the axis of the stirring element must not deviate more than 0.2 mm from the axis of the dissolution vessel which defines centering of stirring shaft to within ±2 mm. Studies indicant that significant increase in dissolution rate up to 13% occurs if shaft is offset 2-6 mm from the center axis of the flask. 3) SAMPLING PROBE POSITION Sampling probe can affect the hydrodynamic of the system & so that change in dissolution rate. For position of sampling, USP states that sample should be removed at approximately half the distance from the basket or paddle to the dissolution medium and not closer than 1 cm to the side of the flask. 110 FACTORS RELATING DISSOLUTION TEST PARAMETERS 1) Temperature Drug solubility is temperature dependent, therefore careful temperature control during dissolution process is extremely important. 2) Dissolution Medium Altering PH Dissolved air tends to release slowly in form of tiny air bubble that circulate randomly and affect hydrodynamic flow pattern Specific gravity decrease thus floating of powder thus wetting and penetration problem. Surface tension: Viscosity Nature of medium: 112 DISSOLUTION TESTING Dissolution and drug release tests are in-vitro tests that measure the rate and extent of dissolution or release of the drug substance from a drug product, usually aq.medium under specified conditions. It is an important QC procedure for the drug product and linked to product performance in-vivo. NEED FOR DISSOLUTION TESTING: Evaluation of bioavailability. Batch to batch drug release uniformity. Development of more efficacious and therapeutically optical dosage forms. Ensures quality and stability of the product. Product development, quality control, research and application. U.S.P B.P E.P TYPE 1 Basket Basket Basket apparatus apparatus apparatus TYPE 2 Paddle Paddle Paddle apparatus apparatus apparatus TYPE 3 Reciprocating Reciprocating Reciprocating cylinder cylinder cylinder TYPE 4 Flow through Flow through Flow through cell cell cell TYPE 5 Paddle over disk Disk assembly Disk assembly method method Paddle over disk Paddle over disk TYPE 6 Rotating Extraction cell Extraction cell cylinder method method TYPE 7 Reciprocating Rotating Rotating disk cylinder cylinder The chewing The chewing apparatus apparatus USP.APPARAT DESCRIPTION ROT.SPEED DOSAGE FORM US TYPE 1 Basket 50-120 IDR,DR,ER apparatus rpm TYPE 2 Paddle 25-50 IDR,DR,ER apparatus rpm TYPE 3 Reciprocating 6-35 rpm IDR,ER cylinder TYPE 4 Flow through N/A ER,Poorly cell soluble API TYPE 5 Paddle over 25-50 TRANSDERMAL disk rpm TYPE 6 Rotating N/A TRANSDERMAL cylinder TYPE 7 Reciprocating 30 rpm ER and others holder APPARATUS-1(ROTATING BASKET) DESIGN: Vessel: -Made of borosilicate glass. -Semi hemispherical bottom -Capacity 1000ml Shaft : -Stainless steel 316 -Rotates smoothly without significance wobble(100 rpm) -Speed regulator Water bath:-Maintained at 37±0.5ºC USE: Tablets, capsules, delayed release suppositories, floating dosage forms. METHOD(Rotating basket): Place the stated volume of the dissolution medium(±1 %) in the vessel and equilibrate dissolution medium to 37±0.5°C. Place 1 tablet or capsule in the apparatus, taking care to exclude air bubbles from the surface of the dosage form unit and immediately operate the apparatus at the rate specified (100rpm). Withdraw a specimen from a zone midway between the surface of the dissolution medium and the top of the rotating basket, not less than 1cm from the vessel wall at each times stated. Replace the aliquots withdrawn for analysis with equal volumes of fresh dissolution medium at 37°C. Keep the vessel covered for the duration of the test and verify the temperature of the mixture under test at suitable times. Perform the analysis as directed in individual monograph and repeat the test with additional dosage form units. Apparatus 1 - Basket Advantages Can do pH change during the test Can be easily automated which is important for routine investigations. Disadvantages Basket screen is clogged with gummy particles. Hydrodynamic dead zone under the basket Degassing is particularly important Mesh gets corroded by HCl solution. APPARATUS-2 (PADDLE) DESIGN: Vessel: -Same as basket apparatus Shaft: -The blade passes through the shaft so that the bottom of the blade fuses with bottom of the shaft. Stirring elements: -Made of tefflon For laboratory purpose -Stainless steel 