![]() ![]() INTRODUCTION This general chapter is provided to determine compliance with the disintegration and dissolution standards for dietary supplements where stated in the individual monographs.
For the purposes of this chapter, dietary supplement dosage forms have been divided into three categories: VitaminMineral Dosage Forms, Botanical Dosage Forms, and Dietary Supplements Other Than VitaminMineral and Botanical Dosage Forms. VitaminMineral Dosage Forms includes articles prepared with vitamins, minerals, or combinations of these dietary ingredients (e.g., USP dietary supplements Class I to Class VI, described below). Botanical Dosage Forms comprises formulations containing ingredients of botanical origin, including plant materials and extracts. Dietary Supplements Other Than VitaminMineral and Botanical Dosage Forms encompasses dietary supplements formulated with lawfully recognized dietary ingredients that are different from those pertaining to the two foregoing categories (e.g., amino acids, chondroitin, and glucosamine.)
Where a dietary supplement represents a combination of the categories mentioned above, and there is a difference between the requirements for the individual categories, the more stringent requirement applies.
Dissolution testing as described in this chapter is a quality-control tool to enable the performance of dietary supplements to be routinely assessed.
DISINTEGRATION This test is provided to determine whether dietary supplement tablets or capsules disintegrate within the prescribed time when placed in a liquid medium at the experimental conditions presented below. Compliance with the limits on Disintegration stated in the individual monographs for dietary supplements is required except where the label states that the products are intended for use as troches, are to be chewed, or are designed as extended-release dosage forms. Dietary supplements claiming to be extended-release dosage forms must comply with standards other than disintegration to verify that the release of the dietary ingredients from the dosage form is for a defined period of time. Dietary supplements claiming to be extended-release dosage forms shall not be labeled as in compliance with USP unless a USP monograph exists for such product. Determine the type of units under test from the labeling and from observation, and apply the appropriate procedure to 6 or more units.
For 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 or adhering to the lower surface of the disk, if used, is a soft mass having no palpably firm core.
Apparatus
Apparatus A
Use the Apparatus described under Disintegration
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Apparatus B
The apparatus1 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
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Basket-Rack Assembly
The basket-rack assembly consists of three open-ended transparent tubes, each 77.5 ± 2.5 mm long and having an inside diameter of 32.0 to 34.6 mm and a wall 2.0 to 3.0 mm thick; the tubes are held in a vertical position by two plastic plates, each about 97 mm in diameter and 7.5 to 10.5 mm in thickness, with three holes, each about 33 to 34 mm 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. A suitable 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 ± 0.13 mm in diameter. The disk is made of a suitable, transparent plastic material having a specific gravity of between 1.18 and 1.20. Seven 3.15 ± 0.1-mm holes extend between the ends of the cylinder, one of the holes being through the cylinder axis and the others parallel with it and equally spaced on a 4.2 ± 0.1-mm radius from it. All surfaces of the disk are smooth.2
Procedure
Uncoated Tablets
Place 1 tablet in each of the tubes of the basket and, if prescribed, add a disk to each tube. Operate the apparatus, using water or the specified medium as the immersion fluid, maintained at 37 ± 2
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Plain Coated Tablets
Place 1 tablet in each of the tubes of the basket and, if the tablet has a soluble external sugar coating, immerse the basket in water at room temperature for 5 minutes. Then, if prescribed, add a disk to each tube, and operate the apparatus, using water or the specified medium as the immersion fluid, maintained at 37 ± 2
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Delayed-Release (Enteric-Coated) Tablets
Place 1 tablet in each of the six tubes of the basket, and if the tablet has a soluble external sugar coating, immerse the basket in water at room temperature for 5 minutes. Then operate the apparatus using simulated gastric fluid TS maintained at 37 ± 2
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Buccal Tablets
Apply the test for Uncoated Tablets. After 4 hours, lift the basket from the fluid, and observe the tablets: all of the tablets disintegrate completely. If 1 or 2 tablets fail to disintegrate completely, repeat the test on 12 additional tablets: not fewer than 16 of the total of 18 tablets tested disintegrate completely.
