972 2030 supplemental information / dietary supplements [2040... · trees (minimum 10 years) when...

972 ⟨2030⟩ Supplemental Information / Dietary Supplements USP 35

ecological balance and conserve biodiversity. Wild collected strips of inner bark are stacked on a clean tarp and laterelm bark that is to be certified organic must be harvested bundled for transport to the drying facility.from a designated area that has had no prohibited sub- Drying—Elm USP requires a loss on drying limit of NMTstance applied to it for a period of 3 years immediately pre- 12%. So long as rain is not expected, fresh elm inner barkceding the harvest, and must be harvested in a manner that can be sun-cured within a temperature range of 32° to 60°.ensures that such harvesting or gathering will not be de- Drying can also be carried out in a warm room with airflowstructive to the environment and will sustain the growth or in a greenhouse. Greenhouse drying takes about 3 to 4and production of the wild crop. Wild crop producers must days. Drying indoors can take 5 to 7 days, depending oncomply with the same organic system plan requirements the heat source. Drying at commercial scale, however, isand conditions, as applicable to their operation, as their done typically in enclosed drying chambers, in which timecounterparts who produce cultivated crops. The producer of and temperature can be better controlled. The strips of elmorganic wild harvested elm bark must initiate practices to bark are placed onto a clean screen floor and dried oversupport biodiversity and avoid, to the extent practicable, about 2 days’ time at about 50° with fan-forced heatany activities that would diminish it. Production practices through the floor. Because of additional phytosanitary re-must maintain or improve the natural resources of the oper- quirements for export of tree barks to Europe, higher heatation, including soil, water, wetlands, woodlands, and wild- exposure is necessary, usually at least 65° but up to 93° forlife. This is accomplished, in part, by developing and execut- up to two days. Post-drying, the strips of inner bark can being a resource management plan that requires wild harvest cut or sawn into pieces of equal length and bound intofrom stable populations, minimizing disruption of priority bundles with wire. The bundles usually consist of flat, ob-species/sensitive habitats, avoiding erosion, allowing reestab- long pieces, about 30 cm in length and from 10 to 15 cmlishment, and monitoring wild crop sustainability. in width. The bark strips can be stored this way until further

Cultivation Practices—Even though the commercial supply processing (e.g., cutting or powdering) is scheduled.is harvested from wild populations, slippery elm trees can be Storage—To maintain pharmacopeial purity and qualitypropagated by cuttings or by seed. For propagation by (e.g., to prevent accumulation of excess moisture), driedseed, the ripe seeds are collected from April to June from elm inner bark should be preserved in well-closed contain-healthy and successful (dominant) trees from an area similar ers, and stored in a cool, dry place.to the proposed planting site. A ripeness indicator is when Adulterants and Contaminants—Common contami-the samaras (fruits) are green. It is best to collect seed from nants that could cause a material not to conform with thetrees within 160 km north or south of the planting site, as identification tests in the Elm monograph in USP wouldpotential for success is optimal within this range from the include other plant parts: for example, greater than 2%parents. Twenty-five seeds per square foot can be scattered, outer bark, which lacks mucilage. Insufficient shaving or0.6 cm deep. Slippery elm may be sown as in its normal rossing of outer bark could cause the material to exceed thecycle in the spring in a raised peat moss soil and sand bed. monograph limit of NMT 2% of adhering outer bark. OtherThe seedbeds may need a wire top to protect young seed- possible contaminants would include visible discolored innerlings. Germination rate is 10% to 25%, with light germina- bark, although no maximum limit has been established (fortion in summer and increased germination the following example, inner bark with visible black streaking obtainedspring. The young trees can be transplanted into tree tubes from a diseased tree). Powdered bark can also be adulter-within the first month of germination and field planted after ated with cornmeal, rice flour, starch, or other starchy sub-one or two years, depending on the size of the tree tube. stances. Consequences of contamination with outer bark orThe tree saplings must be watered during times of drought adulteration with flour or starch are lower mucilage content,and routinely checked for insect predation and indications lower swelling index value, and correspondingly less of aof fertilization needs. therapeutic demulcent effect that is mucilage-dependent.

