D r q Standards
`
`Pharmacopeial Standards and Specifications for
`Bulk Drugs and Solid Oral Dosage Forms
`
`Similarities and Differences
`
`By W. N . FRENCH, F. MATSUI, DENYS COOK, and LEO LEV1
`
`Tests for tablet weight variation, drug content, and disintegration time described
`in the “United States Pharmacopeia,” “The National Formulary,” the “British
`PharmacEpoeia,” the “Pharmacopke Francaise,” the “State Pharmacopoeia of the
`and the “Nordic Pharmacopoea” are compared with regard to method-
`U.S.S.R.,
`ology, apparatus, scope, and compliance. Similarities and differences character-
`izing these standards are discussed. Comparable appraisals are made of assays
`for bulk drugs and compressed tablets included in the United States Pharmacopeia,
`the National Formulary, the British Pharmacopoeia, and the State Pharmacopoeia
`of the U.S.S.R. Discrepancies of sufficient magnitude exist between these tests
`and specifications to warrant closer cooperation among pharmacopeial agencies.
`Such cooperation should ensure greater uniformity of drug testing, encourage
`wider drug trade, and promote better public health throughout the world. These
`objectives are actively pursued by the World Health Organization.
`
`Pharmacopoeia Nordica. .............. 1630
`Similarities and Differences. . . . . . . . . . . 1630
`ASSAYS OF BULK DRUGS AND COMPRESSED
`................................
`TABLETS
`1635
`Bulk Drugs ...........................
`1635
`Compressed Tablets .................. 1637
`...............................
`SUMMARY
`1640
`............................
`REFERENCES
`1640
`
`CONTENTS
`GENERAL STANDARDS APPLICABLE TO SOLID
`..................
`ORAL DOSAGE FORMS..
`1623
`Weight Variation. .....................
`1623
`United States Pharrnacopeia, National
`Formulary, British Pharmacopoeia. .
`Pharmacopee Francaise. ..............
`State Pharmacopoeia U.S.S.R.. ........
`Pharmacopoea Nordica ...............
`Similarities and Differences. ....
`Drug Content .........................
`United States Pharmacopeia, National
`Formulary. .......................
`British Pharmacopoeia. ..............
`Pharmacopee Francaise ...............
`State Pharmacopoeia U.S.S.R.. ...
`Pharmacopoea Nordica. .........
`Canadian Food and Drugs Act and
`lations ............................
`Similarities and Differences. ...........
`Tablet Disintegration. .................
`United States Pharmacopeia, National
`Formulary. ..................
`British Pharmacopoeia. ...............
`Canadian Food and Drugs Act and
`Regulations. ..................
`1628
`Pharmacopee Francaise. ..........
`1629
`State Pharmacopoeia U.S.S.R.. .......
`1629
`Received May 15, 1967, from the Research Laboratories,
`Food and Drug Directorate, Department of National
`Health and Welfare, Ottawa, Ontario, Canada.
`Accepted for publication September 1, 1967.
`The authors express their appreciation to Dr. Lloyd C.
`Miller, the United States Pharmacopeia; Dr. Edward G.
`Feldmann, the National Formulary, Dr. T. C. Denston,
`British Pharmacopoeia Commission; Professor M. D.
`Mashkovsky, Ministry of Health, U.S.S.R., and Dr. Kjeld
`Ilver, Farmakopekommissionens Laboratorium, Copen-
`hagen, Denmark, for courteously reviewing the manuscript.
`They are also indebted to Dr. D. F. Bray, Statistical Services
`Division, Food and Drug Directorate, for valuable dis-
`cussions.
`
`AQUESTIVE EXHIBIT 1033 page 0001
`
`1623
`1623
`1623
`1623
`1623
`1624
`
`1624
`1624
`1625
`1625
`1625
`
`1625
`1625
`1627
`
`1627
`1627
`
`HARMACOPEIAL STANDARDS have been de-
`veloped in many countries.
`Realizing their
`value as mutually acceptable criteria of phar-
`maceutical quality control and their commercial
`importance, some countries have come to agree
`on common standards and specifications. The
`Nordic Pharmacopoea, official in Denmark,
`Finland, Iceland, Norway, and Sweden, may be
`cited as an example, and the European Phar-
`macopoeia-aiming
`to encourage and facilitate
`drug trade between countries of the European
`reflects this trend.
`Common Market-likewise
`Yet a great deal of work remains to be done to
`establish truly international standards as ref-
`erence criteria, i e . , standards that can be used
`conveniently anywhere and mean the same thing
`to analysts working in their national laboratories
`throughout different parts of the world.
`It is the purpose of this paper to point out
`certain differences and similarities which eqist
`between pharmacopeial tests and specifications
`applied in the quality control of bulk drugs and
`1622
`
`

