Dissolution apparatus

Dissolution apparatus

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  Dissolution Apparatus Yasser MohamedSedik 5th Level 2018
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  Topics Outline 1- Introduction 2-Dissolution Apparatus 3- Our Machine "PBSI Version“ 4- Cleaning 5- Components & Validation Material 6- References
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  Introduction 1- What isthe Dissolution Apparatus ?? 2- Difference Between Drug Release & Dissolution 3- Purposes of Dissolution Apparatus Test 4- In-Vitro In-Vivo Correlations “IVIVC”
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  What is theDissolution Apparatus ?? ▪ Tablet Dissolution is a standardized method for measuring the rate of drug release from a dosage form ▪ In the pharmaceutical industry, drug dissolution testing is routinely used to provide critical in vitro drug release information for both quality control purposes, i.e., to assess batch-to-batch consistency of solid oral dosage forms such as tablets, and drug development, i.e., to predict in vivo drug release profiles.
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  Difference Between DrugRelease & Dissolution ▪ Dissolution test is normally used to describe the testing of those forms such as immediate release oral tablets or capsules intended to dissolve rapidly in the test medium. ▪ For non-oral dosage forms such as semisolids, suppositories, topical and transdermal systems, the term “drug release” is normally employed.
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  Purposes of DissolutionApparatus Test 1. Quality-control and quality-assurance purposes 2. In early phase drug development 3. Assess product stability, monitor formulation changes over time 4. Establish in-vitro–in-vivo correlations "IVIVC" 5. Regulatory perspective Particularly in the development and approval of generic dosage forms
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  In-Vitro In-Vivo Correlations“IVIVC” ▪ defined by the U.S. Food and Drug Administration (FDA) as "a predictive mathematical model describing the relationship between an in-vitro property of a dosage form and an in-vivo response". ▪ The United States Pharmacopoeia (USP) also defines IVIVC as "the establishment of a relationship between a biological property, or a parameter derived from a biological property produced from a dosage form, and a physicochemical property of the same dosage form". ▪ Parameters of Biological Property “AUC, Cmax” Physicochemical Property is the “Dissolution Profile” ▪ The main role of IVIVC 1- To use dissolution test as a surrogate for human studies. 2- To supports and/or validate the use of dissolution methods and specifications. 3- To assist in quality control during manufacturing and selecting appropriate formulations
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  Dissolution Apparatus 1- Factors affectingdissolution 2- The Performances of Dissolution Apparatuses 3- Different types of dissolution apparatus according to the pharmacopeias 4- Dissolution Apparatus-1 “Basket Apparatus” 5- Dissolution Apparatus-2 "Paddle Type“ 6- Dissolution Apparatus-3 "Reciprocating Cylinder“ 7- Dissolution Apparatus-4 "Flow through Cell“ 8- Dissolution Apparatus-5 "Paddle over Disc“ 9- Dissolution Apparatus-6 "Rotating
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  Factors Affecting Dissolution 1.Intrinsic properties of the API (e.g., solubility, wettability, particle size, surface area, morphology, polymorphs). 2. The formulation composition and characteristics (e.g., excipients, hardness, manufacturing process) 3. The dissolution method used for its assessment (e.g., apparatus, medium, test conditions, sampling, and sample analysis).
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  The Performances ofDissolution Apparatuses 1. Hydrodynamics its physical property interested mainly with the mechanics of fluid and pressure applied on the particles inside the fluid. 2. The designs of the dissolution apparatuses 3. The ways of operating dissolution apparatuses have huge impacts on the hydrodynamics Note: Hydrodynamic studies in dissolution apparatuses were carried out by researchers over the past few years with both experimental methods and numerical modeling such as Computational Fluid Dynamics (CFD).
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  ▪ Dosage formto be effective must have ability to pass into the systemic circulations then to the site of activity, and this process have 2 main definitions “Dissolution, Absorption”. ▪ Dissolution: is the process of extracting the API out of the dosage form. Absorption: is the process of transporting the drug substance from the gastrointestinal lumen into the systemic circulation. ▪ Dissolution testing method is the characterized method that provide in vivo dissolution information but doesn’t provide information about drug substance absorption. ▪ A dissolution method should have adequate discriminatory power to detect formulation changes that affect the dissolution rate of a drug product.
