`
`‘
`‘
`
`Dissolution Theory,
`Methodology, and
`Testing
`
`Edited by
`Anthony Palmieri Ill
`
`
`
`
`
`
`Dissolution Technologies, Incorporated
`
`Hockessin, Dela ware
`
`ENDO - Ex. 2021
`
`Amneal v. Endo
`
`|PR2014-00360
`
`ENDO - Ex. 2021
`Amneal v. Endo
`IPR2014-00360
`
`

`

`
`
`DISSOLUTION THEORY, METHODOLOGY, AND TESTING
`
`Disclaimer
`
`No responsibility is assumed by the Publisher for any injury and/or damage to perat'ms or property as
`a matter of products liability, negligence or otherwise, or from any use or operation of any methods,
`products, instructions or ideas contained in the material herein. The laboratory procedures described
`herein may involve hazardous material. The authors, speaking for themselves. expressly disclaim any
`liability to users of these lab procedures and apparatus for consequential damages of any kind arising
`out of or connected with their use. Items of apparatus and test methodology described in this book are
`intended to illustrate proper techniques to obtain a quality analysis and are not to be considered official
`and/or required. Official compendia and regulatory requirements are to be considered the only author—
`itative source for such matters.
`'
`
`\
`
`,|_
`1
`
`.
`
`I
`
`
`
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`
`
`All rights reserved. No part of this book may be reproduced or used in any form or by any means
`
`whatsoever without the permission of the publisher except in the case of brief quotations embodied in
`
`critical articles or reviews.
`
`First Edition 2007
`
`
`Library of Congress Control Number 2007929967
` Edited by Anthony Palmieri III.
`
`
`
`Copyright © 2007 by Dissolution Technologies. Inc.
`
`Printed in the United States of America
`
`
`
`Dissolution Theory, Methodology, and Testing
`Includes bibliographical references and index
`ISBN 0-9761519-1-X (hardcover)
`Cover design by Allen Press, Incorporated
`
`
`Published by Dissolution Technologies, Incorporated
`9 Yorkridge Trail, Hockessin, DE 19707 USA.
`www.dissolutiontech.com
`
`
`
`
`

