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Slide 1 - 1 Design and Calibration of a Dissolution Test Equipment Training Workshop on Dissolution, Pharmaceutical Product Interchangeability and Biopharmaceutical Classification System. Kyiv, Ukraine, June 25 - 27 2007 Dr. Sandra Klein, Institute of Pharmaceutical Technology, Johann Wolfgang Goethe University Frankfurt
Slide 2 - 2 Dosage forms to be tested immediate release dosage forms powders, granules / beads, tablets, capsules controlled release dosage forms powders, granules / beads, tablets, capsules transdermal systems implants
Slide 3 - 3 Official Dissolution Monographs United States Pharmacopeia USP XXX (30) European Pharmacopoeia Ph. Eur. 5th Edition, Supplement 5.3 British Pharmacopoeia BP 2007 Japanese Pharmacopoeia JP XIV (14)
Slide 4 - 4 Official dissolution apparatus USP 30 classification Rotating Basket (Ph.Eur./BP/JP) Paddle (Ph.Eur./BP/JP) Reciprocating Cylinder (Ph.Eur.) Flow Through Cell (Ph.Eur./BP/JP) Paddle Over Disk (Ph.Eur.) Rotating Cylinder (Ph.Eur.) Reciprocating Holder
Slide 5 - 5 Which type of dissolution apparatus ? Depends on intention Quality control examining batch homogeneity examining batch to batch conformity examining stability Research & Development examining drug release behavior of preformulations in vitro simulation of the gastrointestinal passage IVIVC
Slide 6 - 6 Apparatus 1 - Basket Useful for capsules beads delayed release / enteric coated dosage forms floating dosage forms surfactants in media Standard volume 900/1000 ml 1, 2, 4 liter vessels
Slide 7 - 7 Apparatus 1 - Basket Advantages breadth of experience (more than 200 monographs) full pH change during the test can be easily automated which is important for routine investigations
Slide 8 - 8 Apparatus 1 - Basket Disadvantages disintegration-dissolution interaction hydrodynamic „dead zone“ under the basket degassing is particularly important limited volume  sink conditions for poorly soluble drugs ?
Slide 9 - 9 Apparatus 1 - Basket
Slide 10 - 10 Apparatus 2 - Paddle Useful for tablets capsules beads delayed release / enteric coated dosage forms Standard volume 900/1000 ml Method of first choice !!!
Slide 11 - 11 Apparatus 2 - Paddle Advantages easy to use robust can be easily adapted to apparatus 5 long experience pH change possible can be easily automated which is important for routine investigations
Slide 12 - 12 Apparatus 2 - Paddle Disadvantages pH/media change is often difficult limited volume  sink conditions for poorly soluble drugs ? hydrodynamics are complex, they vary with site of the dosage form in the vessel (sticking,floating) and therefore may significantly affect drug dissolution „coning“ sinkers for floating dosage forms
Slide 13 - 13 Sinker types JP/ USP / Ph. Eur. 5.3 Sinker „a small loose piece of nonreactive material such as not more than a few turns of wire helix may be attached to dosage units that would otherwise float …“ „…. other validated sinker devices may be used“
Slide 14 - 14 Coning
Slide 15 - 15 Apparatus 2 - Paddle
Slide 16 - 16 Apparatus 3 – Reciprocating cylinder Useful for tablets beads controlled release formulations Standard volume 200-250 ml per station
Slide 17 - 17 Apparatus 3 – Reciprocating cylinder 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
Slide 18 - 18 Apparatus 3 – Reciprocating cylinder
Slide 19 - 19 Apparatus 4 – Flow-Through Cell Useful for low solubility drugs microparticulates implants suppositories controlled release formulations Variations open system closed system
Slide 20 - 20 Cell types Tablets 12 mm Tablets 22,6 mm Powders / Granules Implants Suppositories / Soft gelatine capsules
Slide 21 - 21 Apparatus 4 – Flow-Through Cell Advantages easy to change media pH pH-profile possible sink conditions different modes a) open system b) closed system Disadvantages Deaeration necessary high volumes of media labor intensive
Slide 22 - 22 Apparatus 4 – Flow-Through Cell
Slide 23 - 23 Apparatus 5 – Paddle over disk Useful for transdermal patches Standard volume 900 ml
Slide 24 - 24 Apparatus 5 – Paddle over disk Advantages standard equipment (paddle) can be used, only add a stainless steel disk assembly Disadvantages disk assembly restricts patch size
Slide 25 - 25 Apparatus 6 – Rotating cylinder USP apparatus 7 – Reciprocating holder most probably will be removed from the USP !!!
Slide 26 - 26 Summary Immediate release dosage forms:  apparatus 1 or 2 (preferably 2) Controlled release dosage forms:  apparatus 1 or 2 using different media for QC  apparatus 3 or 4 for R&D purposes Beside the selection of an adequate dissolution apparatus, adequate test conditions are crucial for all purposes !