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  Different types ofdissolution apparatus according to the pharmacopeias I.P U.S. P B. P E. P Type 1 Paddle Apparatus Basket Apparatus Basket apparatus Paddle apparatus Type 2 Basket Apparatus Paddle Apparatus Paddle apparatus Basket apparatus Type 3 Reciprocating Apparatus Flow through cell apparatus Flow through cell apparatus Type 4 Flow through cell Apparatus Type 5 Paddle over disk apparatus Type 6 Rotating Cylinder Type 7 Reciprocating holder
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  Dissolution Apparatus-1 “BasketApparatus” ▪ Adopted in 1970 the rotating basket method of dissolution testing was the first official method. ▪ Design: Vessel: Made of Borosilicate Glass Semi Hemispherical Bottom, Capacity 1000 ml. Shaft: Stainless Steel 316, Speed 50 – 100 RPM. Water Bath: Maintained at 37 +/- 0.5*C Dosage Form is kept in the basket. ▪ Used For: - Beads (use a finer mesh basket where appropriate) - Capsules (preferred over Apparatus 2) - Orally disintegrating (Orodispersibles) - Tablets
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  Dissolution Apparatus-2 "PaddleType" ▪ The dosage form is dropped directly into the medium, which is stirred by means of a paddle attached to the stirring shaft, rotated typically at 50 or 75 rpm ▪ Design: Shaft: Fused with blade bottom Stirring element: Coated with Teflon for laboratory purposes, Stainless Steel is used. Rotation speed: 25-50 RPM Water Bath: Maintain at 37 +/- 0.5*C Sinkers: Platinum wire use to prevent tablet/capsule from floating. ▪ Used For: - Capsules - Powders - Suspensions - Tablets (preferred over Apparatus 1)
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  Dissolution Apparatus-3 "ReciprocatingCylinder" ▪ Is a very versatile device for the in vitro assessment of release characteristics of solid oral dosage forms, because it enables the product to be subjected to different dissolution media and agitation speeds in a single run. ▪ Used for: - Tablet - Beads - Controlled& Extended release formulations
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  Dissolution Apparatus-4 "Flowthrough Cell" ▪ In the closed system configuration, the flow-through cell enables the performance of a dissolution test with a low amount of media in order to achieve the necessary testing environment. ▪ Used for: - Low Solubility drug. - Micro particulate - Implants Suppositories - Controlled release formulations.
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  Dissolution Apparatus-5 "Paddleover Disc" ▪ A variation on Apparatus 2. The dosage form is applied to a stainless- steel disk or watch glass, which is then placed in, the bottom of the vessel prior to being stirred in the conventional manner. Test at 32 degrees C and pH 5-6 to reflect skin conditions. ▪ Used For: - Transdermal Patches "Drug Release Studies" - Products involving delivery through the skin.