Optimal Times for Harvest—Harvest should preferably oc- Excess outer bark could also cause the material to fail thecur in the spring (March to May), but can also take place in quantitative standard of NMT 10% total ash. Methods tothe autumn. In the spring, bark is harvested from mature determine the presence of adulterants include microscopictrees (minimum 10 years) when the sap begins to rise. examination in order to determine the presence of excess

Post-Harvest Handling— outer bark or any other adulterant and the concentration ofmucilage cells. The Elm mucilage test (Identification A) asOptimal Handling and Processing Practices—To producewell as a modified swelling volume test (based on the test inpharmacopeial quality elm inner bark, the outer corky layerthe USP monograph Psyllium Husk) may also be useful toof bark must be removed, exposing the inner bark. If post-investigate if adulteration is suspected.harvest processing occurs at the wild collection site, the

pruned limbs and branches should be placed onto cleantarps and not directly on the ground. The very smallbranches with leaves are stripped off the pruned limbs byhand and discarded. To optimize conformance to standardsfor composition, identity, purity, and quality (e.g., NMT 2%of adhering outer bark, NMT 2% foreign organic matter,NMT 10% total ash, and NMT 0.65% acid-insoluble ash), a ⟨2040⟩ DISINTEGRATION ANDclean bark rosser (hand tool with handle and knife blade)should be used to shave off the outer bark. The rough, scaly DISSOLUTION OF DIETARYmatter on the surface of the bark is called ross, and to rossbark is to scrape or shave the outer bark from the limb. An SUPPLEMENTSexperienced rosser can visually discern that at least 98% ofthe outer bark has been shaved off. The inner bark is whitein color (in the spring; reddish later in the season) in obvi-ous visible contrast to the brown outer bark layer. Aftermost of the outer bark is rossed off, greater care must be INTRODUCTIONexercised to very carefully slice off the remaining thin layerof outer bark so as not to waste any of the inner bark in the This general chapter is provided to determine complianceprocess. After removal of the outer bark, the inner bark can with the disintegration and dissolution standards for dietarythen be removed in strips, squares, or chips. An incision is supplements where stated in the individual monographs.made with a clean knife down the center of the limb. Then For the purposes of this chapter, dietary supplement dos-a clean crowbar is slipped underneath the incision in order age forms have been divided into three categories:to lift and peel the inner bark off from the cambium. The Vitamin–Mineral Dosage Forms, Botanical Dosage Forms, and

Official from May 1, 2012Copyright (c) 2011 The United States Pharmacopeial Convention. All rights reserved.

Accessed from 128.83.63.20 by nEwp0rt1 on Sat Dec 03 02:19:37 EST 2011

USP 35 Dietary Supplements / ⟨2040⟩ Disintegration/Dissolution 973

Dietary Supplements Other Than Vitamin–Mineral and Botani- the downward stroke. At no time should the top of thecal Dosage Forms. Vitamin–Mineral Dosage Forms includes ar- basket-rack assembly become submerged. The time requiredticles prepared with vitamins, minerals, or combinations of for the upward stroke is equal to the time required for thethese dietary ingredients (e.g., USP dietary supplements downward stroke, and the change in stroke direction is aClass I to Class VI, described below). Botanical Dosage Forms smooth transition rather than an abrupt reversal of motion.comprises formulations containing ingredients of botanical The basket-rack assembly moves vertically along its axis.origin, including plant materials and extracts. Dietary Supple- There is no appreciable horizontal motion or movement ofments Other Than Vitamin–Mineral and Botanical Dosage the axis from the vertical.Forms encompasses dietary supplements formulated with Basket-Rack Assembly—The basket-rack assembly (see Fig-lawfully recognized dietary ingredients that are different ure 1) consists of three open-ended transparent tubes, eachfrom those pertaining to the two foregoing categories (e.g., 77.5 ± 2.5 mm long and having an inside diameter of 32.0amino acids, chondroitin, and glucosamine.) to 34.6 mm and a wall 2.0 to 3.0 mm thick; the tubes are

Where a dietary supplement represents a combination of held in a vertical position by two plastic plates, each 97 ± 2the categories mentioned above, and there is a difference mm in diameter and 7.5 to 10.5 mm in thickness, withbetween the requirements for the individual categories, the three holes, 36.0 to 40.6 mm in diameter, equidistant frommore stringent requirement applies. the center of the plate and equally spaced from one an-