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`32
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`31.
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`32.
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`DISSOLUTION THEORY, METHODOLOGY, AND TESTING
`
`Gray, V. A.; Dressman, J. B. Change of pH Requirements for Simulated In-
`testinal Fluid TS. Pharm. Forum 1996, 22 (1), 1943—1945.
`Noory, C.; Tran, N.; Ouderkirk, L.; Brown, 8.; Perry, 1.; Lopez, 1.; Colon, M.;
`Faberlle, M.; Henry, K.; Rorberg, J.-; Ali, S. N.; Shah, V. Rethinking the Use
`of Water as a Dissolution Medium. Dissolution Technol. 1999, 6 (4), 6—7.
`Leeson, L. J. Some Observations on ‘Rethinking the Use of Water as a Dis-
`solution Medium.’ Dissolution Technol. 2000, 7 (2), 16—17.
`Kaniwa, N. Japanese Perspectives on Pharmaceutical Product Release Rate
`Testing. Drug Inform. J. 2002, 36, 407—415.
`Morihara, M.; Aoyagi, N.; Kaniwa, N.; Kojima, S.; Ogata H. Assessment of
`gastric acidity of Japanese subjects over the last 15 years. Biol. Pharm. Bull.
`2001, 24 (3), 313—315.
`Acetaminophen and Codeine Phosphate Capsules. Pharm. Forum 1998, 24 (1),
`5436.
`
`Dissolution <711>. In United States Pharmacopeia XIX; The United States
`Pharmacopeial Convention, Inc.: Rockville, MD, 1975; p 651.
`Hofer, J. D.; Gray, V. A. Examination of Selection of Immediate-Release Dis-
`solution Acceptance Criteria. Pharm. Forum 2003, 29 (1), 335—340.
`Cabana, B. E.; O’Neill, R. FDA’s Report on Drug Dissolution. Pharm. Forum
`1980, 6(1), 71—75.
`Sarapu, A. C.; Lewis, A. R.; Grostic, M. F. Analysis of PMA Collaborative
`Studies of Dissolution Test Calibrators. Pharm. Forum 1980, 6 (2), 172—176.
`Pharmaceutical Research and Manufacturers of America (PhRMA),- Dissolution
`Test Working Group. USP Dissolution Calibrator Tablets: Recommendations
`for Reduced Calibration Testing. Pharm. Forum 1997, 23 (3), 4238—4242.
`Pharmaceutical Research and Manufacturers of America (PhRMA), Subcom-
`mittee on Dissolution Calibrators Dissolution Calibration. Recommendations
`
`for Reduced Chemical Testing and Enhanced Mechanical Calibration. Pharm.
`Forum 2000,26 (4), 1149— 1166.
`Mirza, T.; Grady, L. T.; Foster, T S. Merits of Dissolution System Suitability
`Testing: Response to PhRMA's Proposal on Mechanical Calibration. Pharm.
`Forum 2000, 26 (4), 1167—1169.
`
`
`
`Dissolution Equipment
`
`G. Bryan Crist
`
`DISSOLUTION APPARATUS OVERVIEW
`
`Over the past forty years, two basic techniques have evolved for in vitro dis-
`solution testing, the stirred beaker method and the flow-through procedure.
`The stirred beaker system places the test specimen and a fixed volume of fluid
`in a vessel, and stirring provides mechanical (hydrodynamic) agitation. This system
`was adopted as the official dissolution method in USP XVIII in 1970 and described
`as the rotating basket method, USP Apparatus 1.
`The rotating paddle method was adopted as an official dissolution method by
`the USP. several years later and became USP Apparatus 2. The origin of official
`equipment developed from a number of basket and stirring devices (I) is shown
`in Figure 1.
`Some of the needs for the flow--through type apparatus included a change of pH
`or any other change in the dissolution medium. Difficulties had also arisen for a
`number of sparingly soluble drugs, which were difficult to investigate with a limited
`volume of media. The flow-through system was first adopted by the Deutscher
`Arzneimittelcodex (German Pharmaceutical Codex, DAC) in 1981.
`Two flow-through apparatus were eventually added to the USP in 1990 to over-
`come some of the experimental difficulties from the use of the single vessel meth—
`odology. They became known as USP Apparatus 3, Reciprocating Cylinder, and
`USP Apparatus 4, Flow-Through Cell.
`The most common dissolution apparatus used throughout the world are the has-
`ket and the paddle. These methods are simple and robust and are generally flexible
`enough to allow dissolution testing for a wide variety of drug products. For this
`reason, Apparatus 1 and 2 should be used for dissolution method development
`unless shown to be unsatisfactory. Other in vitro dissolution apparatus such as the
`reciprocating cylinder and the flow-through cell system described in the USP may
`be considered, if needed.
`More drug release equipment, USP Apparatus 5 and 6, deal with transdermal
`systems. USP Apparatus 7 (Alza—type) was developed for the analysis of transder—
`
`33
`
`
`
`

