á2040ñDISINTEGRATION AND DISSOLUTION OF DIETARY SUPPLEMENTS
DISINTEGRATION
This test is provided to determine compliance with the limits on Disintegrationstated below or in the individual class monographs on dietary supplements,including botanical dosage forms.This test applies to uncoated and plain coated tablets and to hard gelatin and soft gelatin capsules.It does not apply to tablets or capsules designed to liberate vitamin or mineral content over an extended period or where the label states that the dosage form is to be chewed.Determine the type of units under test from the labeling and from observation,and apply the appropriate procedure to 6or more dosage units.
For the purposes of this test,disintegration does not imply complete solution of the unit or even of its active constituent.Complete disintegration is defined as that state in which any residue of the unit,except fragments of insoluble coating or capsule shell,remaining on the screen of the test apparatus is a soft mass having no palpably firm core.
Apparatus
Apparatus A—
Use the Apparatusdescribed under Disintegration á701ñfor tablets or capsules that are not greater than 18-mm long.For larger tablets or capsules,use Apparatus B.
Apparatus B—
The apparatus*consists of a basket-rack assembly,a 1000-mL,low-form beaker for the immersion fluid,a thermostatic arrangement for heating the fluid between 35
and 39,and a device for raising and lowering the basket in the immersion fluid at a constant frequency rate between 29and 32cycles per minute through a distance of not less than 5.3cm and not more than 5.7cm.The volume of the fluid in the vessel is such that at the highest point of the upward stroke the wire mesh remains at least 2.5cm below the surface of the fluid and descends to not less than 2.5cm from the bottom of the vessel on the downward stroke.The time required for the upward stroke is equal to the time required for the downward stroke,and the change in stroke direction is a smooth transition,rather than an abrupt reversal of motion.The basket-rack assembly moves vertically along its axis.There is no appreciable horizontal motion or movement of the axis from the vertical.
and 39,and a device for raising and lowering the basket in the immersion fluid at a constant frequency rate between 29and 32cycles per minute through a distance of not less than 5.3cm and not more than 5.7cm.The volume of the fluid in the vessel is such that at the highest point of the upward stroke the wire mesh remains at least 2.5cm below the surface of the fluid and descends to not less than 2.5cm from the bottom of the vessel on the downward stroke.The time required for the upward stroke is equal to the time required for the downward stroke,and the change in stroke direction is a smooth transition,rather than an abrupt reversal of motion.The basket-rack assembly moves vertically along its axis.There is no appreciable horizontal motion or movement of the axis from the vertical.
Basket-Rack Assembly—
The basket-rack assembly consists of three open-ended transparent tubes,each 7.95-±0.05-cm long and having an inside diameter of approximately 33.3-mm and a wall approximately 2.4mm thick;the tubes are held in a vertical position by two plastic plates,each about 9.7cm in diameter and 9.5mm in thickness,with three holes,each about 39mm in diameter,equidistant from the center of the plate and equally spaced from one another.Attached to the under surface of the lower plate is 10-mesh No.23(0.025-inch)W.and M.gauge woven stainless-steel wire cloth having a plain square weave.The parts of the apparatus are assembled and rigidly held by means of three bolts passing through the two plastic plates.Asuitable means is provided to suspend the basket-rack assembly from the raising and lowering device using a point on its axis.
The design of the basket-rack assembly may be varied somewhat provided the specifications for the glass tubes and the screen mesh size are maintained.
Disks—
Each tube is provided with a perforated cylindrical disk 15.3-±0.15-mm thick and 31.4±0.13mm in diameter.The disk is made of a suitable,transparent plastic material having a specific gravity of between 1.18and 1.20.Seven 3.2-mm holes extend between the ends of the cylinder,one of the holes being through the cylinder axis and the others parallel with it equally spaced on a 6-mm radius from it.All surfaces of the disk are smooth.