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  Dissolution Apparatus-6 "RotatingCylinder" ▪ The rotating cylinder which has specific advantages over the paddle over disk methods and reciprocating holder apparatus. The rotating cylinder apparatus is designed to handle much larger patches, while holding the patch to the cylinder wall during the test. This talk will explore the advantages as well as cover the practical use of the apparatus. ▪ Used For: - Mainly Transdermal Product
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  Dissolution Apparatus-7 "ReciprocatingHolder" ▪ This unit is perfectly suited for simulating the pH-changes within the human body. By placing different media in each row, the device echoes varying in vivo gastrointestinal conditions of the body. ▪ An automatic sample transport between the rows allows the reliable testing of the extended or sustained release from different dosage forms in various pH-zones. The simple to program RRT 10 thus, is the perfect unit for multiple media pH-changes for IVIVC testing and dissolution profiling of a variety of release dosage forms "e. g. tablets, coated tablets and oblongs". ▪ Used For - Controlled release dosage form - Non-disintegrating oral formulations
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  Dissolution Apparatus - PBSI 1-What is the PBSI Mean ? 2- Advantages & Disadvantages 3- Material 4- Applied Modifications in our Machine 5- Suggested Modifications 6- Standard Operating Procedure "SOP"
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  What is thePBSI Mean ? ▪ Our machine is different as it works 4 in 1 by using four additions ▪ Paddle They made from Stainless Steel 316 Rotated typically at 50 or 75 rpm Used for: Capsules, Powders Suspensions and Tablets ▪ Basket they made from Stainless Steel 316 Rotated typically at either 50 or 100 rpm Used for: Beads, Capsules, Tablets
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  ▪ Basket Suppositories Normalbasket but used mainly for suppositories. ▪ In-Vivo absorption detection we will use a piece of rabbit intestines to measure the absorption as the intestine like our skin. Absorption of substances through the skin depends on a number of factors the most important of which are : concentration, duration of contact solubility of medication, and physical condition of the skin. Then we will be able to quantify the absorbed drug.
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  Advantages & Disadvantages ▪Advantages: 1- Better reproducibility. 2- Easy to clean. 3- PH change possible. 4- Can be easily automated which is important for routine investigation. 5- Easy in detection absorption of the drug 6- Easy and accurate in sampling method ▪ Disadvantages 1- Tendency of light particles to float at surface after leaving baskets or in paddle method. 2- Sensitivity of apparatus to variables such as vibrations, eccentricity. 3- Rapid corrosion of SS mesh in presence of HCl. 4- Sensitivity of apparatus to any slight changes in paddle orientation.
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  Material ▪ Body ofthe motor – Sheet of metal ▪ Shafts – Stainless steel 316 ▪ Paddle & Basket - Stainless steel 316. ▪ Water Bath – Securit glass ▪ Vessel - Borosilicate glass
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  Applied Modifications inour Machine ▪ In Vivo Basket "Absorption & Penetration Detection“ This idea depending on analyze the amount of dissolute particles absorbed by intestine or skin, the dissolute particles will pass from part of media to all media available through skin or intestine, and we compared it with results from regular basket apparatus. Another modification in this topic we will suspended the part from intestine or skin in the media and will assay the amount of drug absorbed by determination the amount of drug particles in the media by normal apparatus then compared with the concentration of the dug in this media.
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  ▪ Sampling We addedSyringe for each vessel which are stable and connected to vessel by specific needle which are immovable and constant and end of it in the media. ▪ Brush for Cleaning a very soft brush added on the end of the shaft at the place of paddle or basket which main objective to clean the vessel
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  Suggested Modifications ▪ MovingShaft by Pressure Making new shaft tool which moving by pressure from the upper side useful in save money alternatively the automatic machine and have a good appearance. ▪ HPLC Connection The connection part from the media in vessel and HPLC by using different auto samplers. This led to decrease time in handling the sample and inject it in the HPLC and can identify the concentration of the drug in the media rapidly.
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  ▪ In VitroDissolution Absorption System (IDAS) IDAS provides the ability to evaluate absorption, permeation, accumulation, biomarker regulation and metabolism, as well as the ability to test a finished dosage form from a tablet, capsule to suspension. ▪ Consists Mainly From 1- Two L-Shaped Chamber 2- Buffer mimicking the protein ion and glucose content in the Plasma of human blood 3- Caco-2 Layer which fixed in the end of the chamber they are intestinal Human cells used mainly in research of absorption system. 4- Special vessel "500 ML" ▪ Samples are taken normally from the open in the cover of the vessel to assay the dissolution in the same time we take sample from the eye of the chamber to detect the absorption
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  ▪ Protection thePaddle or Basket We can cover the paddle or basket by using the Gold, Titanium, and PTFE. are very important in preventing corrosion ▪ Vibrator in Water Bath The vibrator make a very low moving in the water which keep it in the movable phase and prevent the salts and other adulterants from precipitation on the wall.