`

`34
`
`DISSOLUTION THEORY, METHODOLOGY, AND TESTING
`
`Dissolution Equipment
`
`35
`
`Dissolution, Bloavallablllty and Bloequlvalence
`
`scribed in pharmacopeia throughout the world, but for purposes of discussion, ref-
`erences will be made to the USP regarding specifications and operation.
`
`Rotating Basket
`
`A general description of the rotating basket apparatus consists of shaft and basket
`component fabricated from 316 stainless steel. Unless otherwise specified in a lest
`method or official monograph, a 40-mesh basket is used, The basket shaft assembly
`containing the product is lowered into a IOOO-mL vessel and rotated at a specific
`speed within media. which is maintained at a specific temperature. The rotating
`basket method is routinely used for capsule formulations at an agitation speed of
`50—100 rpm. Rates outside a range of 50—150 rpm are generally unacceptable
`because of irreproducibility associated with the hydrodynamics below 50 rpm and
`turbulence above 150 rpm. High turbulence in the vessel leads to a loss of dis-
`criminatory power associated with the dissolution method.
`The vessel used for Apparatus 1 and 2 is typically a 1000-mL hemispheric—
`shaped vessel made of glass or suitably inert material. Vessel volume should be
`between 500 and 1000 mL with 900 mL used historically. One-liter vessels are
`tubing-based with dimensions of 98406 mm i.d. and loll—210 mm in height.
`Larger vessels have been developed over the years to allow more volume for poorly
`soluble compounds. The USP Z—L vessel has dimensions of 98—106 mm i.d. and
`280—300 mm in height. The USP 4—L vessel has dimensions of 145—155 mm i.d.
`and 280—300 mm in height.
`The official basket used for Apparatus 1 is a 40-mesh design, meaning there are
`40 openings per linear inch. Openings are equal in both directions producing a
`standard square weave. USP specifies that 40—mesh (40 X 40) screen be manufac-
`tured with wire having a 0.010” diameter. Dissolution baskets are fragile and require
`proper handling and care’. Attachment to or removal from Ihe basket shaft requires
`holding the upper rim. When not in use, baskets should be stored in protective
`cases. Baskets should be carefully inspected for damage or excessive wear since
`defective or misshaped baskets will affect test results. The standard 40-mesh basket
`with a 0.01" wire size results in a 0.381-mm square aperture. For comparison, the
`Japanese Pharmacopeia specifies U.Ul.|” wire diameter resulting in 0,425-mm
`square hole resulting in a 36-mesh basket. The baskets are not interchangeable and
`could result in a 24% difference in USP. El”. and JP baskets when testing the USP
`disintegrating calibrator, Prednisone.
`
`Current Physical Parameters and Tolerances:
`Wobble
`:1 mm basket lower rim
`Dimensions
`per USP
`Height
`25 i 2 mm
`Centering
`:2 mm center line
`Speed
`:4% of set speed
`Vessel Temp.
`37 i 0.5 °C
`Timepoints
`i2% of specified time
`
`Beaker-stirrer
`Lm-Nlpdluo)
`
`Paddle-flank
`Pool- (nu)
`
`Rotutin ballot
`hrn-mllg-Uootllu)
`
`U
`
`3:053"
`
`
`
`UCJUU
`
`
`Bout bath!
`rim," title?!)
`
`
`Planor we
`Stationary basket Magnetic basket
`Gum's.)
`Sunni.” ll(l.7!) mahonflalunb'rl)
`
`Figure 1. Difi‘erent designs of dissolution vessels and stirrers that have been uti-
`lized in major nonojj‘icial methods. (Reprinted with permission from ref 1. Copy-
`right 1982 Advanstar Communications, Inc.)
`
`mal systems as well as a variety of drug release systems such as osmotic pumps
`and Implants. Because of the diversity of delivery systems and the evolving nature
`of understanding in the area of drug release, different experimental modifications
`may be needed to obtain a suitable in vivo correlation with in vitro release data.
`Alternatives or modifications to established methodology should be considered on
`the basis of proven superiority for a particular product. If the release of the active
`drug substance from an individual drug product cannot be accommodated by one
`of the major compendial apparatus, appropriate modifications have to be developed.
`However, unnecessary proliferation of alternative dissolution apparatus should not
`be encouraged due to the reproducibility problems that plagued early dissolution
`equrpment; this will also hinder regulatory acceptance.
`
`USP APPARATUS 1 AND 2—ROTATING BASKET AND PADDLE
`
`USP Apparatus l and 2 are described officially in USP Physical Test Chapter
`<711> Dissolution (2). USP Apparatus 1 is called the rotating basket apparatus
`and USP Apparatus 2 is called the rotating paddle apparatus. They are also de-
`
`
`
`