Dissolution testing as described in this chapter is a qual- other. Attached to the undersurface of the lower plate is 10-ity-control tool to enable the performance of dietary supple- mesh No. 23 (0.025-inch) W. and M. gauge woven stain-ments to be routinely assessed. less-steel wire cloth having a plain square weave. The parts

of the apparatus are assembled and rigidly held by means ofthree bolts passing through the two plastic plates. A suitableDISINTEGRATION means is provided to suspend the basket-rack assembly fromthe raising and lowering device, using a point on its axis.This test is provided to determine whether dietary supple- The design of the basket-rack assembly may be variedment tablets or capsules disintegrate within the prescribed somewhat, provided that the specifications for the glasstime when placed in a liquid medium at the experimental tubes and the screen mesh size are maintained.conditions presented below. Compliance with the limits on

Beaker—Low form, 1000 mL; the difference between theDisintegration stated in the individual monographs for die-diameter of the plastic plates, which hold the tubes in atary supplements is required except where the label statesvertical position, and the inside diameter of the beakerthat the products are intended for use as troches, are to beshould not be more than 6 mm.2chewed, or are designed as extended-release dosage forms.

Disks—Each tube is provided with a perforated cylindricalDietary supplements claiming to be extended-release dosagedisk 15.3 ± 0.15 mm thick and 31.4 ± 0.13 mm in diame-forms must comply with standards other than disintegrationter. The disk is made of a suitable, transparent plastic mate-to verify that the release of the dietary ingredients from therial having a specific gravity of between 1.18 and 1.20.dosage form is for a defined period of time. Dietary supple-Seven 3.15 ± 0.1-mm holes extend between the ends of thements claiming to be extended-release dosage forms shallcylinder, one of the holes being through the cylinder axisnot be labeled as in compliance with USP unless a USPand the others parallel with it and equally spaced on a 4.2-monograph exists for such product. Determine the type ofmm radius from it. All surfaces of the disk are smooth.3units 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 Procedurecomplete solution of the unit or even of its active constitu-

ent. Complete disintegration is defined as that state inUncoated Tablets—Place 1 tablet in each of the tubes ofwhich any residue of the unit, except fragments of insoluble

the basket and, if prescribed, add a disk to each tube. Oper-coating or capsule shell, remaining on the screen of the testate the apparatus, using water or the specified medium asapparatus or adhering to the lower surface of the disk, ifthe immersion fluid, maintained at 37 ± 2°. At the end of 30used, is a soft mass having no palpably firm core.minutes, lift the basket from the fluid, and observe the tab-lets: all of the tablets disintegrate completely. If 1 or 2 tab-

Apparatus lets fail to disintegrate completely, repeat the test on 12additional tablets. The requirement is met if not fewer than16 of the total of 18 tablets tested disintegrate completely.Apparatus A—Use the Apparatus described under Disinte-

gration ⟨701⟩ for tablets or capsules that are not greater Plain Coated Tablets—Place 1 tablet in each of thethan 18 mm long. For larger tablets or capsules, use Appara- tubes of the basket and, if the tablet has a soluble externaltus B. sugar coating, immerse the basket in water at room temper-

ature for 5 minutes. Then, if prescribed, add a disk to eachApparatus B—The apparatus1 consists of a basket-racktube, and operate the apparatus, using water or the speci-assembly, a 1000-mL low-form beaker for the immersionfied medium as the immersion fluid, maintained at 37 ± 2°.fluid, a thermostatic arrangement for heating the fluid be-At the end of 30 minutes, lift the basket from the fluid, andtween 35° and 39°, and a device for raising and loweringobserve the tablets: all of the tablets disintegrate com-the basket in the immersion fluid at a constant frequencypletely. If 1 or 2 tablets fail to disintegrate completely, re-rate between 29 and 32 cycles per minute through a dis-peat the test on 12 additional tablets. The requirement istance of not less than 53 mm and not more than 57 mm.met if not fewer than 16 of the total of 18 tablets testedThe volume of the fluid in the vessel is such that at thedisintegrate completely.highest point of the upward stroke the wire mesh remains

at least 15 mm below the surface of the fluid and descends 2 1000-mL low-form beakers, designed in compliance with the current ASTMto not less than 25 mm from the bottom of the vessel on E 960 Type I or Type II or ISO 3819 specifications, meet the size

requirements.1 An apparatus and disks meeting these specifications are available from 3 The use of automatic detection using modified disks is permitted where theVarian Inc., 13000 Weston Parkway, Cary, NC 27513, or from laboratory use of disks is specified or allowed. Such disks must comply with the require-supply houses. ments for density and dimensions given in this chapter.