316 Water-bath: -Maintains at 37±0.5°C Sinkers : -Platinum wire used to prevent tablet/capsule from floating METHOD It consists of a special coated paddle formed from a blade and a shaft that minimizes turbulence due to stirring. The coated material is inert. The paddle is attached vertically to a variable -speed motor that rotates at a controlled speed. The tablet or capsule is placed into a round-bottom dissolution flask and the apparatus is housed in a constant temperature water bath maintained at 37°C. Most common operating speeds are 50rpm for solid oral dosage forms and 25 rpm for suspensions. A sinker, such as few turns of platinum wire may be used to prevent a capsule or tablet from floating Used for film coated tablets that stick to the vessel walls or to help to position tablet/capsule under the paddle. Advantages Easy to use Robust Can be easily automated which is important for routine investigations Disadvantages pH/media change is often difficult Hydrodynamics are complex, they vary with site of the dosage form in the vessel (sticking,floating) and therefore may significantly affect drug dissolution Sinkers for floating dosage forms Coning Paddle apparatus: Sinker Types: Coning: However, this configuration often causes accumulation of particles near the bottom of the vessel due to insufficient agitation underneath the paddle. This phenomenon is often referred as “coning” or “heap formation”. Once the coning phenomena occurred, the dissolution rate of a drug could become slower and more variable compared to well-suspended cases. The occurrence of coning phenomena depends on the particle size, the particle density, the fluid viscosity, the fluid density, the Coning: APPARATUS-3(RECIPROCATING CYLINDER) DESIGN: Vessel: -Set of cylindrical flat bottom glass vessels -Set of reciprocating cylinders -stainless steel fittings (type 316) and screens made of nonsorbing or non-reactive materials. Agitation type: -Reciprocating -5-35 rpm Volume of dissolution medium:-200-250ml Water bath:- Maintain at 37±0.5°C USE: Tablets, beads, pallets controlled and extended release formulations METHOD(Reciprocating cylinder): Place the stated volume of dissolution medium in each vessel of the apparatus, assemble the apparatus, equilibrate the dissolution medium to 37±0.5 and remove the thermometer Place one dosage form unit in each of the cylinders taking care to exclude the air bubbles from the surface of each dosage unit and immediately operate the apparatus as specified in the monograph. During the upward and downward stroke, the reciprocating cylinder moves through a total distance of 9.9 to 10.1cm. Within the time interval specified raise the cylinders and withdraw a portion of the solution under test from a zone midway between the surface of the dissolution medium and bottom of each vessel. Advantages Easy to change the pH pH-profiles Hydrodynamics can be directly influenced by varying the dip rate Disadvantages Small volume (max. 250 ml) Little experience Limited data APPARATUS-4 (FLOW THROUGH CELL) DESIGN: Reservoir : -For dissolution medium Pump : -Forces dissolution medium through cell -Holding a sample -Flow rate 10-100ml/min -Laminar flow is maintained -Peristaltic/centrifugal pumps are not recommended Water bath:- Maintain at 37±0.5°C USE: Low solubility drugs, microparticulates, implants, suppositories controlled release formulations METHOD(Flow through cell): The flow through cell is transparent & inert mounted vertically with filters. Standard cell diameters are 12 & 22.6 mm. The bottom cone usually filled with glass beads of 1 mm diameter. Tablet holder used for positioning special dosage form Place the glass beads into the cell as specified in the monograph. Place one dosage unit on top of the beads or on a wire carrier. Assemble the filter head and fix the parts together by means of a suitable clamping device. Introduce by the pump of the dissolution medium warmed to 37±0.5 through the bottom of the cell to obtain the flow rate specified and measured with an accuracy of 5%. Collect the eluate by fractions at each of the times stated. Advantages easy to change media pH pH-profile possible Sink conditions maintained. different modes a) open system b) closed system Disadvantages Deaeration necessary high volumes of media labor intensive Cell types: Tablets 12 mm Tablets 22.6 mm Powders / Granules