`

`36
`
`DISSOLUTION THEORY, METHODOLOGY, AND TESTING
`
`Dissolution Equipment
`
`37
`
`Q
`
`6.3 to 6.5 or
`9.4 to 10.1 rrm
`
`Vent hole
`2.0 t 0.5 m diameter
`
`Retention spring with
`a lengeon 120° centers
`
`Clear opening
`202 :1: 0.1 mm
`
`37.01:
`-3.0 rrln
`
`.
`
`—r—
`27.0
`:t: 1.0 mm
`09°"
`
`Nate—Maximum allmable
`runoutal 'A' Is 11.0mmMIen
`the pertls rotated on anie
`with basket mounted.
`
`[
`Screen 0.D.
`
`22.2 t 1.0 mm
`Screen with welded seam:
`40 X 40 mesh. 025-mm wire
`diameter with wire openings of
`0.40 :r: 0.04 mm: where 20-
`mesh screen is specified. use
`20 X 20 mesh, GAO—mm wire
`diameter with wire openings of
`0.90 d: 0.09 mm. [Nore—
`Aller welding. the screen may
`be slightly altered]
`
`
`
`
`
`
`
`Figure 2. Various dissolution vessels.
`
`In addition to the current physical parameters, some pharmaceutical laboratories
`have adopted more stringent parameters gleaned from a PhRMA Subcommittee on
`Dissolution Calibration proposal to the USP (3) to maintain a higher degree of
`control over the rotating basket apparatus:
`
`Optional Parameters and Tolerances:
`Shaft wobble
`$0.5 mm total runout
`Basket wobble
`51.0 mm total runout
`Basket exam
`No defects at time of use
`
`Shaft verticality
`Speed
`Vibration
`
`Vertical using bubble level
`:2% set speed
`$0.2-mil displacement
`
`Typical products tested with the rotating basket are capsules, tablets, floaters,
`modified—release products, beads, and suppositories. Suppository testing may be
`performed with a slotted Palmieri basket with or without glass beads.
`Several allowable variations of the standard 40-mesh basket exist including a
`basket with a gold coating 2.5—um thick (0.0001-inch). Larger vessels accommo—
`dating up to two and four liters are now allowable variations in the USP. Such
`vessels are advantageous for poorly soluble drugs.
`Some non-official variations of the rotating basket include Teflon baskets, o-ring
`
`20211.0n'm
`
`'
`
`..
`
`-- 25.0: 3.0 mm
`
`Figure 3. Official basket used for USP Apparatus I.
`
`baskets, lO-mesh through 2300-mesh (5-micron), three-fin, mini, and bolus baskets
`for veterinary products. Examples of these baskets are shown in Figure 4.
`Occasionally a small volume apparatus may be required for low-dose, high—
`potency products. Such a variation consists of a mini-basket apparatus based on
`USP Apparatus 1 with 100- or 200-mL vessels. Small volume apparatus has a
`typical operational minimum volume of 30-mL. Shown in Figure 5 are a mini
`basket and an official rotating basket.
`
`
`
`

`

`‘38
`
`DISSOLUTION THEORY, METHODOLOGY, AND TESTING
`
`Dissolution Equipment
`
`39
`
`
`
`Figure 4. Examples of non-ofi‘icial variations of the rotating basket.
`
`Rotating Paddle
`
`General Apparatus 2 Description
`
`USP Apparatus 2, the rotating paddle method, followed the development of the
`rotating basket method with better stirring characteristics. The paddle blade is fixed
`to the bottom of the shaft and rotates at a height of 25 mm from the inner bottom
`of the vessel. The paddle consists of a metallic or suitably inert, rigid blade and
`shaft composing a single entity. The paddle blade and shaft may be coated with a
`suitable inert material.
`
`The paddle is lowered into a lOOO-mL vessel and rotated at a specific speed
`within media, which is maintained at a specific temperature. The rotating paddle
`method is routinely used at an agitation speed of 25 to 75 rpm. Rates outside a
`
`
`
`Figure 5. Mini basket and ofi‘icial rotating basket.
`
`
`
`Figure 6. Typical dissolution setup.
`
`range of 25 to 75 rpm are generally unacceptable because of irreproducibility of
`the hydrodynamic effects below 25 rpm and turbulence above 100 rpm. High tur-
`bulence in the vessel leads to a loss of discriminatory power associated with the
`method. Agitation rates around 25 rpm but less that 50 rpm are acceptable for
`suspensions. For solid dosage forms with excessive coning, rotational speeds
`around 75 rpm may be necessary to improve the data. As with any variance from
`normal operating parameters, atypical conditions must be supported with data from
`normally accepted conditions for justification of USP Apparatus 2. When disso-
`lution profiles exhibit inappropriately dissolving drug substance during method de-
`velopment, adjustments outside the normal rotational speed may be warranted.
`Any time a method references USP General Chapter <7ll>, the dosage unit
`must be allowed to settle to the bottom of the vessel before rotation of the paddle
`begins. To aid the dosage unit settling to the bottom of the vessel, a small, loose
`piece of stainless steel wire consisting of a few turns may be attached to a dosage
`unit that would otherwise float.
`
`
`
`