974 ⟨2040⟩ Disintegration/Dissolution / Dietary Supplements USP 35

Figure 1. Basket-rack assembly, Disintegration, Apparatus B (dimensions in mm).

Delayed-Release (Enteric-Coated) Tablets—Place 1 tab- mersion fluid. After 1 hour of operation in simulated gastriclet in each of the six tubes of the basket, and if the tablet fluid TS, lift the basket from the fluid and observe thehas a soluble external sugar coating, immerse the basket in softgels: the softgels show no evidence of disintegration orwater at room temperature for 5 minutes. Then operate the rupture permitting the escape of the contents. Operate theapparatus using simulated gastric fluid TS maintained at apparatus with disks, using simulated intestinal fluid TS,37 ± 2° as the immersion fluid. After 1 hour of operation in maintained at 37 ± 2°, as the immersion fluid. Lift the basketsimulated gastric fluid TS, lift the basket from the fluid, and from the fluid, and observe the capsules. All the capsulesobserve the tablets: the tablets show no evidence of disinte- disintegrate completely within 60 minutes. If 1 or 2 capsulesgration, cracking, or softening. Operate the apparatus, using fail to disintegrate completely, repeat the test on 12 addi-simulated intestinal fluid TS, maintained at 37 ± 2°, as the tional capsules: not fewer than 16 of a total of 18 capsulesimmersion fluid for the time specified in the monograph. tested disintegrate completely.Lift the basket from the fluid, and observe the tablets: all of Buccal Tablets—Apply the test for Uncoated Tablets. Afterthe tablets disintegrate completely. If 1 or 2 tablets fail to 4 hours, lift the basket from the fluid, and observe the tab-disintegrate completely, repeat the test on 12 additional lets: all of the tablets disintegrate completely. If 1 or 2 tab-tablets: not fewer than 16 of the total of 18 tablets tested lets fail to disintegrate completely, repeat the test on 12disintegrate completely. additional tablets: not fewer than 16 of the total of 18 tab-

Delayed-Release (Enteric-Coated) Soft Shell lets tested disintegrate completely.Capsules—Place 1 softgel capsule in each of the six tubes of Sublingual Tablets—Apply the test for Uncoated Tablets.the basket. Use two baskets for a total of six tubes for Appa- At the end of the time limit specified in the individual mon-ratus B. Omit the use of a disk. Operate the apparatus using ograph, all the tablets disintegrate completely. If 1 or 2 tab-simulated gastric fluid TS maintained at 37 ± 2° as the im- lets fail to disintegrate completely, repeat the test on 12




additional tablets: not fewer than 16 of the total of 18 tab- (USP Apparatus 4). The lower part (1) is made up of twolets tested disintegrate completely. adjacent chambers connected to an overflow device. The

dissolution medium passes through chamber A and is sub-Hard Shell Capsules—Apply the test for Uncoated Tab-jected to an upward flow. The flow in chamber B is directedlets, using as the immersion fluid, maintained at 37 ± 2°, adownward to a small-size bore exit that leads upward to a0.05 M acetate buffer prepared by mixing 2.99 g of sodiumfilter assembly. The middle part (2) of the cell has a cavityacetate trihydrate and 1.66 mL of glacial acetic acid withdesigned to collect lipophilic excipients that float on thewater to obtain a 1000-mL solution having a pH of 4.50 ±dissolution medium. A metal grid serves as a rough filter.0.05. Attach a removable wire cloth, as described underThe upper part (3) holds a filter unit for paper, glass fiber,Basket-Rack Assembly, to the surface of the upper plate ofor cellulose filters.the basket-rack assembly. At the end of 30 minutes, lift the

basket from the fluid, and observe the capsules: all of thecapsules disintegrate except for fragments from the capsuleshell. If 1 or 2 capsules fail to disintegrate completely, re-peat the test on 12 additional capsules: not fewer than 16of the total of 18 capsules tested disintegrate completely.

Soft Shell Capsules—Proceed as directed under RuptureTest for Soft Shell Capsules.

Use of Disks—VITAMIN–MINERAL 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 VITAMIN–MINERAL AND

BOTANICAL DOSAGE FORMS—Omit the use of disks unless other-wise specified in the individual monograph.

NOTE—The use of disks for enteric-coated tablets is notpermitted.