Procedure
VITAMIN-MINERAL DOSAGE FORMS
Uncoated Tablets and Film-Coated Tablets—
Place 1tablet in each of the tubes of the basket,add a disk to each tube,and operate the apparatus,using water maintained at 37±2as the immersion fluid.At the end of 30minutes,lift the basket from the fluid,and observe the tablets:all of the tablets disintegrate completely.If 1or 2tablets fail to disintegrate completely,repeat the test on 12additional tablets:not fewer than 16of the total of 18tablets tested disintegrate completely.
as the immersion fluid.At the end of 30minutes,lift the basket from the fluid,and observe the tablets:all of the tablets disintegrate completely.If 1or 2tablets fail to disintegrate completely,repeat the test on 12additional tablets:not fewer than 16of the total of 18tablets tested disintegrate completely.
Plain Coated Tablets (Other Than Film-Coated Tablets)—
Place 1tablet in each of the tubes of the basket and,if the tablet has a soluble external coating,immerse the basket in water at room temperature for 5minutes.Then add a disk to each tube,and operate the apparatus,using water maintained at 37±2as the immersion fluid.After 45minutes of operation in water,lift the basket from the fluid,and observe the tablets:all of the tablets have disintegrated completely.If 1or 2tablets fail to disintegrate completely,repeat the test on 12additional tablets:not fewer than 16of the total of 18tablets tested disintegrate completely.
as the immersion fluid.After 45minutes of operation in water,lift the basket from the fluid,and observe the tablets:all of the tablets have disintegrated completely.If 1or 2tablets fail to disintegrate completely,repeat the test on 12additional tablets:not fewer than 16of the total of 18tablets tested disintegrate completely.
Hard Gelatin Capsules—
Apply the test for Uncoated Tablets,using 0.05Macetate buffer,prepared by mixing 2.99g of sodium acetate trihydrate and 1.66mLof glacial acetic acid with water to obtain 1000mLof solution having a pHof 4.50±0.05,maintained at 37±2as the immersion fluid.At the end of 45minutes,lift the basket from the fluid,and observe the capsules:all of the capsules disintegrate except for fragments from the capsule shell.If 1or 2capsules fail to disintegrate completely,repeat the test on 12additional capsules:not fewer than 16of the total of 18capsules tested disintegrate completely.
as the immersion fluid.At the end of 45minutes,lift the basket from the fluid,and observe the capsules:all of the capsules disintegrate except for fragments from the capsule shell.If 1or 2capsules fail to disintegrate completely,repeat the test on 12additional capsules:not fewer than 16of the total of 18capsules tested disintegrate completely.
Soft Gelatin Capsules—
Proceed as directed under Hard Gelatin Capsules.
BOTANICAL DOSAGE FORMS
Uncoated Tablets and Film-Coated Tablets—
[NOTE—Omit the use of disks unless otherwise specified in the individual monograph.]Place 1tablet in each of the tubes of the basket,and operate the apparatus,using water maintained at 37±2as the immersion fluid.At the end of 20minutes,lift the basket from the fluid,and observe the tablets:all of the tablets disintegrate completely.If 1or 2tablets fail to disintegrate completely,repeat the test on 12additional tablets:not fewer than 16of the total of 18tablets tested disintegrate completely.
as the immersion fluid.At the end of 20minutes,lift the basket from the fluid,and observe the tablets:all of the tablets disintegrate completely.If 1or 2tablets fail to disintegrate completely,repeat the test on 12additional tablets:not fewer than 16of the total of 18tablets tested disintegrate completely.
Plain Coated Tablets (other than Film-Coated Tablets)—
[NOTE—Omit the use of disks,unless otherwise specified in the individual monograph.]Place 1tablet in each of the tubes of the basket and,if the tablet has a soluble external coating,immerse the basket in water at room temperature for 5minutes.Operate the apparatus using water maintained at 37±2as the immersion fluid.After 20minutes of operation in water,lift the basket from the fluid,and observe the tablets:all of the tablets have disintegrated completely.If 1or 2of the tablets fail to disintegrate completely,repeat the test on 12additional tablets:not fewer than 16of the total of 18tablets tested disintegrate completely.
as the immersion fluid.After 20minutes of operation in water,lift the basket from the fluid,and observe the tablets:all of the tablets have disintegrated completely.If 1or 2of the tablets fail to disintegrate completely,repeat the test on 12additional tablets:not fewer than 16of the total of 18tablets tested disintegrate completely.