`

`38
`
`DISSOLUTION THEORY, METHODOLOGY, AND TESTING
`
`Dissolution Equipment
`
`39
`
`
`
`Figure 4. Examples of non-ofiicial variations of the rotating basket.
`
`Rotating Paddle
`General Apparatus 2 Description
`
`USP Apparatus 2, the rotating paddle method, followed the development of the
`rotating basket method with better stirring characteristics. The paddle blade is fixed
`to the bottom of the shaft and rotates at a height of 25 mm from the inner bottom
`of the vessel. The paddle consists of a metallic or suitably inert, rigid blade and
`shaft composing a single entity. The paddle blade and shaft may be coated with a
`suitable inert material.
`
`The paddle is lowered into a lOOO—mL vessel and rotated at a specific speed
`within media, which is maintained at a specific temperature. The rotating paddle
`method is routinely used at an agitation speed of 25 to 75 rpm. Rates outside a
`
`
`
`Figure 5. Mini basket and ofi‘icial rotating basket.
`
`
`
`Figure 6. Typical dissolution setup.
`
`range of 25 to 75 rpm are generally unacceptable because of irreproducibility of
`the hydrodynamic effects below 25 rpm and turbulence above 100 rpm. High tur-
`bulence in the vessel leads to a loss of discriminatory power associated with the
`method. Agitation rates around 25 rpm but less that 50 rpm are acceptable for
`suspensions. For solid dosage forms with excessive coning, rotational speeds
`around 75 rpm may be necessary to improve the data. As with any variance from
`normal operating parameters, atypical conditions must be supported with data from
`normally accepted conditions for justification of USP Apparatus 2. When disso-
`lution profiles exhibit inappropriately dissolving drug substance during method de-
`velopment, adjustments outside the normal rotational speed may be warranted.
`Any time a method references USP General Chapter <7ll>, the dosage unit
`must be allowed to settle to the bottom of the vessel before rotation of the paddle
`begins. To aid the dosage unit settling to the bottom of the vessel, a small, loose
`piece of stainless steel wire consisting of a few turns may be attached to a dosage
`unit that would otherwise float.
`
`
`
`

`

`40
`
`DISSOLUTION THEORY, METHODOLOGY, AND TESTING
`
`Dissolution Equipment
`
`41
`
`
`
`Figure 7. Examples of Apparatus 2 paddels.
`
`Since the construction of the sinker has such an impact on the hydrodynamics
`in the bottom of the vessel, individuals have sought to standardize the USP design.
`A unique standardization utilizing cork borers was presented in the Pharmacopeial
`Forum as a stimuli article (4). The guidance suggested a method to construct sink-
`ers by hand with the use of a cork borer which would minimize the variability
`resulting from different interpretations of the construction of a USP sinker.
`In addition to sinking floating dosage forms, sinkers may assist in keeping a
`dosage form from sticking to the vessel inappropriately as in the case with some
`film-coated tablets. Sinkers must be adequately described in laboratory standard
`operating procedures to eliminate hydrodynamic variation associated with different
`sinker devices. Sinkers of other descriptions may be used if properly validated.
`Many different sinkers have evolved, some of which are based on the wire helix
`design.
`
`
`Current Physical Parameters and Tolerances:
`Wobble
`Not specified in USP
`Dimensions
`per USP
`Height
`25 t 2 mm
`Centering
`:2 mm center line
`Speed
`:4% of set speed
`Vessel Temp.
`37 i 0.5 °C
`Timepoints
`:2% of specified time
`
`As mentioned in the previous section on physical parameters for basket, some
`
`9.4 to 10.1mm diameter
`before coating
`
`
`
`
`
`
`
`
`
`
`
`
`
`NOTES—
`") Shaft and blade material.-
`303 (or equivalent)
`stainless steel.
`(2) A and 8 dimensions are
`not to vary more than
`0.5 mm when part is
`rotated on 1 axis.
`(3) Tolerances an.I $1.0 mm,
`unless otherwise stated.
`
`
`
`
`
`4 I. 5 mm radius
`
`1.2 mm radii/5V
`
`4 01 1.0 mm
`
`L— 74.0 mm to 75.0 mm -—~[
`Figure 8. USP Apparatus 2 paddle specifications.
`
`laboratories have adopted more stringent parameters for the paddle apparatus to
`maintain a higher degree of control.
`
`Optional Parameters and Tolerances:
`Shaft wobble
`50.5 mm total runout
`Paddle exam
`No defects at time of use
`
`Shaft verticality
`
`Vertical using bubble level
`
`
`
`