RUPTURE TEST FOR SOFT SHELL CAPSULES

Medium: water; 500 mL.Apparatus—Use Apparatus 2 as described under Dissolu-

tion ⟨711⟩, operating at 50 rpm.Time: 15 minutes.Procedure—Place 1 capsule in each vessel, and allow the

capsule to sink to the bottom of the vessel before startingrotation of the blade. Use sinkers if the capsules float. Ob-serve the capsules, and record the time taken for each cap-sule shell to rupture. Figure 2. Flow-through cell designed for lipid-filled soft gela-

tin capsules (dimensions in mm).Tolerances—The requirements are met if all of the cap-sules tested rupture in not more than 15 minutes. If 1 or 2of the capsules rupture in more than 15 but not more than For hard or soft gelatin capsules and gelatin-coated tab-30 minutes, repeat the test on 12 additional capsules: not lets that do not conform to the dissolution specification, re-more than 2 of the total of 18 capsules tested rupture in peat the test as follows. Where water or a medium with amore than 15 but not more than 30 minutes. For soft gela- pH of less than 6.8 is specified as the Medium in the individ-tin capsules that do not conform to the above rupture test ual monograph, the same Medium specified may be usedacceptance criteria, repeat the test with the addition of puri- with the addition of purified pepsin that results in an activityfied pepsin to the Medium that results in an activity of of 750,000 Units or less per 1000 mL. For media with a pH750,000 Units or less per 1000 mL. 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 ofChange to read: known technological problems that may arise as a result of

coatings, lubricants, disintegrants, and other substances in-herent in the manufacturing process. For dosage forms con-taining botanical extracts, this dissolution measurement al-DISSOLUTIONlows an assessment of the extent of decomposition of theextract to polymeric or other nondissoluble compounds thatThis test is provided to determine compliance with themay have been produced by excessive drying or other ma-Dissolution requirements where stated in the individual mon-nipulations involved in the manufacture of botanical ex-ograph for dietary supplements, except where the labeltracts. The operative assumption inherent in this procedurestates that tablets are to be chewed.is that if the index or marker compound(s) or the extract isSee Dissolution ⟨711⟩ for description of apparatus used,demonstrated to have dissolved within the time frame andApparatus Suitability Test, and other related information. Ofunder conditions specified, the dosage form does not sufferthe types of apparatus described in ⟨711⟩, use the one spec-from any of the above formulation or manufacturing relatedified in the individual monograph.problems.•Soft gelatin capsule preparations of dietary supplements

meet the requirements for Disintegration.Official until December 1, 2011 Vitamin–Mineral Dosage Forms•(RB 1-Jun-2011)

Figure 2 shows the schematic view of a flow-through cellAll dietary supplements belonging to USP Classes II to VI,specifically intended for lipid-filled soft gelatin capsules. It

prepared as tablets or capsules, are subject to the dissolu-consists of three transparent parts that fit into each other




tion test and criteria described in this chapter for folic acid Medium: 45 mM citrate buffer, pH 6.0; 250 mL(if present) and for index vitamins and index minerals. This Apparatus 3: 30 dpmtest is required because of the importance of the relation- Screen (Top & Bottom): 56-meshship between folate deficiency and the risk of neural tube

Time: 1 hdefects. The accompanying table lists the dissolution re-NOTE—Compliance with the dissolution requirements forquirements for the individual USP classes of dietary supple-

folic acid does not exempt the product from dissolutionments. Class I dietary supplements are combinations of oil-testing of the pertinent index vitamin or the correspondingsoluble vitamins for which dissolution standards are not es-index mineral.tablished; hence, dissolution requirements do not apply to

the oil-soluble vitamins contained in formulations belongingto Class IV or Class V. Vitamin–mineral combinations that DISSOLUTION CONDITIONS FOR INDEX WATER SOLUBLEmay not be strictly covered by USP Classes I to Class VI are

VITAMINS AND INDEX MINERALSsubject to the dissolution test and criteria specified in theindividual monographs.