Implants Suppositories / Soft gelatin capsules Flow-Through Cell: APPARATUS-5(PADDLE-OVER-DISK) DESIGN: Vessel Shaft Stirring elements- rotating speed 25-50 rpm Sample holder:-disk assembly that hold a product in such a way that release surface is parallel with paddle -Paddle is directly attached over disk assembly -Samples are drawn between surface off the medium and top of the paddle blade Volume:900ml Temperature:32°C USE: Transdermal patches, ointments, floaters , emulsions. Modification: Disk design and volume Advantages: Easy to handle Sink conditions are maintained. Membrane effect is minimum. i.e. drug is placed on a disc at the bottom. Disadvantages: Disk assembly restricts the patch size Borosilicate glass 17 mesh is standard(others available) Accommodates patches up to 90mm. METHOD(Paddle over disk) This method is used for testing the release of drugs from transdermal products. The apparatus consists of a sample holder or disc assembly that holds the product. The entire preparation is placed in a dissolution flask filled with specified medium maintained at 32ºC. The paddle is placed directly over the disc assembly. The disk assembly holds the system flat and is positioned such that release surface is placed parallel with the bottom of the paddle blade. Vessel is covered to minimize evaporation during test. Samples are drawn midway between the surface of dissolution medium and the top of the paddle blade at specified times. APPARATUS-6(ROTATING CYLINDER) DESIGN: Vessel:- In place of basket, cylinder is used. Shaft :-Stainless steel 316 Sample :- Mounted to cuprophan (inner porous cellulosic material) an entire system adheres to cylinder. - Dosage unit is placed in cylinder and release from side out. Water-bath: maintained at 32±0.5°C USE: Transdermal patches cannot be cut into small size. Solid dosage forms, pH profile , small volumes METHOD( Rotating cylinder): Use the assembly from apparatus 1 except to replace the basket and shaft with a stainless steel cylinder stirring element. The temperature is maintained at 32±0.5°C. The dosage unit is placed on the cylinder with side out. The dosage unit is placed to the exterior of the cylinder such that long axis of the system fits around the circumference of the cylinder and removes trapped air bubbles. Place the cylinder in the apparatus and immediately rotate at the rate specified in the individual monograph. Samples are drawn midway between the surface of the dissolution medium and the top of the rotating cylinder for analysis. Rotating cylinder: Advantages: -Equipment (apparatus 1) available with the manufacturers can be used with modification as apparatus 6. Disadvantages:-Large volume of medium is required. -Drug gets diluted & causes difficulties in analysis -Difficult to clean the cylinder. APPARATUS-7(RECIPROCATING-HOLDER) shaft DESIGN: Vessel:-Flat bottomed cylindrical vessel dissolution medium -Volume of dissolution medium disk Shaft : constant temp Sample : -Placed on disk shaped holders water bath Agitation :-Reciprocation -Reciprocating frequency 30 cycle/sec Water-bath:-Maintain at 32±0.5°C USE: Transdermal patches METHOD(Reciprocating Holder): The assembly consists of a set of volumetrically calibrated solution containers made of glass or suitable inert material, a motor , a drive assembly used to reciprocate the system vertically. The samples are placed on the disk shaped holders using cuprophan supports The test is carried out at 32°C. The reciprocating frequency is 30cycles/min. Advantages:-Convenient method for selecting the volume of the medium. -sink conditions can be maintained. -more sensitivity Disadvantages: -Investment is high because the design is totally different from standard equipment already available in industry. UNOFFICIAL METHODS 1.ROTATING/STATIC DISK METHOD Developed by late Eino nelson and described by Levy and Sahli. In this method ,the drug is compressed in a non-disintegrating disc without excipients. The disc is mounted in a holder so that only one face of the disc is exposed to the dissolution medium. The holder and disc are immersed in medium and held in a fixed position as in static disc method and rotated at a given speed in rotating disc method. Samples are collected at predetermined times. Surface area of the drug through which dissolution occurs is kept constant –intrinsic dissolution rate. 2.BEAKER METHOD: Reported by Levy and Hayes(1960). Dissolution medium, 250ml of 0.1N HCl at 37°C placed in a 400ml beaker. Agitation by three blade polyethylene stirrer,5cm diameter and rotates at 60 rpm. Stirrer immersed to a depth of 2.7 cm in medium and in the center. Tablets are placed in a beaker and test was carried out. Samples are removed and assayed for the content. Stagnant studies are also performed. 