`

`
`
`42
`
`DISSOLUTION THEORY, METHODOLOGY, AND TESTING
`
`Dissolution Equipment
`
`43
`
`
`
`
`Figure 10. Sinkers constructed using cork borers.
`
`
`
`Figure 11. Examples of sinker designs.
`
`Speed
`Vibration
`
`:2 RPM of set speed
`$0.2-mil displacement
`
`Typical products tested by the paddle method are tablets, capsules (with sinkers),
`hydrogel tablets, suspensions, powders, microparticles, and transdermals (paddle-
`over-disk method).
`
`Calibration of USP Apparatus 1 and 2
`
`In the early 19705, scientists began to evaluate significant apparatus-to-apparatus
`differences in dissolution results. Monograph specifications could not be enforced
`due to variability in results from lab to lab and apparatus to apparatus. In 1978,
`the USP established and issued the first official dissolution calibrator tablets and
`reference standards. The primary purpose was to control vibration since most other
`parameters could be controlled by mechanical measurements.
`Since that time, dissolution apparatus used under current Good Manufacturing
`Practices (cGMPs) should be challenged with an apparatus suitability test as out-
`lined in the USP Chapter <711> Dissolution. At the time of this printing, the
`suitability test must be conducted with USP dissolution calibrators of the disinte-
`grating and non-disintegrating type, Prednisone and Salicylic Acid tablets, respec-
`tively. The word calibration is somewhat of a misnomer since the “calibrator”
`tablets do not actually calibrate anything, as a weight would be used to calibrate
`an analytical balancej At this time there is no predefined period of calibration;
`however, our current Good Manufacturing Practices as outlined in 21 CFR Parts
`210 and 211 require calibration of analytical equipment according to prescribed
`schedules. These prescribed schedules are generally established by various orga-
`nizations to limit the liability originating from test results obtained on apparatus
`
`
`
`