Sublingual Tablets
Apply the test for Uncoated Tablets. At the end of the time limit specified in the individual monograph, all of the tablets disintegrate completely. If 1 or 2 tablets fail to disintegrate completely, repeat the test on 12 additional tablets: not fewer than 16 of the total of 18 tablets tested disintegrate completely.
Hard Shell Capsules
Apply the test for Uncoated Tablets, using as the immersion fluid, maintained at 37 ± 2
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Soft Shell Capsules
Proceed as directed under Rupture Test for Soft Shell Capsules.
Use of Disks
vitaminmineral dosage forms
Add a disk to each tube unless otherwise specified in the individual monograph.
botanical dosage forms
Omit the use of disks unless otherwise specified in the individual monograph.
dietary supplements other than vitaminmineral and botanical dosage forms
Omit the use of disks unless otherwise specified in the individual monograph.
noteThe use of disks for enteric-coated tablets is not permitted.
RUPTURE TEST FOR SOFT SHELL CAPSULES
Medium:
water; 500 mL.
Time:
15 minutes.
Procedure
Place 1 capsule in each vessel, and allow the capsule to sink to the bottom of the vessel before starting rotation of the blade. Observe the capsules, and record the time taken for each capsule shell to rupture.
Tolerances
The requirements are met if all of the capsules tested rupture in not more than 15 minutes. If 1 or 2 of the capsules rupture in more than 15 but not more than 30 minutes, repeat the test on 12 additional capsules: not more than 2 of the total of 18 capsules tested rupture in more than 15 but not more than 30 minutes.
DISSOLUTION This test is provided to determine compliance with the Dissolution requirements where stated in the individual monograph for dietary supplements, except where the label states that tablets are to be chewed.
See Dissolution
![]() ![]() ![]() ![]() 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 greater, pancreatin can be added to produce not more than 1750 USP Units of protease activity per 1000 mL.
This nonspecific dissolution is intended to be diagnostic of known technological problems that may arise as a result of coatings, lubricants, disintegrants, and other substances inherent in the manufacturing process. For dosage forms containing botanical extracts, 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.
VitaminMineral Dosage Forms
All dietary supplements belonging to USP Classes II to 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 required because of the importance of the relationship between folate deficiency and the risk of neural tube defects. The accompanying table lists the dissolution requirements for the individual USP classes of dietary supplements. Class I dietary supplements are combinations of oil-soluble vitamins for which dissolution standards are not established; hence, dissolution requirements do not apply to the oil-soluble vitamins contained in formulations belonging to Class IV or Class V. Vitaminmineral combinations that may not be strictly covered by USP Classes I to Class VI are subject to the dissolution test and criteria specified in the individual monographs.
Dietary SupplementsVitaminMineral
Dosage Forms
Unless otherwise stated in the individual monograph, test 6 dosage units for dissolution as directed under Dissolution
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dissolution conditions for folic acid
notePerform this test under light conditions that minimize photo degradation.
Medium:
water; 900 mL. If the units tested do not meet the requirements for dissolution in water, test 6 additional dosage units for dissolution in a medium of 900 mL of 0.05 M pH 6.0 citrate buffer solution, prepared by mixing 9.5 mL of 0.1 M citric acid monohydrate and 40.5 mL of 0.1 M sodium citrate dihydrate in a 100-mL volumetric flask, diluting with water to volume, mixing, and adjusting to a pH of 6.0 by using either 0.1 M hydrochloric acid or 0.1 M sodium hydroxide solution.
Apparatus 1:
100 rpm, for capsules.
Apparatus 2:
75 rpm, for tablets.
