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4.24 DISSOLUTION TEST

      This test is provided to determine compliance with the dissolution requirements where stated in the individual monograph for dosage forms administered orally. In this appendix, a dosage unit is defined as one tablet or one capsule or the amount specified. Of the types of apparatus described herein, use the one specified in the individual monograph. Where the label states that a dosage form is enteric-coated, and where a dissolution or disintegration test that does not specifically state that it is to be applied to delayed-release dosage forms is included in the individual monograph, the procedure and interpretation given for DelayedRelease Dosage Forms is applied unless otherwise specified in the individual monograph. For hard or soft gelatin capsules and gelatin-coated tablets that do not conform to the dissolution specification, repeat the test as follows. Where water or a medium with a pH of less than 6.8 is specified as the medium in the individual monograph, the same medium specified may be used with the addition of purified pepsin that results in an activity of 750,000 Units or less per 1000 ml. For media with a pH of 6.8 or more pancreatin can be added to produce not more than 1750 Units of protease activity per 1000 ml.

APPARATUS

Apparatus 1 (Basket apparatus, Fig. 1) The assembly consists of the following: a covered vessel (C) made of borosilicate glass or other inert, transparent material; a motor; a metallic drive shaft (A); and a cylindrical basket (B). The vessel is partially immersed in a suitable water-bath of any convenient size that permits holding the temperature inside the vessel at 37º±0.5º during the test and keeping the bath fluid in constant, smooth motion. No part of the assembly, including the environment in which the assembly is placed, contributes significant motion, agitation, or vibration beyond that due to the smoothly rotating stirring element. Apparatus that permits observation of the specimen and stirring element during the test is preferable. The vessel is cylindrical, with a hemispherical bottom and with one of the following dimensions and capacities: for a nominal capacity of 1000 ml, the height is 185±25 mm and its inside diameter is 102±4 mm; for a nominal capacity of 2000 ml, the height is 290±10 mm and its inside diameter is 102±4 mm; and for a nominal capacity of 4000 ml, the height is 290±10 mm and its inside diameter is 150±5 mm. Its sides are flanged at the top. A fitted cover may be used to retard evaporation¹ . The shaft is positioned so that its axis is not more than 2 mm at any point from the vertical axis of the vessel and rotates smoothly and without significant wobble. A speed-regulating device is used that allows the shaft rotation speed to be selected and maintained at the rate specified in the individual monograph, within ±4 per cent.

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¹If a cover is used it provides sufficient openings to allow ready insertion of the thermometer and withdrawal of specimens.

      The basket consists of two components. The top part is of solid metal with a vent and is attached to the shaft. It is fitted with three spring clips or other suitable means that allow removal of the lower part for introduction of the dosage unit and that firmly hold the lower part of the basket concentric with the axis of the vessel during rotation. The shaft and basket components are made of stainless steel of suitable quality. The lower detachable part of the basket is made of weldedseam, stainless steel cloth formed into a cylinder with a narrow rim of sheet metal around the top and bottom; unless otherwise prescribed, the cloth has a wire thickness of 0.28±0.03 mm in diameter with wire openings of 0.40±0.04 mm. A basket having a gold coating 2.5 μm (0.0001 inch) thick may be used with acidic media. The dosage unit is placed in a dry basket at the beginning of each test. The distance between the inside bottom of the vessel and the basket is maintained at 25±2 mm during the test.

Apparatus 2 (Paddle apparatus, Fig. 2) Use the assembly from Apparatus 1, except that a paddle (D) formed from a blade and a shaft is used as the stirring element. The shaft is positioned so that its axis is not more than 2 mm at any point from the vertical axis of the vessel, and rotates smoothly without significant wobble. The vertical centre line of the blade passes through the axis of the shaft so that the bottom of the blade is flush with the bottom of the shaft. The paddle conforms to the specifications shown in the figure. The distance of 25±2 mm between the blade and the inside bottom of the vessel is maintained during the test. The metallic or suitably inert, rigid blade and shaft comprise a single entity. A suitable two-part detachable design may be used provided the assembly remains firmly engaged during the test. The paddle blade and shaft may be coated with a suitable coating so as to make them inert. The dosage unit is allowed to sink to the bottom of the vessel before rotation of the blade is started. 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. An alternative sinker device is shown in Fig. 2a. Other validated sinker devices may be used.

      Apparatus 3 (Flow-through cell apparatus, Fig. 3) The assembly consists of a reservoir and a pump for the dissolution medium, a flow-through cell and a waterbath that maintains the dissolution medium at 37º±0.5º. The cell size is specified in the individual monograph.

      The pump forces the dissolution medium upwards through the flow-through cell. The pump has a delivery range between 240 and 960 ml per hour, with standard flow rates of 4, 8, and 16 ml per minute. It must be volumetric to deliver a constant flow (±5 per cent of the nominal flow rate) independent of flow resistance in the filter device; the flow profile is sinusoidal with a pulsation of 120±10 pulses per minute. The flow-through cell (Figs. 3a and 3b), of transparent and inert material, is mounted vertically with a filter system (specified in the individual monograph) that prevents escape of undissolved particles from the top of the cell; standard cell diameters are 12 and 22.6 mm; the bottom cone is usually filled with small glass beads of the cell; standard cell diameters are 12 and 22.6 mm; the bottom cone is usually filled with small glass beads of about 1-mm diameter with one bead of about 5 mm positioned at the apex to protect the fluid entry tube; a tablet holder (Figs. 3a and 3b) is available for positioning of special dosage forms such as inlay tablets. The cell is immersed in a water-bath and the temperature is maintained at 37º±0.5º. The apparatus uses a clamp mechanism and two O-rings for the fixation of the cell assembly. The pump is separated from the dissolution unit in order to shield the latter against any vibrations originating from the pump. The position of the pump should not be on a level higher than the reservoir flasks. Tube connections are as short as possible. Use suitably inert tubing, such as polytef, with about 1.6-mm inner diameter and chemically inert flanged-end connections.

      Apparatus suitability The determination of suitability of the apparatus to perform dissolution testing must include conformance to the dimensions and tolerances of the apparatus as given above. In addition, critical test parameters that have to be monitored periodically during use include volume and temperature of the dissolution medium, rotation speed (Apparatus 1 and Apparatus 2), and flow rate of medium (Apparatus 3).

      Determine the acceptable performance of the dissolution test apparatus periodically.

PROCEDURE 

Immediate-Release Dosage Forms (Capsules, Uncoated Tablets and Plain Coated Tablets)​

Apparatuses 1 and 2 Place the stated volume of the dissolution medium (±1 per cent) in the vessel of the apparatus specified in the individual monograph, assemble the apparatus, equilibrate the dissolution medium to 37º±0.5º, and remove the thermometer. Place one tablet or one 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 in the individual monograph. Within the time interval specified, or at each of the times stated, withdraw a sample from a zone midway between the surface of the dissolution medium and the top of the rotating basket or blade, not less than 1 cm from the vessel wall. (Note Where multiple sampling times are specified, replace the aliquots withdrawn for analysis with equal volumes of fresh dissolution medium at 37º or, where it can be shown that replacement of the medium is not necessary, correct for the volume change in the calculation. 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 the individual monograph. (Note Test specimens are filtered immediately upon sampling unless filtration is demonstrated to be unnecessary. Use an inert filter that does not cause adsorption of the active ingredient or contain extractable substances that would interfere with the analysis.) Repeat the test with additional dosage-form units.

      If automated equipment is used for sampling or the apparatus is otherwise modified, verification that the modified apparatus will produce results equivalent to those obtained with the standard apparatus described in this appendix is necessary.

      Dissolution medium Use the solvent specified in the individual monograph. The volume specified refers to measurements made between 20º and 25º. If the dissolution medium is a buffered solution, adjust the solution so that its pH is within 0.05 unit of the pH specified in the individual monograph. (Note Dissolved gases can cause bubbles to form which may change the results of the test. In such cases, dissolved gases should be removed prior to testing¹ .)

      Time Where a single time specification is given, the test may be concluded in a shorter period if the requirement for minimum amount dissolved is met. If two or more times are specified, sample are to be withdrawn only at the stated times, within a tolerance of ±2 per cent.

Procedure for a Pooled Sample for Immediate-Release Dosage Forms

      Use this procedure where Procedure for a pooled sample is specified in the individual monograph. Proceed as directed under Procedure for ImmediateRelease Dosage Forms. Combine equal volumes of the filtered solutions of the six or twelve individual samples withdrawn, and use the pooled sample as the test solution. Determine the average amount of the active ingredient dissolved in the pooled sample.

      Where capsule shells interfere with the analysis, remove the contents of not less than 6 capsules as completely as possible, and dissolve the empty capsule shells in the specified volume of dissolution medium. Perform the analysis as directed in the individual monograph. Make any necessary correction. Correction factors greater than 25 per cent of the labelled content are unacceptable.

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¹One method of deaeration is as follows: heat the medium, while stirring gently, to about 41º, immediately filter under vacuum using a filter having a porosity of 0.45 μm or less, with vigorous stirring, and continue stirring under vacuum for about 5 minutes. Other validated deaeration techniques for removal of dissolved gases may be used.

      Dissolution medium and Time Proceed as directed for Immediate-Release Dosage Forms under Apparatus 1 and Apparatus 2.

      Apparatus 3 Place the glass beads into the cell specified in the monograph and one dosage-form unit on top of the beads or, if specified in the monograph, on a tablet holder. Assemble the filter head and fix the parts together by means of a suitable clamping device. Introduce by the pump the dissolution medium warmed to 37º±0.5º through the bottom of the cell to obtain the flow rate specified in the individual monograph and measured with an accuracy of 5 per cent. Collect the eluate by fractions at each of the times stated. Perform the analysis as directed in the individual monograph. Repeat the test with additional dosage form units.

Extended-Release Dosage Forms

      Use the apparatus specified in the individual monograph.

      Apparatus 1, Apparatus 2, Apparatus 3, Apparatus suitability, Dissolution medium and Procedure Proceed as directed under Immediate-Release Dosage Forms.

      Time The test-time point, generally three, are expressed in hours. Samples are to be withdrawn within a tolerance of ±2 per cent of the stated time.

      Delayed-Release (Enteric-Coated) Dosage forms

      Use Method A or Method B and Apparatus 1 or 2 specified in the individual monograph. All test times stated are to be observed within a tolerance of ±2 per cent, unless otherwise specified.

METHOD A: 

      Procedure (unless otherwise directed in the individual monograph)

      ACID STAGE Place 750 ml of 0.1 M hydrochloric acid in the vessel and assemble the apparatus. Allow the medium to equilibrate to a temperature of 37º±0.5º. Place one tablet or one capsule in the apparatus, cover the vessel, and operate the apparatus for 2 hours at the rate specified in the monograph.

      After 2 hours of operation in 0.1 M hydrochloric acid, withdraw an aliquot of the fluid, and proceed immediately as directed under Buffer stage.

      Perform an analysis of the aliquot using the Procedure specified in the test for Dissolution in the individual monograph.

      BUFFER STAGE (Note Complete the operations of adding the buffer, and adjusting the pH within 5 minutes.) With the apparatus operating at the rate specified in the monograph, add to the fluid in the vessel 250 ml of 0.20 M trisodium phosphate that has been equilibrated to 37º±0.5º. Adjust, if necessary, with 2 M hydrochloric acid or 2 M sodium hydroxide to a pH of 6.8±0.05. Continue to operate the apparatus for 45 minutes, or for the time specified in the individual monograph. At the end of the time period, withdraw an aliquot of the fluid, and perform the analysis using the Procedure specified in the test for Dissolution in the individual monograph. The test may be concluded in a shorter time period than that specified for the Buffer stage if the requirement for minimum amount dissolved is met at an earlier time.

METHOD B:

      Procedure (unless otherwise directed in the individual monograph)

      ACID STAGE Place 1000 ml of 0.1 M hydrochloric acid in the vessel, and assemble the apparatus. Allow the medium to equilibrate to a temperature of 37º±0.5º. Place one tablet or one capsule in the apparatus, cover the vessel, and operate the apparatus for 2 hours at the rate specified in the individual monograph. After 2 hours of operation in 0.1 M hydrochloric acid, withdraw an aliquot of the fluid and proceed immediately as directed under Buffer stage.

      Perform an analysis of the aliquot using the Procedure specified in the test for Dissolution in the individual monograph.

      BUFFER STAGE (Note For this stage of the procedure, use buffer that previously has been equilibrated to a temperature of 37º±0.5º). Drain the acid from the vessel, and add to the vessel 1000 ml of pH 6.8 phosphate buffer, prepared by mixing 0.1 M hydrochloric acid with 0.2 M trisodium phosphate (3:1) and adjusting, if necessary, with 2 M hydrochloric acid or 2 M sodium hydroxide to a pH of 6.8±0.05. (Note This may be accomplished also by removing from the apparatus the vessel containing the acid and transferring the dosage unit to the vessel containing the buffer.) Continue to operate the apparatus for 45 minutes, or for the time specified in the individual monograph. At the end of the time period, withdraw an aliquot of the fluid, and perform the analysis using the Procedure specified in the test for Dissolution in the individual monograph. The test may be concluded in a shorter time period than that specified for the Buffer stage if the requirement for minimum amount dissolved is met at an earlier time.

INTERPRETATION 

Immediate-Release Dosage Forms (Capsules, Uncoated Tablets and Plain Coated Tablets)​

      Unit Sample Unless otherwise specified in the individual monograph, the requirements are met if the quantities of active ingredient dissolved from the dosage units tested conform to the accompanying Acceptance Table 1 for Unit Sample. Continue testing through the three stages unless the results conform at either S1 or S2. The quantity, Q, is the amount of dissolved active ingredient specified in the individual monograph, expressed as a percentage of the labelled content of dosage unit; the 5 per cent, 15 per cent and 25 per cent values in the Acceptance Table 1 are percentages of the labelled content so that these values and Q are in the same terms.

Acceptance Table 1 for Unit Sample

      Pooled Sample Unless otherwise specified in the individual monograph, the requirements are met if the quantities of active ingredient dissolved from the pooled sample conform to the accompanying Acceptance Table 1 for a Pooled Sample. Continue testing through the three stages unless the results conform at either S₁ or S₂. The quantity, Q, is the amount of dissolved active ingredient specified in the individual monograph, expressed as a percentage of the labelled content.

Acceptance Table 1 for a Pooled Sample

Extended-Release Dosage Forms​

      Unless otherwise specified in the individual monograph, the requirements are met if the quantities of active ingredient dissolved from the units tested conform to Acceptance Table 2. Continue testing through the three levels unless the results conform at either L₁ or L₂. Limits on the amounts of active ingredient dissolved are expressed in terms of the percentage of labelled content. The limits embrace each value of Q_i , the amount dissolved at each specified fractional dosing interval. Where more than one range is specified in the individual monograph, the acceptance criteria apply individually to each range. 

Acceptance Table 2

Delayed-Release (Enteric-Coated) Dosage Forms​

      ACID STAGE Unless otherwise specified in the individual monograph, the requirements of this portion of the test are met if the quantities, based on the percentage of the labeled content, of active ingredient dissolved from the units tested conform to Acceptance Table 3. Continue testing through all levels unless the results of both acid and buffer stages conform at an earlier level.

Acceptance Table 3 

      BUFFER STAGE Unless otherwise specified in the individual monograph, the requirements are met if the quantities of active ingredient dissolved from the units tested conform to Acceptance Table 4. Continue testing through the three levels unless the results of both stages conform at an earlier level. The value of Q in Acceptance Table 4 is 75 per cent dissolved unless otherwise specified in the individual monograph. The quantity, Q, specified in the individual monograph, is the total amount of active ingredient dissolved in both the acid and buffer stages, expressed as a percentage of the labelled content. The 5 per cent, 15 per cent and 25 per cent values in Acceptance Table 4 are percentages of the labelled content so that these values and Q are in the same terms.

Acceptance Table 4