Delayed-Release (Enteric-Coated)Tablets—
Place 1tablet in each of the six tubes of the basket,and if the tablet has a soluble external coating,immerse the basket in water at room temperature for 5minutes.Then operate the apparatus using simulated gastric fluid TSmaintained at 37±2as the immersion fluid.After 1hour of operation in simulated gastric fluid TS,lift the basket from the fluid,and observe the tablets:the tablets show no evidence of disintegration,cracking,or softening.Operate the apparatus,using simulated intestinal fluid TS,maintained at 37±2as the immersion fluid,for the time specified in the monograph.Lift the basket from the fluid,and observe the tablets:all of the tablets disintegrate completely.If 1or 2tablets fail to disintegrate completely,repeat the test on 12additional tablets:not fewer than 16of the total of 18tablets tested disintegrate completely.
as the immersion fluid.After 1hour of operation in simulated gastric fluid TS,lift the basket from the fluid,and observe the tablets:the tablets show no evidence of disintegration,cracking,or softening.Operate the apparatus,using simulated intestinal fluid TS,maintained at 37±2as the immersion fluid,for the time specified in the monograph.Lift the basket from the fluid,and observe the tablets:all of the tablets disintegrate completely.If 1or 2tablets fail to disintegrate completely,repeat the test on 12additional tablets:not fewer than 16of the total of 18tablets tested disintegrate completely.
Hard Gelatin Capsules—
Apply the test for Uncoated Tablets,using 0.05Macetate buffer,prepared by mixing 2.99g of sodium acetate trihydrate and 1.66mLof glacial acetic acid with water to obtain 1000mLof solution having a pHof 4.50±0.05,maintained at 37±2as the immersion fluid.At the end of 20minutes,lift the basket from the fluid,and observe the capsules:all of the capsules disintegrate except for fragments from the capsule shell.If 1or 2capsules fail to disintegrate completely,repeat the test on 12additional capsules:not fewer than 16of the total of 18capsules tested disintegrate completely.
as the immersion fluid.At the end of 20minutes,lift the basket from the fluid,and observe the capsules:all of the capsules disintegrate except for fragments from the capsule shell.If 1or 2capsules fail to disintegrate completely,repeat the test on 12additional capsules:not fewer than 16of the total of 18capsules tested disintegrate completely.
Soft Gelatin Capsules—
Proceed as directed under Hard Gelatin Capsules.
DISSOLUTION
Vitamin–Mineral Dosage Forms
This test is provided to determine compliance with the dissolution requirements where stated in the individual class monographs for a tablet or capsule dosage form,except where the label states that the tablets are to be chewed.It does not apply to tablets or capsules designed to release vitamin or mineral content over a delayed or extended period of time.Soft gelatin capsule preparations of dietary supplements meet the requirements for Disintegration.
All dietary supplements belonging to USPClasses IIto VI,prepared as tablets or capsules,are subject to the dissolution test and criteria described in this chapter for folic acid (if present)and for index vitamins and index minerals.This test is also required if the product labeling includes a health claim concerning the relationship between folate deficiency and the risk of neural tube defects.The accompanying table lists the dissolution requirements for the individual USPclasses of dietary supplements.Class Idietary supplements are combinations of oil-soluble vitamins,which are exempt from dissolution requirements;hence,dissolution requirements do not apply to the oil-soluble vitamins contained in formulations belonging to Class IVor Class V.