Test 1Medium: 0.1 N hydrochloric acid; 900 mLDietary Supplements—Vitamin–Mineral

Dosage Forms Apparatus 1: 100 rpm, for capsulesApparatus 2: 75 rpm, for tabletsCombination of

USP Vitamins or Minerals Time: 1 hClass Present Dissolution Requirement For formulations containing 25 mg or more of the index

vitamin, riboflavin, use the following conditions:Vitamin A (ifpresent)—for Medium: 0.1 N hydrochloric acid; 1800 mL

I Oil-Soluble Vitamins tablets only Apparatus 1: 100 rpm, for capsulesOne index vitamin; folic Apparatus 2: 75 rpm, for tablets

II Water-Soluble Vitamins acid (if present) Time: 1 hOne index vitamin and

Test 2 (Not suitable for Minerals)Water-Soluble Vitamins one index element;If the product complies with this test, the labeling indi-III with Minerals folic acid (if present)

cates that it meets USP Dissolution Test 2.One index water-soluble

Medium: 45 mM citrate buffer, pH 6.0; 250 mLOil- and Water-Soluble vitamin; folic acidApparatus 3: 30 dpmIV Vitamins (if present)Screen (Top & Bottom): 56-meshOne index water-soluble

Oil- and Water-Soluble vitamin and one Time: 1 hVitamins with index element; folic NOTE—Compliance with dissolution requirements for the

V Minerals acid (if present) pertinent index vitamin or index mineral does not exemptVI Minerals One index element the product from dissolution testing of folic acid, if present.

SELECTION OF INDEX VITAMINS AND INDEX ELEMENTSDISSOLUTION CONDITIONS FOR VITAMIN A TABLETS

Compliance with the dissolution requirements for dietaryNOTE—Perform this test under light conditions that mini- supplements representing combinations of water-soluble vi-

mize photo degradation. tamins (Water-Soluble Vitamins Capsules and Water-Soluble Vi-tamins Tablets) and combinations of oil- and water-solubleMedium: 1% (w/v) sodium ascorbate and 1% (w/v)vitamins (Oil- and Water-Soluble Vitamins Capsules and Oil-octoxynol 9 in 0.05 M phosphate buffer pH 6.8; 900 mLand Water-Soluble Vitamins Tablets) is determined by measur-Apparatus 2: 75 rpming the dissolution of a single index vitamin from the water-Time: 45 min soluble vitamins present. Riboflavin is the index vitaminwhen present in the formulation. For formulations that donot contain riboflavin, pyridoxine is the index vitamin. IfDISSOLUTION CONDITIONS FOR FOLIC ACIDneither riboflavin nor pyridoxine is present in the formula-tion, the index vitamin is niacinamide (or niacin), and in theNOTE—Perform this test under light conditions that mini-absence of niacinamide (or niacin), the index vitamin is thia-mize photodegradation.mine. If none of the above four water-soluble vitamins isTest 1 present in the formulation, the index vitamin is ascorbic

Medium: Water; 900 mL. If the units tested do not acid.meet the requirements for dissolution in water, test 6 addi- Compliance with the dissolution requirements for dietarytional dosage units for dissolution in a medium of 900 mL supplements representing combinations of minerals (Miner-of 0.05 M pH 6.0 citrate buffer solution, prepared by mix- als Capsules and Minerals Tablets) is determined by measur-ing 9.5 mL of 0.1 M citric acid monohydrate and 40.5 mL ing the dissolution of only one index element. Iron is theof 0.1 M sodium citrate dihydrate in a 100-mL volumetric index element when present in the formulation. For formu-flask, diluting with water to volume, mixing, and adjusting lations that do not contain iron, the index element is cal-to a pH of 6.0 by using either 0.1 M hydrochloric acid or cium. If neither iron nor calcium is present, the index ele-0.1 M sodium hydroxide solution. ment is zinc, and in the absence of all three of these

Apparatus 1: 100 rpm, for capsules elements, magnesium is the index element.Compliance with the dissolution requirements for dietaryApparatus 2: 75 rpm, for tablets

supplements representing combinations of water-soluble vi-Time: 1 htamins and minerals (Water-Soluble Vitamins with Minerals

Test 2: If the product complies with this test, the labeling Capsules and Water-Soluble Vitamins with Minerals Tablets)indicates that it meets USP Dissolution Test 2. and combinations of oil- and water-soluble vitamins and

minerals (Oil- and Water-Soluble Vitamins with Minerals Cap-sules and Oil- and Water-Soluble Vitamins with Minerals Tab-lets) is determined by measuring the dissolution of one in-




dex water-soluble vitamin and one index element, in comparison with a Standard solution having a known con-designated according to the respective hierarchies described centration of USP Folic Acid RS in the same Medium.above. Niacin or Niacinamide, Pyridoxine, Riboflavin, and