Slide 27 - 27 Qualification of Dissolution Systems
Slide 28 - 28 Calibration Why ? to confirm suitability of the equipment and proper operation of the apparatus How ? mechanical calibration (verification of physical parameters) chemical calibration („Apparatus Suitability Test“ – USP) When ? before using new test equipment after relocation or major maintenance at regular intervals („every 6 months“)
Slide 29 - 29 Factors that may affect reliability of the test Proper alignment/geometry of dissolution apparatus dimensions of vessels, paddles, baskets, cylinders height, centering and wobble Proper conditions during dissolution test temperature agitation speed degassing sampling (sampling zone, timing, filtration, dilution) vibration Proper validation of analytical method specified in USP Chapter <1225>
Slide 30 - 30 Mechanical calibration Verification of physical parameters specified in the pharmacopoeia: USP apparatus 1 and 2
Slide 31 - 31 Mechanical calibration - Parameters Height – Vertical Position of the Paddle or Basket the vertical position of paddle or basket affects the hydrodynamics condition in the vessel each paddle or basket should be individually adjusted to the compendial distance in the pharmacopoeia, a distance of 2.5 + 0.2 cm is specified different kinds of height gauges can be used to align or check* this parameter *
Slide 32 - 32 Mechanical calibration - Parameters Rotational Speed – Stirring Rate input variable that affects the hydrodynamics changes in the rotational speed result in a changing liquid-solid interface between the solvent and the dosage form the rotational speed can be checked by using a digital tachometer* the compendia specify a rotational speed tolerance of + 4 % *
Slide 33 - 33 Mechanical calibration - Parameters Shaft Wobble – Eccentricity of Stirring Device assumed to alter the pattern of fluid movement in both paddle and basket apparatus and therefore may influence the dissolution rate can be measured with a micrometer* measured is the sum of distance between both sides (180°) of the axis of rotation *
Slide 34 - 34 Mechanical calibration - Parameters Centering (Vessel / Shaft) the axis of the rotating shaft must coincide at all points with the axis of the vessel to within + 1 mm “the shaft has to positioned so that is axis is not more than 2^mm at any point from the vertical axis of the vessel and rotates smoothly without significant wobble” *
Slide 35 - 35 Mechanical calibration Measurement tools all mechanical tools used for calibration should be certified to assure their reliability the results of mechanical calibration have to be documented
Slide 36 - 36 Apparatus suitability test (USP) if all parts ( apparatus, geometry, test conditions, analytical method) are within compliance – why perform an apparatus suitability test? the apparatus suitability is to check for parameters that can not be conveniently measured (vibration, vessel cleanliness, medium degassing ...) and also to provide an overall check of the system
Slide 37 - 37 Apparatus suitability test (USP) first established in 1978 routine test in most pharmaceutical laboratories calibration at regular intervals (every 6 months) standard calibrator substances according USP chapter <711> only the method(s) to be used have to be calibrated ! if six units are tested – all have to pass
Slide 38 - 38 Apparatus suitability test (USP) Standard calibrators according to USP chapter <711> Apparatus I, II and V: disintegrating type USP Prednisone Tablets nondisintegrating type USP Salicylic acid Tablets Apparatus III: USP Chlorpheniramine Maleate Extended-Release Tablets
Slide 39 - 39 Information supplied with calibrators http:/
Slide 40 - 40 Apparatus suitability test (USP) USP Prednisone Tablets RS – current lot P0E203 (10 mg nominal prednisone content per tablet) disintegrating type paddle and basket, 50 rpm 500 ml deaerated water, 37°C quantity of prednisone released after 30 minutes is determined specified ranges Lot P0E203: Apparatus 1: 47-82 % Apparatus 2: 37-70 %
Slide 41 - 41 Apparatus suitability test (USP) USP Salicylic acid Tablets RS – current lot Q0D200 (300 mg nominal salicylic acid content per tablet) nondisintegrating type paddle and basket, 100 rpm 900 ml deaerated phosphate buffer, 37°C quantity of salicylic acid, released after 30 minutes is determined specified ranges Lot Q0D200: Apparatus 1: 23-30 % Apparatus 2: 17-25 %
Slide 42 - 42 Apparatus suitability test (USP) Controversies regarding the current test the variability in the intrinsic performance of the USP calibrator tablets is so great that it exceeds the variability in intrinsic performance of modern test dissolution assemblies this variability becomes obvious in both vessel-to-vessel variability and inter-laboratory variability of results for a given lot of calibrators
Slide 43 - 43 Calibrator Tablets: always check the incoming tablets ! right lot of calibrators ? are the tablets broken, fused or severely chipped ? particularly salicylic acid tablets are often subject to sublimation ( dust on the tablets and the inner surface of the container) use correct storage conditions ! take the tablets out of the original container immediately before test ! Troubleshooting
Slide 44 - 44 Standard / Standard solution: USP Standard used ? drying procedure conducted ? standard solution prepared on day of test ? standard solution filtered in the same manner as sample ? amount of alcohol used in the standard < 5% ? Troubleshooting