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  Standard Operating Procedure"SOP" 1. Switch „ON” the power, instrument will initialize. 2. Press the RPM, TEMP, TIME, and OPTN keys from the front panel to set the parameters of the test. 3. Change protocol no. using Increment / Decrement keys. 4. Press the ENTER key to register the set parameter in the protocol, such 20 protocols can be prepared. RPM Settings 1. Press the RPM key from the front panel. Set the RPM from 25 to 200 using the UP / DOWN / DIGIT SCROLL key as per requirement. 2. To start or stop the stirrer use F1 or F2 keys respectively.
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  Temperature Setting: 1. Pressthe TEMP key from the front panel. Set the temperature from 30.0°C to 40.0°C by using UP / DOWN / DIGIT SCROLL key. 2. Switch heater ON/OFF BY using the function key F1/F2 Press ENTER key to register the change. 3. “TEMP ON” LED on the front panel will glow after switching on heater. The pump and the Heater ON LED on temperature Controller Unit will glow. Dissolution Medium Preparation: Prepare the dissolution medium as per specified under monograph or procedure, filter through 0.45 mm filter paper under vacuum and stirring. Note: Replace the water from the bath weekly or early if required Sample Withdraw Procedure: Withdraw sample from a zone midway between the surface of the dissolution medium and top of rotating basket/paddle, not less than 10
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  Cleaning 1- Paddles andBasket Shafts 2- Baskets 3- Vessels 4- Cannulas 5- Auto samplers 6- Important Notes
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  Paddles and BasketShafts ▪ Clean with soap and water. A paper towel with soapy water can be used to clean the shafts, and then followed with a squirt bottle of DI Water. ▪ If the product or media is viscous in any way, you may need to use alcohol or other products as well. ▪ If polymer is left on the shafts, it will also have acid/salt/etc. of the media with it which will concentrate and lead to rapid rusting.
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  Baskets 1. Rinse themgently in the sink 2. Put them in a beaker with ethanol or methanol and sonicate them for about 5 minutes. 3. Remove them and allow them to air dry. 4. Place them into a protective container when done. Baskets should appear shiny, if they appear dull/flat in color (like the basket pictured on the right of the header picture) it is time to replace them.
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  Vessels ▪ Clean withsoap and water, and a non-abrasive washcloth or other item. ▪ When removing from the dissolution bath, remove back vessels first to reduce the chance of accidentally spilling your media into your water bath. ▪ Dishwashers are acceptable for glass-lipped vessels, but may not be for plastic-lipped ones.
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  ▪ Cannulas -Treat these the same as shafts. Cannulas are often overlooked when cleaning. ▪ Auto samplers - - DI Water works best for salts, sugars, and surfactants. you can heat DI Water to 50-60C to improve solubilization of residues in lines. - Alcohols work well for polymers and difficult to clean products. - Some auto samplers, such as the Agilent 850-DS, can have an integrated auto clean which will occur immediately after the final time point to prevent drying.
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  Important Notes 1. Cleanas soon as possible after a run is complete - prevents drying or precipitation of your drug, excipients, and media components in tubing - it reduces the attack of acids on stainless steel and other components. 2. don't use any abrasives or anything that could damage the components 3. The cleaning being performed should be based on the samples you've run. Different samples and media will often require different cleaning approaches. - Surfactants and salts is often cleaned best with DI Water. - Polymers may require use of alcohols to help clean the system. - Surfactants/salts/polymers may require several rinses of Water/Alcohol/Water.