Thiamine—Determine the amount of the designated indexvitamin dissolved by using the procedure set forth in thePROCEDURES Assay for Niacin or Niacinamide, Pyridoxine Hydrochloride, Ri-boflavin, and Thiamine in Water-Soluble Vitamins Tablets.In the following procedures, combine equal volumes of

Ascorbic Acid—Determine the amount of C6H8O6 dis-the filtered solutions of the 6 individual specimens with-solved by adding 10 mL of 1.0 N sulfuric acid and 3 mL ofdrawn, and determine the amount of vitamin A, folic acid,starch TS to 100.0 mL of sample solution, and titrating im-or the index vitamin or element dissolved, based on themediately with 0.01 N iodine VS. Perform a blank determi-average of 6 units tested. Make any necessary modificationsnation, and make any necessary correction.including concentration of the analyte in the volume of

Iron, Calcium, Magnesium, and Zinc—Determine theSample solution taken. Use the Medium for preparation ofamount of the designated index element dissolved by usingthe Standard solution and dilution, if necessary, of the Sam-the procedure set forth in the appropriate assay in Mineralsple solution.Capsules.Vitamin A: Determine the percentage of retinyl acetate or

retinyl palmitate dissolved by using the followingprocedure. TOLERANCES

Sample solution: Withdraw a portion of the solutionunder test, pass through a suitable filter of 0.45-µm pore The requirements are met if not less than 75% of thesize, and use the pooled sample as the test specimen. labeled content of vitamin A, not less than 75% of the la-

Standard solution: Dissolve a suitable amount of USP beled content of folic acid, and not less than 75% of theRetinyl Acetate RS or USP Retinyl Palmitate RS in isopropyl labeled content of the index vitamin or the index elementalcohol, and dilute with Medium to obtain a concentration from the units tested is dissolved.similar to that expected in the Sample solution. [NOTE—Theamount of alcohol should be 5%–10%.]

Botanical Dosage FormsSolution A: Methanol and water (90:10)Solution B: Methanol and isopropyl alcohol (55:45) Compliance with dissolution requirements necessitates theMobile phase: See the gradient table below. testing of 6 dosage units individually, or testing 2 or more

dosage units in each of the 6 vessels of the dissolution ap-paratus, and measuring the dissolution of one or more in-Time Solution A Solution Bdex/marker compound(s) or the extract specified in the in-(min) (%) (%)dividual monograph.0 100 0

8 0 10013 0 100 PROCEDURES

13.1 100 0Combine equal volumes of the filtered solutions of the 615 100 0

or more individual specimens withdrawn, and use thepooled sample as the sample solution. Determine the aver-Chromatographic systemage amount of index or marker compound(s) or the extract(See Chromatography ⟨621⟩, System Suitability.)dissolved in the pooled sample by the procedure specifiedMode: LC in the individual monograph. Make any necessary modifica-

Detector: UV 325 nm tions, including concentration of the analyte in the volumeColumn: 4.6-mm × 10-cm; 3-µm packing L1 of the sample solution taken. Use the Medium for prepara-

tion of the Standard solution and dilution, if necessary, ofFlow rate: 1.0 mL/minthe sample solution.Injection size: 50 µL

System suitabilityTOLERANCESSample: Standard solution

Suitability requirementsUnless otherwise specified in the individual monograph,Tailing factor: NMT 1.5 for retinyl acetate and NMT the requirements are met if not less than 75% of the la-2.0 for retinyl palmitate beled content of the index or marker compound(s) or the

Relative standard deviation: NMT 2.0% extract from the units tested is dissolved in 1 hour.Analysis

Samples: Standard solution and Sample solution Dietary Supplements Other ThanVitamin–Mineral and Botanical Dosage FormsResult = (rU/rS) × (CS × V/L) × 100

Unless otherwise stated in the individual monographs forrU = peak area of the all-trans-retinyl ester from the Sam-dietary supplement dosage forms in this category, compli-ple solutionance requires the testing of 6 individual units, measuringrS = peak area of the all-trans-retinyl ester from thethe dissolution of the dietary ingredient as the average ofappropriate Standard solutionthe 6 units tested.CS = concentration of retinol (C20H30O) in the appropri-

ate Standard solution (µg/mL)V = volume of Medium, 900 mL

PROCEDURESL = label claim of vitamin A, as retinol (C20H30O) (µg/Tablet)