`

`44
`
`DISSOLUTION THEORY, METHODOLOGY, AND TESTING
`
`Dissolution Equipment
`
`45
`
`that may fall out of calibration as a result of age, environmental factors, or relo-
`cation.
`
`In the event of obtaining an outside-of—target dissolution result or a suspect result
`during calibration or routine analysis, a detailed review of the equipment, method,
`materials, and analyst documentation should take place. The investigation should
`be thoroughly documented and include all observations and explanations for the
`aberrant result by showing a cause—and-effect relationship, corrective action, and
`eventually the retest. One change at a time should be made prior to retesting to
`isolate the cause of the aberrant result. Recheck all physical parameters after any
`adjustments are made and perform retesting on a set of six tablets.
`A laboratory review checklist consisting of the following areas should be im-
`plemented to perform a thorough evaluation: check calculations, reread samples
`that were non-conforming, examine spectrophotometer and any automatic sampling
`equipment, review sampling technique, review stande preparation, review media
`preparation, Documentation of the investigation should include a description of the
`failure with a full data summary, the laboratory review checklist, description of
`the findings, corrective actions, additional physical adjustment of the apparatus,
`specific reasons for the run to be invalidated such as a crack in the vessel, and the
`retest(s).
`
`Aberrant Dissolution Data Investigation
`The most common sources of error in dissolution testing for the rotating basket
`and paddle methods are deaeration, paddles and baskets conformance, condition of
`vessels, vibration and environmental issues, sampling technique, and filtering is-
`sues.
`
`Deaeration
`
`While numerous deaeration techniques have been utilized, some are better than
`others. The USP recommends heating media to approximately 41 °C followed by
`vacuum filtration through a 0.45pm filter under vigorous stirring. After filtration,
`continue to draw the vacuum for five additional minutes. In theory, the best way
`to remove dissolved gases is through boiling, but this is a waste of energy and
`time resources. However, heating media to 41 °C and applying a vacuum can
`achieve boiling at a lower temperature. The filter is simply used to provide a
`pressure gradient. Once the media passes through the filter, air is immediately and
`efficiently stripped out. Media is then measured and gently poured into the disso-
`lution vessel and allowed to equilibrate to 37 °C in the vessel. Alternate deaeration
`techniques have been used such as helium sparging or vacuum ultrasonication.
`Critical parameters for helium-sparging methods include gas flow rate, type of
`diffuser, and time per volume. The efficiency of alternate deaeration techniques
`must be demonstrated and documented through validation.
`Historically, media has been measured and gently added to the vessel with the
`aid of a cylinder or other calibrated “to deliver” device. Media should be delivered
`with an accuracy of :l%, which currently rules out most “class A” graduated
`
`cylinders because they are calibrated in lO-mL increments and are not capable of
`measuring the i9-mL tolerance for the typical 900-mL media volume. Alternately,
`media could be measured in a “to deliver” class A volumetric flask if it has been
`calibrated at the intended measuring temperature. An alternate media-measuring
`technique employed by many automated systems is gravimetric measurement.
`Dissolution media at a controlled elevated temperature may also be weighed by
`correcting for pre-determined density. This is how many automated delivery sys-
`tems measure and transfer media to the vessel.
`
`Vibration
`
`For dissolution equipment to operate correctly, the area must be maintained free
`from excessive vibration from sources such as centrifuges, vacuum pumps, fume
`hoods, shakers, ultrasonic cleaners, and unstable bench top and construction. All
`such sources of external vibration must be eliminated. Internal sources of vibration
`may be caused by tension or dirt on drive belt, worn parts and bearings, and
`turbulence in the water bath. Make sure the deflector shield is in place in the water
`bath.
`
`Preferably use a vibration meter during calibration periods to obtain a baseline
`measurement. If suspect 01' aberrant dissolution results are obtained on the appa—
`ratus, current vibration measurements may be compared to the level obtained during
`calibration to see if this could have contributed to the suspect data. Vibration mea-
`surements should be part of the routine physical calibration of the apparatus to
`detect vibration from unwanted sources prior to obtaining data.
`
`Sampling and Filtering
`The filter is essential to stop the dissolution test by removing undissolved drug
`product as well as particulate matter and turbidity from the sample. Filters must
`be tested for drug adsorptivity to show that they do not bind drug substance. Filters
`should also be evaluated for efficiency to demonstrate that drug substance did not
`pass through the filter and continue to dissolve. Separate, clean, dry filters and
`glassware must be used when sampling each vessel. Generally, the first several
`milliliters should be discarded prior to sample collection for analysis but the specific
`amount discarded must be determined through validation. Sample aliquots must be
`filtered immediately after the sample is drawn, otherwise the dissolution process
`continues.
`
`Baskets and Paddles
`
`Basket and paddle stirring elements must be checked for USP conformance.
`Routine physical observations of baskets and shafts should be conducted to ensure
`integrity of the stirring element. Physical observation of basket and shafts should
`include that they are straight and roll evenly on a flat surface. Any Teflon coating
`must not be chipped or peeling, which adds to the turbulence in the vessel. Check
`surfaces for corrosion or discoloration due to prolonged exposure to hydrochloric
`acid. Stainless steel, while resistant to rust and corrosion, will be attacked by chlo—
`
`
`
`