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  Component & Validation Material 1- DissolutionVessel 2- Dissolution Basket 3- Dissolution Paddle 4- Controlling Temperature 5- Capsule Sinkers 6- Controlling Wobble 7- Level and Verticality Issues 8- Centering of Stirring Element 9- Height of Basket or Paddle above Bottom of Vessel 10- Rotational Speed 11- Dissolution Filters 12- Dissolution Sampling 13- Commonly Used Dissolution Media
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  Dissolution Vessel ▪ Specification USPFor a 1 liter Vessel Height: 160-210mm. Outside Diameter: 98-106mm Hemispherical Bottom Critical Part of the Apparatus Amber vessels are used to reduce the amount of light that can get into the vessel for light sensitive applications
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  ▪ Unfortunately allthe major bath manufacturers specify different diameter glass, meaning there is no “one size fits all” vessel. ▪ Vessels should be guaranteed to meet the specification of the original vessels. ▪ All vessels should be serialized and where possible used in the same bath location and orientation to minimize the physical differences. ▪ Plastic vessels are easily scratched, crack very quickly and have much poorer heat transmission than glass vessels Plastic vessels (or PTFE coated glass vessels) are sometimes used where the dosage form will stick to a glass vessel. ▪ Because of the poor thermal qualities, to ensure the temperature inside the vessel remains at 37C the temperature of the water bath has to be set higher than normal.
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  Dissolution Baskets ▪ Dissolutionbaskets are a precise and fragile piece of precision instrumentation and are easily damaged ▪ A good basket should be rigid with no movement.
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  ▪ Simple Test- hold a basket rims between the thumb and forefinger on both hands and gently twist back and forth. If there is any movement in the mesh of the basket then there is a real potential that the basket will easily deform, and worse, that it will not pass the basket wobble test. ▪ Good baskets are reproducible baskets and reproducibility is the goal of any dissolution testing. ▪ Baskets should be individually serialized and certified. ▪ Correct handling of baskets is important and avoids both physical damage and contamination. ▪ The use of a simple basket storage rack, which is both inexpensive and easy to use, is the best way to ensure that baskets maintain their integrity during storage.
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  Dissolution Paddle ▪ Mostwidely used method in dissolution testing, Originally developed by Poole (1969) and was refined by scientists at the FDA for Drug Analysis in St Louis. ▪ The dimensions of the paddle are closely controlled. Any variations can easily have a detrimental effect on reproducibility from vessel to vessel. For this reason, paddles should be treated as a precision piece of equipment, stored correctly, and inspected regularly for scratches, dents or other imperfections. ▪ Coating by PTFE, The purpose of the coating is to reduce the interaction between steel and the dosage form. As steel quality improves, the need for coating reduces, but care should be exercised to use paddles of suitable steel quality.
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  Capsule Sinkers ▪ Floatingdosage forms can present a real problem and may be weighted with a sinker which should be heavy enough to cause it to sink to the bottom of the vessel. ▪ A sinker is commonly formed from a wire helix. ▪ The USP states “A small, loose piece of non-reactive material, such as not more than a few turns of wire helix, may be attached to dosage units that would otherwise float. An alternative sinker device is shown in Figure 2a. Other validated sinker devices may be used.” Japanese Sinker (Figure 2a Ref USP Above) Spiral or Coil Sinker 3 Prong Sinker 'Sotax Style' Spiral Sinker Basket Sinker Breath Film Sinker
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  Controlling Temperature ▪ Specifications: USPToolkit: ± 0.5oC but all vessels should agree within 0.4oC ▪ Temperature is critical because it has a linear effect of dissolution results. ▪ Using a calibrated thermometer, the temperature should be tested in each vessel prior to each test. ▪ If plastic vessels have to be used, their heat transfer is poor compared with glass and the water bath temperature will need to be correspondingly higher. ▪ Factors affect the temperature around the dissolution tester. 1- Heat loss from one end of the bath to the other 2- Inadequate water pumping 3- Air conditioning
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  Controlling Wobble ▪ Specifications: ShaftWobble USP Toolkit: ≤1.0 mm run out, 1 cm above the paddle or basket Basket Wobble USP Toolkit: ≤1.0 mm run out at bottom of basket ▪ Wobble is the movement from the center line of a shaft or basket as it rotates. This causes a disruption in the flow profile in the vessel and can have a significant impact on dissolution rate. ▪ Measurements are performed using a Wobble meter
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  Level and VerticalityIssues ▪ Specifications Horizontal Level USP: <0.5° from horizontal at 2 points 90° apart Shaft Verticality USP: <0.5° from vertical at 2 points 90° apart Vessel Verticality USP: <0.5° from vertical at 2 points 90° apart ▪ Using Digital Protractor to detect the level and verticality
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  Centering of StirringElement ▪ Specifications USP Toolkit: ≤2.0 mm, not more than 2 cm below the flange of the vessel ▪ Centering measures whether the paddle or basket is exactly in the center of the vessel. If they are not then irregular media flow patterns can result. ▪ The centering test relies on the fact that the vessels are good, and so only fully dimensionally certified vessels should be used.