Slide 45 - 45 Vibration vibration produces unwanted variation in dissolution data and mostly results in an increased dissolution rate internal vibration may be caused e.g. from frayed drive belts external vibration may be caused by e.g. magnetic stirrers, centrifuges, vacuum pumps, old fridges, nearby construction, ... inability to properly measure vibration levels at various points within an apparatus is the main reason why calibrator tablets were originally developed Troubleshooting
Slide 46 - 46 Vibration effects – case example: Effect of vibration levels of the dissolution apparatus on the dissolution rate of enteric coated granules of Cefalexin. The vertical dotted line indicates 0.05 m/s2. Kaniwa N. et al. (1998) Int J Pharm, 175, 119-129 „Low vibration“: < 0.05 m/s2 „High vibration“: > 0.05 m/s2 Troubleshooting
Slide 47 - 47 Vibration: dissolution equipment placed planar ? drive chain or belt free of tension and/or dirt ? torn parts replaced ? correctly functioning gear plates ? individual spindles are not surging ? bench/table stable ? no sources of vibration nearby ? Troubleshooting
Slide 48 - 48 Dissolution medium: correctly degassed ? correct amount used (900/500 ml) ? correct amount dosed (weight/volume) ? dosing procedure gentle (resaturation/spillage) ? buffer correct (pH + 0.05 units, buffer salts, molarity) ? correct temperature during test (32°C / 37°C + 0.5°C)? evaporation during test negligible ? Troubleshooting
Slide 49 - 49 Importance of degassing: insufficient degassing may result in decreased dissolution rates of several drugs e.g. prednisone tablets but also a range of poorly soluble drugs are very sensitive to the amount of dissolved gases in the dissolution medium the degassing procedure should therefore be efficient and reproducible for every test Troubleshooting
Slide 50 - 50 Deaeration method USP heat the dissolution medium to about 41°C vacuum filter through a 0.45-µm-porosity membrane into a flask, stirring with a magnetic stirrer continue to draw a vacuum and stir for an additional 5 min gently transfer the medium directly into the vessel rotating the apparatus 2 shafts to speed equilibration to 37°C is discouraged!!! use medium promptly after equilibration Troubleshooting
Slide 51 - 51 Alternative deaeration methods the USP states that „other validated deaeration techniques for removal of dissolved gases may be used“ other techniques include: heating sonication vacuum helium sparging (expensive) Troubleshooting
Slide 52 - 52 Sampling take each sample at the correct time point  sampling time points (+ 2%) use a single glass syringe for each vessel sample from the right location within the vessel  between media surface and top of the paddle blade  n.l.t. 10 mm from vessel wall Troubleshooting
Slide 53 - 53 Sampling always use a suitable filter  check filter adsorption check the clearity of the filtered sample filter the sample immediately after sampling for automated sampling also check the tubings Troubleshooting
Slide 54 - 54 Physical conditions of the apparatus vessels scrupulously clean ? vessel surface smooth and curvature appropriate ? Apparatus 1 the conditions of the baskets, particularly of their clips is critical check all baskets for corrosion and blocked meshes before using them align the air holes to prevent air cushions emerging during the test Troubleshooting
Slide 55 - 55 Advantages high throughput of samples minimizes analyst-to-analyst variability in sampling and filtration reduces the average costs per analysis very promising for QC purposes (Semi) Automation
Slide 56 - 56 automated mixing of water and concentrate preheating of medium deaeration (vacuum and stirring) media can be dispensed directly into the vessel Media preparation
Slide 57 - 57 Offline system
Slide 58 - 58 Online system
Slide 59 - 59 On- / Offline system
Slide 60 - 60 HPLC - online system
Slide 61 - 61 always validate automated methods, including analytical and sampling methods validation should be performed using manual analysis, withdrawing samples at the same times and comparing to the automated results: not highly variable dissolution results: two concurrent runs highly variable dissolution results: simultaneous sampling pay attention to automated dilution and filtering processes Automation
Slide 62 - 62 FIP Guidelines for dissolution testing of solid oral products. Dissolution Technologies 4:5-14 (1997).    SM Diebold, JB Dressman. Dissolved oxygen as a measure for de- and re-aeration of aqueous media for dissolution testing. Dissolution Technologies 5: 13-16 (1998). S Qureshi. Calibration – the USP dissolution apparatus suitability test. Drug Inf. J. 30, 1055-1061 (1996). N Kaniwa et al. Collaborative study on the development of a standard for evaluation of vibration levels for dissolution apparatus. Int. J. Pharm. 175: 119-129 (1998). VA Gray, CK, Brown, JB Dressman, LJ Leeson. A new general information chapter on dissolution. Pharmacopoeial Forum 27 (6) [Nov.-Dec. 2001] W Brown. General information <1092> The dissolution procedure: development and validation Pharmacopoeial Forum 30 (1) [Jan.-Feb. 2004]   Of general interest: Dissolution Technologies: Suggested reading
Slide 63 - 63 Dr. Sandra Klein Johann Wolfgang Goethe University Institute of Pharmaceutical Technology 9 Max von Laue Street Frankfurt, 60438, Germany e-mail: