The Dissolution Test is a method to test the disso-lution of active ingredients from solid preparations for internal use, and aims at confirming the quality of solid preparations for internal use in relation to a fixed standard and also at preventing significant bioinequivalence. In this test, a dosage unit is defined as 1 tablet or 1 capsule or the amount specified equiva-lent to minimum dose.
Apparatus
(1) Method 1 (Rotatory basket method, Apparatus 1)
The assembly consists of the following: a vessel, which may be covered, made of glass or other inert,
transparent material*1 a motor; a drive shaft; and a cy-lindrical basket. The vessel is partially immersed in a suitable device such as a heating jacket. The water bath or heating device permits holding the temperature in-side the vessel at 37 ± 0.5 °C during the test and keep-ing 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. Make the apparatus to permit observation of the specimen and stirring element dur-ing the test. The vessel is cylindrical, with a hemi-spherical bottom and a capacity of 1 liter. Its height is 160 mm to 210 mm and its inside diameter is 98 mm to 106 mm. Its sides are flanged at the top. Use a fitted cover to retard evaporation.*2 The shaft is positioned so that its axes is not more than 2 mm at any point from the vertical axis of the vessel and rotates smoothly and without significant wobble that could affect the results.
Adjust a speed-regulating device to maintain the shaft rotation speed at a specified rate, within ± 4 %.
Shaft and basket components of the stirring ele-ment shown in figure 1 are fabricated of stainless steel (SUS316) or other inert material. A basket having a gold coating of about 0.0001 inch (2.5 μm) thick may be used. 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 bottom of the basket is maintained at 25 ± 2 mm during the test.
(2) Method 2 (Paddle method, Apparatus 2) Use the assembly from apparatus 1, except that a paddle 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 from the vertical axis of the vessel, at any point, and rotates smoothly without sig-nificant wobble that could affect the results. The verti-cal center 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 distance of 25 ± 2 mm between the bottom of 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 if it provide that the assembly remains firmly en-gaged 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.
When specified in the individual monograph, a small, loose piece of nonreactive material, such as not more than a few turns of wire helix, may be attached to dos-age units that would otherwise float. An alternative sinker device is shown in figure 2a. Other validated sinker devices may be used. If the use of sinker is spec-ified, unless otherwise specspec-ified, use the sinker device shown in figure 2a.
(3) Method 3 (Flow-through cell method, Appa-ratus 3)
The assembly consists of a reservoir and a pump for the dissolution medium; a flow-through cell; a wa-ter bath that maintains the dissolution medium at 37 ± 0.5 °C. Use the cell size specified in the individual monograph.
The pump forces the dissolution medium upwards through the flow-through cell. The pump has a delivery range between 4 and 16mL per minute, with standard flow rates of 4, 8, and 16mL per minute. It must deliver a constant flow (± 5 percent of the nominal flow rate);
the flow profile should be sinusoidal with a pulsation of 120 ± 10 pulses per minute. A pump without the pulsation can also be used.
The flow-through cell (see figures 3 and 4), of transparent and inert material, is mounted vertically with a filter system (specified in the individual mono-graph 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 about 1-mm diameter with one bead of about 5 mm positioned at the apex to pro-tect the fluid entry tube; a tablet holder (see Figures 3 and 4) is available for positioning of special dosage forms. The cell is immersed in a water bath, and the temperature is maintained at 37 ± 0.5 °C.
The apparatus uses a clamp mechanism of two Orings to assemble the cell. 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 inert flanged-end connections.
(4) Apparatus suitability The determination of suitability of a test assembly to perform dissolution testing must include conformance to the dimensions and tolerances of the apparatus as given above. In addi-tion, critical test parameters that have to be monitored periodically during use include volume and tempera-ture of the dissolution medium, rotation speed (Basket method and Paddle method), and flow rate of medium (Flow-through cell method).
Determine the acceptable performance of the dissolu-tion test assembly periodically.
Dissolution medium
(1) Solution 1 — dissolve 2.0 g of sodium chlo-ride in 7.0mL of hydrochloric acid and water and fill water to 1000mL. This solution is colorless and trans-parent and pH of this solution is 1.2.
(2) Solution 2 — mixture of phosphate buffer so-lution of pH 6.8 and water (1 : 1).
Procedure
(1) Method 1 and Method 2 (i) Immediate-release dosage forms
Procedure — Place the stated volume of the dis-solution medium (± 1 %) in the vessel of the specified apparatus, assemble the apparatus, equilibrate the
dis-solution medium to 37 ± 0.5 °C, and remove the ther-mometer. Place 1 dosage unit in the apparatus, taking care to exclude air bubbles from the surface of the dos-age unit, and immediately operate the apparatus at the specific rate. 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 10 mm from the vessel wall. [NOTE –Where multiple sampling times are specified, replace the ali-quots withdraw for analysis with equal volumes of fresh Dissolution medium at 37 °C 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 veri-fy the temperature of the mixture under test at suitable times.] Perform the analysis using an indicated assay method.*3 Repeat the test with additional dosage 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 chapter, is necessary.