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  Height of Basketor Paddle above Bottom of Vessel ▪ Specifications: USP: 25mm ± 2mm ▪ Height setting for baskets and paddles is necessary prior to each test. Although it is part of the qualification process every six months, it should not be assumed that the height does not change between those times, and a check before each test ensures that the tester has been correctly set-up by the operator. DEPSET-MI 25mm Ball Spacer DEPSET-25 25mm Spacer DDAPT-Q Digital Depth Gauge
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  Rotational Speed ▪ Specifications USPToolkit: +/- 1rpm at 50rpm and 100rpm ▪ With current motor technology there is no reason why dissolution testers should not be within 0.1rpm and certainly 1rpm is easily achievable. ▪ The simplest way to measure rotational speed is with an optical tachometer. This reads a reflective marker placed on the spindle. It is ideal to measure this at both 50 rpm and 100rpm which are the two most common test speeds.
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  Dissolution Filters ▪ Themajority of filters are manufactured from porous Polyethylene or porous PVDF and are designed to fit on the end of a sampling cannula. That requires that the hole in the filter is exactly correct for the diameter of sampling cannula used. 1/8" Standard Filter 1/16" Standard Filter VanKel Style Filter Filter with Color Coding Distek Style Disc Filter Filter Tip
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  Dissolution Sampling ▪ Samplingcan present the opportunity for a number of errors, especially for multiple point dissolution tests. ▪ Placing sampling devices in the media can have an immediate effect on the hydrodynamics in the vessel, especially if they are large, such as a pipette for example. ▪ Sampling Position The USP states: “Within the time interval specified, or at each of the times stated, withdraw a specimen from a zone midway between the surface of the Dissolution Medium and the top of the rotating basket or blade, not less than 1cm from the vessel wall” The zone is clearly interpreted as a horizontal area in the vessel. 1cm away from the vessel wall to ensure that the media is free flowing.
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  Commonly Used DissolutionMedia: ▪ Purified water ▪ Dilute acid " 0.001N - 0.1N HCL " ▪ Stimulated Gastric Fluid ▪ Stimulated intestinal fluid ▪ Surfactants " e.g. Polysorbate, SLS " ▪ Aqueous buffers " PH 5-7 "
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  References ▪ http://www.labhut.com/education-centre/about-dissolution-testing.html ▪ http://www.pharmtech.com/dissolution-testing-3 ▪https://slideplayer.com/slide/1595894/ ▪ https://www.slideshare.net/pharmaguideline/dissolution-testing-in-pharmaceuticals?qid=2149e606-b0c1-458e-a496-22038a4c378f&v=&b=&from_search=6 ▪ https://www.slideshare.net/karankar71/dissolution-testing-apparatus-76645957?qid=2149e606-b0c1-458e-a496-22038a4c378f&v=&b=&from_search=5 ▪ https://www.slideshare.net/BShamim/dissolution-testing-apparatus-60496485?qid=2149e606-b0c1-458e-a496-22038a4c378f&v=&b=&from_search=4 ▪ http://www.copleyscientific.com/ ▪ http://www.erweka.com/ ▪ https://www.agilent.com/en/products/dissolution/apparatus/708-ds-dissolution-apparatus ▪ https://www.pharmaguideline.com/2017/11/different-types-of-dissolution-apparatus.html ▪ https://www.usp.org/sites/default/files/usp/document/harmonization/gen-method/stage_6_monograph_25_feb_2011.pdf
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  Thank You Yasser MohamedSedik