3.FLASK STIRRER METHOD Developed by Poole(1969).It includes RBF and a stirring element similar to that of beaker method. RBF used to avoid the formation of moulds of particles in different positions on the flat bottom of a beaker. 4.PERISTALSIS METHOD: To stimulate hydrodynamic condition of GIT tract in an in-vitro dissolution device. It consists of rigid plastic cylindrical tubing fitted with septum and rubber stopper at both ends. Dissolution chamber consists of a space between septum and lower stopper. Dissolution medium is pumped with peristaltic action through the dosage form. 5.ROTATING BOTTLE METHOD: It consists of rotating rack to hold sample drug products in bottles and they are capped tightly & rotated in 37°C temperature bath. Sample are decanted through a 40 mesh screen and residue are assayed. 6.DIALYSIS METHOD: Cell consist of 32mm inflated membrane. Plugged at the lower end by tight fitting cylindrical perspex box. Upper end of the tube held by thin perspex ring inserted into the tube and secured by an elastic band. The cell suspended , from the arm of the tablet disintegration apparatus and containing the dosage form in 150ml of distilled water at 37°C. The cell is raised or lowered 30times a min, into 150ml of distilled water at same temperature. Agitation by slight flexing and stretching of the dialysis membrane as it enters and leaves the bath. Rotated at 60rpm.. 7.DIFFUSION CELL Static or flow through diffusion cells are used to characterize in- vitro drug release and drug permeation kinetics from a topical drug product eg: Ointment, cream or transdermal drug product. The Franz diffusion cell is static diffusion system used to characterize drug permeation through skin model. The skin is mounted on the Franz diffusion cell and the drug product is placed on the skin surface. The drug permeates across the skin into a receptor fluid compartment that may be sampled at various times. This system is used for selection of appropriate formulation that has optimum drug delivery. Diffusion cell 154 DISSOLUTION Content Uniformity Test Content Uniformity Test The content uniformity test is to ensure that every dosage form contains equal amount of drug substance i.e. active pharmaceutical ingredient within a batch. Mainly it is used for testing the consistency of Amount of active pharmaceutical ingredient within individual units of tablets or capsules. Content Uniformity Test Normally testing is confirmed by performing specific assay to determine the content of drug material contained in particular dosage form. Content Uniformity Tests: pharmacopoeial comparison The major pharmacopoeias used widely are: The International Pharmacopoeia (IP) The British Pharmacopoeia (BP) The United States Pharmacopoeia (USP) The European Pharmacopoeia (Ph. Eur.) United States Pharmacopoeia(USP), procedure for content uniformity test *Stage1: Take 10 units randomly and perform the assay. It passes the test if the relative standard deviation (RSD) is less than 6% and no value is outside 85- 115%. Fails the test if one or more values are outside 75-125%. *Stage2: But if one unit is outside the limits of 85% to 115% and within 75%to125%. Take 20 more units and perform the assay procedure. Passes the test if RSD of all the 30 tablets is less than 7.8%, not more than one value is outside 85-115%, and no value is outside 75-125%. Or else the batch fails the test. RELATIVE STANDARD DEVIATION (RSD) In probability theory and statistics, the coefficient of variation (CV), also known as relative standard deviation (RSD), is a standardized measure of dispersion of a probability distribution or frequency distribution. It is often expressed as a percentage, and is defined as the ratio of the standard deviation to the mean (or its absolute value). The CV or RSD is widely used in analytical chemistry to express the precision and repeatability of an assay. Formula for Excel = (STDEV(Data Range) / AVERAGE(Data Range))*100