Time:
1 hour.
noteCompliance with the dissolution requirements for folic acid does not exempt the product from dissolution testing of the pertinent index vitamin or the corresponding index mineral.
dissolution conditions for index vitamins and index minerals
Medium:
0.1 N hydrochloric acid; 900 mL.
Apparatus 1:
100 rpm, for capsules.
Apparatus 2:
75 rpm, for tablets.
Time:
1 hour.
For formulations containing 25 mg or more of the index vitamin, riboflavin, use the following conditions:
Medium:
0.1 N hydrochloric acid; 1800 mL.
Apparatus 1:
100 rpm, for capsules.
Apparatus 2:
75 rpm, for tablets.
Time:
1 hour.
noteCompliance with dissolution requirements for the pertinent index vitamin or index mineral does not exempt the product from dissolution testing of folic acid, if present.
selection of index vitamins and index elements
Compliance with the dissolution requirements for dietary supplements representing combinations of water-soluble vitamins (Water-Soluble Vitamins Capsules and Water-Soluble Vitamins Tablets) and combinations of oil- and water-soluble vitamins (Oil- and Water-Soluble Vitamins Capsules and 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 Capsules and 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 Capsules and Water-Soluble Vitamins with Minerals Tablets) and combinations of oil- and water-soluble vitamins and minerals (Oil- and Water-Soluble Vitamins with Minerals Capsules and 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 6 individual specimens withdrawn, and determine the amount of folic acid or the index vitamin or element dissolved, based on the average of 6 units tested. Make any necessary modifications including concentration of the analyte in the volume of test solution taken. Use the Medium for preparation of the Standard solution and dilution, if necessary, of the test solution.
Folic Acid
Determine the amount of C19H19N7O6 dissolved by employing the procedure set forth in the Assay for folic acid under Oil- and Water-Soluble Vitamins with Minerals Tablets, in comparison with a Standard solution having a known concentration of USP Folic Acid RS in 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 thiamine under Water-Soluble Vitamins Tablets.
Ascorbic Acid
Determine the amount of C6H8O6 dissolved by adding 10 mL of 1.0 N sulfuric acid and 3 mL of starch TS to 100.0 mL of test solution, and titrating immediately with 0.01 N iodine 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 Assay under 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 1 hour.
Botanical Dosage Forms
Compliance with dissolution requirements necessitates the testing of 6 dosage units individually, or testing 2 or more dosage units in each of the 6 vessels of the dissolution apparatus, and measuring the dissolution of one or more index/marker compound(s) or the extract specified in the individual monograph.
procedures
Combine equal volumes of the filtered solutions of the 6 or 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 Procedure specified in the individual monograph. Make any necessary modifications, including concentration of the analyte in the volume of the test solution taken. Use the Medium for 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 Q are in the same terms.
Acceptance Table for a Pooled Sample
Dietary Supplements Other Than VitaminMineral and Botanical Dosage Forms
Unless otherwise stated in the individual monographs for dietary supplement dosage forms in this category, compliance requires the testing of 6 individual units, measuring the dissolution of the dietary ingredient as the average of the 6 units tested.
procedures
Combine equal volumes of the filtered solutions of the 6 specimens withdrawn, and use the pooled sample as the test solution. Determine the average amount of dietary ingredient dissolved in the pooled sample by the Procedure specified in the individual monograph. Make any necessary modifications, including concentration of the analyte in the volume of the test solution taken. Use the Medium for preparation of the Standard solution and for dilution, if necessary, of the test solution.
tolerances
Because of the diversity of chemical characteristics and solubilities of dietary ingredients pertaining to this category, general tolerances cannot be established. See individual monographs for Tolerances.
1
An apparatus and disks meeting these specifications are available from Varian Inc., 13000 Weston Parkway, Cary, NC 27513, or from laboratory supply houses.
2
The use of automatic detection employing modified disks is permitted where the use of disks is specified or allowed. Such disks must comply with the requirements for density and dimensions given in this chapter.
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USP32NF27 Page 782
Pharmacopeial Forum: Volume No. 34(2) Page 435
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