Dissolution Medium – A specified dissolution medium is used. If the dissolution medium is buffered solution, adjust the solution so that its pH is within 0.05 unit of the specified pH. [NOTE –Dissolved gases can cause bubbles to form, which may change the change of the results of the test. If dissolved gases in-fluence the dissolution results, remove dissolved gases prior to testing.*4]
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.
Specimens are to be withdrawn only at the stated times, within a tolerance of ± 2 %.
(ii) Extended-release dosage forms
Procedure—Proceed as described for Immediate-release dosage forms.
Dissolution medium—Proceed as directed under Im-mediate-release dosage forms.
Time—The test-time points, generally three, are ex-pressed in hours.
(iii) Delayed-release dosage forms
Procedure — Unless otherwise specified, proceed the acid stage test and buffer stage test separately as described for immediate-release dosage forms.
Dissolution medium — Acid stage: Unless solu-tion 1 for dissolusolu-tion test is used, proceed as directed under immediate-release dosage forms. Buffer stage:
Unless solution 2 for dissolution test is used, proceed as directed under Immediate-release dosage forms.
Time — Acid stage: Generally, test time is 2 hours for tablets and capsules, and 1 hour for granules. Buff-er stage: The same as directed undBuff-er Immediate- re-lease dosage forms. All test times stated are to be ob-served within a tolerance of ± 2 %, unless otherwise specified.
(2) Method 3
(i) Immediate-release dosage forms
Procedure — Place the glass beads into the cell specified in the individual monograph. Place 1 dosage unit on top of the beads or, if specified, on a wire carri-er. 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 37 ± 0.5 °C through the bottom of the cell to obtain the flow rate specified and measured with an accuracy of 5 %.
Collect the eluent by fractions at each of the times stat-ed. Perform the analysis as directstat-ed. Repeat the test with additional dosage units.
Dissolution medium — Proceed as directed in Immediate-release dosage forms under Method 1 and Method 2.
Time — Proceed as directed under Immediate-release dosage forms under Method 1 and Method 2.
(ii) Extended-release dosage forms
Procedure—Proceed as described for Immediate- release dosage forms.
Dissolution medium—Proceed as directed under Immediate-release dosage forms.
Time—The test-time points, generally three, are ex-pressed in hours.
Interpretation
(1) Immediate-release dosage forms
Follow interpretation 1 when the value Q is speci-fied in the individual monograph, otherwise follow interpretation 2.
(i) Interpretation 1: Unless otherwise specified, the requirements are met if the quantities of active in-gredient dissolved from the dosage units tested con-form to Acceptance Table 1. Continue testing through the three stages unless the results conform at either S1 or S2.
The quantity, Q, is the specified amount of dissolved active ingredient, expressed as a percentage of the la-beled content of the dosage unit; the 5 %, 15 %, and 25 % values in the Acceptance Table are percentage of the labeled content so that three values and Q are in the same terms.
Acceptance Table 1.
Stage Number
tested Acceptance criteria S1 6 Each value is not less than Q
+5 %
S2 6
Average value of the 12 dos-age units (S1 + S2) is equal to
or greater than Q, and no val-ue is less than Q –15 %.
S3 12
Average value of the 24 dos-age units (S1 + S2 + S3) is equal to or greater than Q, not
more than 2 values are less than Q –15 %, and no value
is less than Q –25 %.
(ii) Interpretation 2: Unless otherwise specified, perform the test on 6 dosage forms: if the individual dissolution rate meet the requirements specified in the individual monograph, the dosage forms conform to the test. When individual dissolution rates of 1 or 2 dosage forms fail to meet the requirements, repeat the test on 6 additional dosage forms: if individual dissolu-tion rates of not less than 10 dosage forms out of 12 meet the requirements, the dosage forms conform to the test.
Acceptance Table 2.
Level Number
tested Criteria
L1 6
No individual value lies outside each of the stated ranges and no individual value is less than the stated amount at the final test time
L2 6
The average value of the 12 dosage units (L1 + L2) lies within each of the stated ranges and is not less than the stated amount at
the final test time; no value is more than 10 % of labeled con-tent outside each of the stated ranges; and no value is more than 10 % of labeled content below the stated amount at the final test time.
L3 12
The average value of the 24 dosage units (L1 + L2 + L3) lies within each of the stated ranges, and is not less than the stated amount at the final test time; not more than 2 of the 24 values are more than 10 % of labeled content outside each of the stated ranges; not more than 2 of the 24 values are more than 10 % of labeled content below the stated amount at the final test time; and no value is more than 20 % of labeled content outside each of the stated rang-es or more than 20 % of labeled content below the stated amount at the final test time.