`

`48
`
`DISSOLUTION THEORY, METHODOLOGY, AND TESTING
`
`Dissolution Equipment
`
`49
`
`SIationary Tablet Basket Configuration Dlagrarn
`
`
`
`Figure 13. Small-volume dissolution apparatus.
`
`purpose was to improve the mixing characteristics within the vessel, eradicate con—
`ing, and produce better stirring from a low energy system that will not cause
`particle shear. The mega paddle may also be useful for Z-L and 4-L vessels where
`greater fluid movement is required. This modified paddle has not been as widely
`accepted as the peak vessel for improving hydrodynamics within the vessel.
`
`Stationary Basket
`
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`
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`
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`
`The stationary basket assembly is used with traditional rotating paddle apparatus.
`This modification suspends the dosage unit contained in a basket device Just above
`
`Figure 15. Stationary basket design.
`
`
`
`Figure 14. Mega paddle.
`
`the rotating paddle. Several variations of the stationary basket have eVolved. One
`system utilizes a basket held in place by a disk with clips similar to the rotating
`basket apparatus with the exception that a 0.25-inch shaft mounts the stationary
`basket to the evaporation cover. In addition to a standard USP 40-mesh basket, 10-
`and 20-mesh baskets have been used. Another variation was introduced in the USP
`
`26 First Supplement for a Felodipine monograph. This design utilizes a quadran-
`gular basket of stainless steel wire gauze, which is suspended 1 mm above the
`rotating paddle.
`
`Qualification of Non-Compendial Equipment
`
`While no USP specifications or calibration procedure are available for small and
`large volume vessels, peak vessels, mega paddles, or stationary baskets, the per-
`tinent physical characteristics should be measured. Detailed specifications of the
`modified equipment must be documented and reliable sources for the equipment
`should be available. Apparatus should be calibrated with one—liter vessels to indi-
`cate that the apparatus is suitable under standard conditions. Physical parameters
`of height, centering, speed, wobble, and temperature need to be measured against
`current USP criteria and documented.
`
`
`
`

`

`46
`
`DISSOLUTION THEORY, METHODOLOGY, AND TESTING
`
`ride ions, which will cause pitting in the surfaces and a reduction in the wire
`diameter used in the baskets. A basket will maintain specifications of 40-mesh
`unless it is misshapen, but the basket micron rating will change over its lifetime
`due to corrosion. A non-lustrous pewter appearance is an indication that the basket
`integrity is failing. Particles may fall out of the basket too early causing lower
`results if the wire diameter is significantly reduced due to corrosion. Gold coating
`up to 2.5—p.m thick is an allowable variation for baskets to inhibit corrosion asso-
`ciated with a stainless steel basket. The basket surface must be smooth, not wrin-
`
`kled or misshapen, and must not have a frayed appearance; the basket should be
`replaced, if necessary.
`USP basket clips must be tight since loose clips impart excessive wobble. Non-
`USP baskets such as o-ring attachments without clips must be validated to show
`that there is no change in test results. USP Prednisone calibrator tablets run in
`o-ring baskets have exhibited up to a 10% suppressed result over the USP clip-
`type basket.
`Regarding air bubbles, several observations should be made when starting a
`dissolution run. Bubbles occasionally form underneath the disk and sometimes hold
`a tablet in the upper portion of the basket and do not allow one side of the dosage
`unit to contact the media for several minutes. If this is not noticed, a non-disinte-
`
`grating dosage form similar to the salicylic acid calibrator tablet will produce results
`on the low side of the expected range. Bubbles that form under a basket will alter
`the performance of the basket and cause failures since dissolution media will not
`circulate through the basket properly. Bubbles forming in the mesh will alSo change
`the characteristics of the basket by blocking the openings and virtually changing
`the mesh of the basket. The latter condition is usually a result of poor media
`deaeration.
`/
`
`Vessels
`
`Dissolution vessels should be serialized or numbered and maintained in their
`
`original positions. This reduces the opportunity for a defective vessel to be moved
`from one apparatus to another, causing random failures. The inner surface of vessels
`should be routinely checked for irregularities, scratches, cracks, pits, and uneven-
`ness or surface aberrations. Vessels should be acquired from a reputable manufac-
`turer since the inner surface must have a defect—free hemispheric bottom. Vessels
`manufactured with poor quality control will exhibit shallow, protruding, or asym-
`metrical bottoms, which will greatly affect the dissolution results due to increased
`turbulence.
`
`Vessels need to be checked for cleanliness. Scum, film, or sticky residues build
`up over time and can greatly affect dissolution rates. Vessels must be scrupulously
`clean. Tablets are to be dropped into non-rotating medium and allowed to settle to
`the bottom of the vessel prior to starting the rotation of paddles. Observe the dosage
`unit after introduction and record unusual observations such as sticking, floating,
`bubbles, and irregular shape of the cone.
`
`
`
`Dissolution Equipment
`
`47
`
`
`
`Fig