Combine equal volumes of the filtered solutions of the 6Folic Acid—Determine the amount of C19H19N7O6 dis- specimens withdrawn, and use the pooled sample as thesolved by using the procedure set forth in the assay for Folic Sample solution. Determine the average amount of dietaryAcid in Oil- and Water-Soluble Vitamins with Minerals Tablets, ingredient dissolved in the pooled sample by the procedure




specified in the individual monograph. Make any necessary Soft Capsulesmodifications, including concentration of the analyte in thevolume of the Sample solution taken. Use the Medium for Proceed as directed under Hard Capsules, but determinepreparation of the Standard solution and for dilution, if nec- the net weight of the contents of individual capsules as fol-essary, of the Sample solution. lows. Weigh the intact capsules individually to obtain their

gross weights, taking care to preserve the identity of eachcapsule. Then cut open the capsules by means of a suitableTOLERANCES clean, dry cutting instrument, such as scissors or a sharpopen blade, and remove the contents by washing with aBecause of the diversity of chemical characteristics and suitable solvent. Allow the occluded solvent to evaporatesolubilities of dietary ingredients pertaining to this category, from the shells at room temperature over a period of aboutgeneral tolerances cannot be established. See individual 30 minutes, taking precautions to avoid uptake or loss ofmonographs for Tolerances. moisture. Weigh the individual shells, and calculate the netcontents. The requirements are as stated under HardCapsules.

TABLETS

Tablets conform to the criteria given in the accompanying⟨2091⟩ WEIGHT VARIATION OFtable.

DIETARY SUPPLEMENTSUncoated Tablets and Film-Coated Tablets

The following tests provide limits for the permissible varia- Weigh individually 20 whole tablets, and calculate the av-tions in the weights of individual tablets or capsules, ex- erage weight. The requirements are met if the weights ofpressed in terms of the allowable deviation from the average not more than 2 of the tablets differ from the averageweight of a sample. Separate procedures and limits are de- weight by more than the percentage listed in the accompa-scribed herein for capsules, uncoated tablets, and coated nying table and no tablet differs in weight by more thantablets that are intended for use as dietary supplements. double that percentage.

CAPSULES Coated Tablets (Other Than Film-CoatedTablets)Capsules meet the requirements of the following test with

respect to variation in weight of contents. Weigh individually 20 whole tablets, and calculate the av-erage weight. If the coated tablets do not conform to thecriteria in the accompanying table, place 20 tablets in aHard Capsulesbeaker of water at 37°, and swirl gently for not more than 5minutes. Examine the cores for evidence of disintegrationWeigh 20 intact capsules individually, and determine theand repeat the procedure for a shorter time if disintegrationaverage weight. The requirements are met if each of thehas begun. Dry the cores at 50° for 30 minutes. Accuratelyindividual weights is within the limits of 90% and 110% ofweigh 20 individual tablet cores, and calculate the averagethe average weight.weight.If not all of the capsules fall within the aforementioned

The requirements are met if the weights of not more thanlimits, weigh the 20 capsules individually, taking care to pre-2 of the tablets differ from the average weight by moreserve the identity of each capsule, and remove the contentsthan the percentage listed in the accompanying table andof each capsule with the aid of a small brush or pledget ofno tablet differs in weight by more than double thatcotton. Weigh the emptied shells individually, and calculatepercentage.for each capsule the net weight of its contents by sub-

tracting the weight of the shell from the respective grossweight. Determine the average net content from the sum of Criteriathe individual net weights. Then determine the differencebetween each individual net content and the average netcontent: the requirements are met if (a) not more than 2 of

Weight Variation Tolerances for Uncoated Tablets, Film-Coatedthe differences are greater than 10% of the average netTablets, and Coated Tablets (Other Than Film-Coated Tablets)content and (b) in no case is the difference greater than

25%. PercentageIf more than 2 but not more than 6 capsules deviate from Average Weight of Tablet, mg Difference

the average between 10% and 25%, determine the net 130 or less 10contents of an additional 40 capsules, and determine the

From 130 through 324 7.5average content of the entire 60 capsules. Determine the 60More than 324 5deviations from the new average: the requirements are met

if (a) in not more than 6 of the 60 capsules does the differ-ence exceed 10% of the average net content and (b) in nocase does the difference exceed 25%.



972 2030 supplemental information / dietary supplements [2040... · trees (minimum 10 years) when...

Documents