(2) Extended-release dosage forms
(i) Interpretation 1: Unless otherwise specified, the requirements are met if the quantities of active in-gredient dissolved from the dosage units tested con-form to Acceptance Table 2. Continue testing through L3 unless the results conform at either L1 or L2. Limits on the amounts of active ingredient dissolved, are ex-pressed as a percentage of the labeled content. The limits embrace each value of Qi. The amount dissolved
at each specified fractional dosing interval. Where more than one range is specified, the acceptance crite-ria apply individually to each range.
(ii) Interpretation 2: Unless otherwise specified, perform the test on 6 dosage forms: if the individual dissolution rate meet the requirements specified in the individual monograph, the dosage forms conform to the test. When individual dissolution rates of 1 or 2 dosage forms fail to meet the requirements, repeat the test on 6 additional dosage forms: if individual dissolu-tion rates of not less than 10 dosage forms out of 12 meet the requirements, the dosage forms conform to the test. Where more than one range is specified, the acceptance criteria apply individually to each range.
(1) Delayed-release dosage forms
Follow interpretation 1 when the value Q is speci-fied using solution 2 for dissolution test in the individ-ual monograph, otherwise follow interpretation 2.
Acceptance Table 3.
Level Number
tested Criteria
A1 6 No individual value exceeds 10 % dissolved.
A2 6
The average value of the 12 dosage units (A1 + A2) is not more than 10 % dissolved, and no value is greater than 25 % dissolved.
A3 12
The average value of the 24 dosage units (A1 + A2 + A3) is not more than 10 % dis-solved, and no value is greater than 25 % dissolved.
(i) Interpretation 1
Test using solution 1 for dissolution test: Unless otherwise specified, the requirements of this portion of the test are met if the quantities, based on the percent-age of the labeled content, of active ingredient dis-solved from the units tested conform to Acceptance Table 3. Continue testing through A3 unless the result conforms at A2 that no value is greater than 25 % dis-solved and the average value meet the requirement.
Test using solution 2 for dissolution test: Unless otherwise specified, the requirements are met if the quantities of active ingredient dissolved from the dos-age units tested conform to Acceptance Table 4. Con-tinue testing through B3 unless the results conform at an earlier B1 or B2. The value of Q in Acceptance Ta-ble 4 is the amount specified in monograph of active ingredient dissolved, expressed as a percentage of the labeled content; the 5 %, 15 %, and 25 % values in the Acceptance Table 4 are percentages of the labeled con-tents so that these values and Q are in the same terms.
Acceptance Table 4.
Level Number
test-ed Criteria
B1 6 No value is less than Q + 5 %
B2 6
The average value of the 12 dosage units (B1 + B2) is equal to or greater than Q, and no value is less than Q –
15 %.
B3 12
The average value of the 24 dosage units (B1 + B2 + B3) is equal to or greater than Q, not more than 2 values are less than Q – 15 %, and no value is less
than Q –25 %.
(ii) Interpretation 2: Unless otherwise specified, both the tests using solution 1 for dissolution test and solution 2 for dissolution test in acid and buffer stages, perform the test on 6 dosage forms: if the individual dissolution rate meet the requirements specified in the individual monograph, the dosage forms conform to the test. When individual dissolution rates of 1 or 2 dosage forms fail to meet the requirements, repeat the test on 6 additional dosage forms: if individual dissolu-tion rates of not less than 10 samples out of 12 meet the requirements, the dosage forms conform to the test.
*1 The materials should not sorb, react, or interfere with the specimen being tested.
*2 If a cover is used, it provides sufficient open-ings to allow ready insertion of the thermometer and withdrawal of specimens.
*3 Test specimens are filtered immediately upon sampling unless filtration is demonstrated to be unnec-essary. Use an inert filter that does not cause adsorp-tion of the ingredient or contain extractable substances that would interfere with the analysis.
*4 One method of deaeration is as follows: Heat the medium, while stirring gently, to about 41 °C, im-mediately 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.
Figure 1. Apparatus 1, Basket stirring element
Notes :
(1) A and B dimensions are not to vary more than 0.5 mm when part is rotated on centering axis.
(2) Tolerances are ±1.0 mm unless otherwise stat-ed.
Figure 2. Apparatus 2. Paddle stirring element
A: Acid-resistant wire clasp B: Acid-resistant wire support
Figure 2a
Figure 3. Apparatus 3
Large cell for tablets and capsules (top); tablet holder for the large cell (bottom)
(All dimensions are expressed in mm unless otherwise noted.)
Figure 4. Apparatus 3.
Small cell for tablets and capsules (top); tablet holder for the small cell (bottom)
(All dimensions are expressed in mm unless otherwise noted.)