Dietary Supplements—Vitamin–Mineral
Dosage Forms
Dosage Forms
| USP Class |
Combination of Vitamins or Minerals Present |
Dissolution Requirement |
| I | Oil-Soluble Vitamins | not applicable |
| II | Water-Soluble Vitamins | one index vitamin;folic acid (if present) |
| III | Water-Soluble Vitamins with Minerals |
one index vitamin and one index element; folic acid (if present) |
| IV | Oil-and Water-Soluble Vitamins |
one index water-soluble vitamin;folic acid (if present) |
| V | Oil-and Water-Soluble Vitamins with Minerals |
one index water-soluble vitamin and one index element;folic acid (if present) |
| VI | Minerals | one index element |
Unless otherwise stated in the individual monograph,test 6dosage units for dissolution as directed under Dissolution á711ñ.
DISSOLUTION CONDITIONS FOR FOLIC ACID
NOTE—Perform this test under subdued light.
NOTE
Medium:
water;900mL.If the units tested do not meet the requirements for dissolution in water,test 6additional dosage units for dissolution in a medium of 900mLof 0.05MpH6.0citrate buffer solution,prepared by mixing 9.5mLof 0.1Mcitric acid monohydrate and 40.5mLof 0.1Msodium citrate dihydrate in a 100-mLvolumetric flask,diluting with water to volume,mixing,and adjusting to a pHof 6.0by using either 0.1Mhydrochloric acid or 0.1Msodium hydroxide solution.
Apparatus 1:
100rpm,for capsules.
Apparatus 2:
75rpm,for tablets.
Time:
1hour.
DISSOLUTION CONDITIONS FOR INDEX VITAMINS AND INDEX MINERALS
Medium:
0.1Nhydrochloric acid;900mL.
Apparatus 1:
100rpm,for capsules.
Apparatus 2:
75rpm,for tablets.
Time:
1hour.
For formulations containing 25mg or more of the index vitamin,riboflavin,use the following conditions:
Medium:
0.1Nhydrochloric acid;1800mL.
Apparatus 1:
100rpm,for capsules.
Apparatus 2:
75rpm,for tablets.
Time:
1hour.
SELECTION OF INDEX VITAMINS AND INDEX ELEMENTS
Compliance with the dissolution requirements for dietary supplements representing combinations of water-soluble vitamins (Water-Soluble Vitamins Capsulesand Water-Soluble Vitamins Tablets)and combinations of oil-and water-soluble vitamins (Oil-and Water-Soluble Vitamins Capsulesand Oil-and Water-Soluble Vitamins Tablets)is determined by measuring the dissolution of a single index vitamin from the water-soluble vitamins present.Riboflavin is the index vitamin when present in the formulation.For formulations that do not contain riboflavin,pyridoxine is the index vitamin.If neither riboflavin nor pyridoxine is present in the formulation,the index vitamin is niacinamide (or niacin),and in the absence of niacinamide (or niacin),the index vitamin is thiamine.If none of the above four water-soluble vitamins is present in the formulation,the index vitamin is ascorbic acid.
Compliance with the dissolution requirements for dietary supplements representing combinations of minerals (Minerals Capsulesand Minerals Tablets)is determined by measuring the dissolution of only one index element.Iron is the index element when present in the formulation.For formulations that do not contain iron,the index element is calcium.If neither iron nor calcium is present,the index element is zinc,and in the absence of all three of these elements,magnesium is the index element.
Compliance with dissolution requirements for dietary supplements representing combinations of water-soluble vitamins and minerals (Water-Soluble Vitamins with Minerals Capsulesand Water-Soluble Vitamins with Minerals Tablets)and combinations of oil-and water-soluble vitamins and minerals (Oil-and Water-Soluble Vitamins with Minerals Capsulesand Oil-and Water-Soluble Vitamins with Minerals Tablets)is determined by measuring the dissolution of one index water-soluble vitamin and one index element,designated according to the respective hierarchies described above.
PROCEDURES
In the following procedures,combine equal volumes of the filtered solutions of the 6individual specimens withdrawn,and determine the amount of folic acid or the index vitamin or element dissolved,based on the average of 6units tested.Make any necessary modifications including concentration of the analyte in the volume of test solution taken.Use Dissolution Mediumfor preparation of the Standard solution and dilution,if necessary,of the test solution.
Folic Acid—
Determine the amount of C19H19N7O6dissolved by employing the procedure set forth in the Assay for folic acidunder Oil-and Water-Soluble Vitamins with Minerals Tablets,in comparison with a Standard solution having a known concentration of USP Folic Acid RSin the same medium.
Niacin or Niacinamide,Pyridoxine,Riboflavin,and Thiamine—
Determine the amount of the designated index vitamin dissolved by employing the procedure set forth in the Assay for niacin or niacinamide,pyridoxine,riboflavin,and thiamineunder Water-Soluble Vitamins Tablets.
Ascorbic Acid—
Determine the amount of C6H8O6dissolved by adding 10mLof 1.0Nsulfuric acid and 3mLof starch TSto 100.0mLof test solution,and titrating immediately with 0.01Niodine VS.Perform a blank determination,and make any necessary correction.
Iron,Calcium,Magnesium,and Zinc—
Determine the amount of the designated index element dissolved by employing the procedure set forth in the appropriate Assayunder Minerals Capsules.
TOLERANCES
The requirements are met if not less than 75%of the labeled content of folic acid and not less than 75%of the labeled content of the index vitamin or the index element from the units tested is dissolved in 1hour.
Botanical Dosage Forms
This test is provided to determine compliance with the dissolution requirements where stated in the individual monograph for a tablet or capsule dosage form.See Dissolution á711ñfor description of apparatus used,Apparatus Suitability Test,and other related information.Of the types of apparatus described in á711ñ,use the one specified in the individual monograph.Where the label states that an article is enteric-coated,and a dissolution or disintegration test that does not specifically state that it is to be applied to enteric-coated articles is included in the individual monograph,the test for Delayed-Release Articlesunder Drug Release á724ñis applied,unless otherwise specified in the individual monograph.Compliance with dissolution requirements is determined by testing 6dosage units individually,or testing 2or more counted number of dosage units in each vessel,and measuring the dissolution of one or more index/marker compound(s)or the extract specified in the individual monograph.This nonspecific dissolution is intended to be diagnostic of known technological problems that may arise due to coatings,lubricants,disintegrants,and other substances inherent in the manufacturing process.Further,this dissolution measurement allows an assessment of the extent of decomposition of the extract to polymeric or other nondissoluble compounds that may have been produced by excessive drying or other manipulations involved in the manufacture of botanical extracts.The operative assumption inherent in this procedure is that if the index or marker compound(s)or the extract is demonstrated to have dissolved within the time frame and under conditions specified,the dosage form does not suffer from any of the above formulation or manufacturing related problems.
PROCEDURES
Combine equal volumes of the filtered solutions of the 6or more individual specimens withdrawn,and use the pooled sample as the test solution.Determine the average amount of index or marker compound(s)or the extract dissolved in the pooled sample by the Procedurespecified in the individual monograph.Make any necessary modifications,including concentration of the analyte in the volume of the test solution taken.Use Dissolution Mediumfor preparation of the Standard solution and dilution,if necessary,of the test solution.
INTERPRETATION
Pooled Sample—
Unless otherwise specified in the individual monograph,the requirements are met if the quantities of the index or marker compound(s)or the extract dissolved from the pooled sample conform to the accompanying acceptance table.The quantity,Q,is the amount of dissolved index or marker compound(s)or the extract specified in the individual monograph,expressed as a percentage of the labeled content.The 5%,15%,and 25%values in the acceptance table are percentages of the labeled content so that these values and Qare in the same terms.
Acceptance Table for a Pooled Sample
| Stage | Number Tested | Acceptance Criteria |
| S1 | 6 | Average amount dissolved is not less than Q+10% |
| S2 | 6 | Average amount dissolved (S1+S2)is equal to or greater than Q+5% |
| S3 | 12 | Average amount dissolved (S1+S2+S3)is equal to or greater than Q |
*
An apparatus and disks meeting these specifications are available from VanKel Technology Group,13000Weston Parkway,Cary,NC27513,or from laboratory supply houses.