`

`Vol. 56, No. 12, December 1967
`TABLE I-WEIGHT VARIATION TOLERANCES~
`(USP XVII, NF XII, B.P. 1963)
`
`1623
`
`No Tablet Differs
`from Av. Wt.
`--Av.
`Wt. of Tablet (mg.) from 20 Determinations-.
`USP XVII
`by More Than
`B.P. 1963
`N F XI1
`< 13b
`f30%b
`< 120
`< 130
`*20%
`13-130
`*15%
`130-324
`120-300
`130-324
`*:lo%
`>324
`>300
`>324
`Not applicable to sugar-coated, compression-coated, or enteric-coated tablets. Deleted in Second Supplement to N F
`XII.
`
`Not More Than
`Two Tablets Differ
`from Av. Wt.
`by More Than
`1k15%~
`+lo%
`2k7.575
`4=5%
`
`TABLE 11-WEIGHT VARIATION TOLERANCES"
`VIII j
`(PHARMACOP~E FRAN~AISE
`
`Tbeoret. Wt.
`of Tablet, mg.
`<150
`>150
`
`Tolerance, yo
`f 7 . 5
`f 5
`
`a Not applicable to coated tablets.
`
`TABLE 111-WEIGHT VARIATION TOLERANCES5
`
`(STATE PHARMACOPOEIA U.S.S.R. TX)
`
`Av. Wt.
`of Tablet, mg.
`<120
`>120
`
`Tolerance
`from Av. Wt., yo
`f 10
`f 5
`
`a Not applicable to coated tablets.
`
`tablet preparations, and to emphasize the need
`for greater interpharmacopeial uniformity.
`
`GENERAL STANDARDS APPLICABLE
`TO SOLID ORAL DOSAGE FORMS
`Weight Variation
`Pharmacopeial standards and specifications have
`been established to provide limits for permissible
`variations
`in the weights of
`individual dosage
`forms, expressed in terms of the allowable deviation
`from the average weight of a representative sample.
`Separate procedures and limits are described in most
`reference compendia for uncoated tablets, capsules,
`and sterile solids.
`United States Pharmacopeia, National Formulary,
`and British Pharmacopoeia-USP XVII (I), NF
`XI1 (2), and B.P. 1963 (3) specify that 20 whole
`tablets be weighed individually, the average weight
`calculated, and the variations compared with
`specifications. Samples meet requirements if weight
`variations observed are not greater than those
`shown in Table I.
`The British Pharmacopoeia allows performance of
`this test on 10 tablets also, specifying that in this
`case not more than one tablet may deviate from the
`average weight by a percentage greater than that
`shown in the table, and none of the tablets differ
`from the average by more than double that per-
`centage.
`Pharmacop6e Fransaise VIII (Codex MBdica-
`mentarius Gallicus) (4)-This compendium specifies
`that 10 tablets be weighed individually from a
`batch of homogeneous manufacture, the average
`weight determined, and the variations compared
`
`with specifications. Samples meet the require-
`ments if weight variations observed are not greater
`than those shown in Table 11.
`State Pharmacopoeia U.S.S.R. IX (S)-This
`compendium specifies that 10 tablets he weighed
`collectively and the average weight calculated.
`Another 10 tablets are to be weighed individually
`(each to within 10 mg.) and the variations com-
`pared with specifications. Samples meet require-
`ments if weight variations observed are not greater
`than those shown in Table 111.
`I11
`com-
`(6)-This
`Pharmacopoea Nordica
`pendium requires that 100 tablets' be weighed
`collectively (to within 1 mg. if the tablet is lighter
`than 80 mg. and to within 10 mg. if the tablet is
`heavier than 80 mg.) and the average weight
`calculated (to within 0.1 mg. if the tablet is lighter
`than 80 mg. and to within 1 mg. if the tablet is
`heavier than 80 mg.). Thirty tablets are selected
`at random from this sample and weighed indi-
`vidually (to within 0.2 mg. if the tablet is lighter
`than 80 mg. and to within 1 mg. if the tablet is
`heavier than 80 mg.). Requirements are met if
`weight variations determined are in accord with
`specifications shown in Table IV.
`the tests
`Similarities and Diff erences-Although
`described are simple, easily carried out, and serve
`the same purpose-namely,
`the establishment of
`the weight uniformity of uncoated, compressed
`tablets from a given lot-they differ markedly in
`both methodology and requirements for compliance.
`Methodology-The USP and NF tests are based
`on the use of a representative sample of 20 tablets
`weighed collectively and
`individually. Results
`based on similar examination of only 10 tablets
`are accepted by the B.P. The French pharma-
`copeia also specifies that 10 tablets be taken for
`the test, while the Russian pharmacopeia requires
`that 10 tablets be weighed collectively to assess
`the average weight and another 10 be weighed
`individually to appraise variations from the average
`weight. The Nordic pharmacopeia generally calls
`for the weighing of 100 tablets to compute their
`average weight and the examination of 30 of these
`tablets to determine individual variations from the
`average weight.
`Compliance-Tolerances are generally a function
`of average tablet weight. The greater the average
`tablet weight, the smaller are the weight variations
`permitted. Yet,
`the
`trend
`lacks uniformity.
`While the N F recognized four ranges (one range
`deleted, see Footnote b, Table I) of average tablet
`weights and specified corresponding tolerances, it,
`
`1 If i t is not possible lo use 100 tablets, weight determina-
`tion may be made with a smaller number, but not less than 20.
`
`AQUESTIVE EXHIBIT 1033 page 0002
`
`

`

`1624
`
`as well as the B.P. and USP, now cover three such
`classifications. The French and Russian pharma-
`copeias both designate relevant parameters for
`only two categories-limiting
`tablet weights being
`150 mg. and 120 mg., respectively. For uncoated
`compressed tablets weighing 80 mg. or more, the
`Nordic pharmacopeia, unlike other compendia,
`avoids step-wise changes in variability with respect
`to permitted tablet weight by using the formula:
`y = 4 f O.O5x, where y is the tolerance allowed in
`mg. (90% of sample), and x is the average weight
`In general, therefore, different tolerances
`in mg.
`are assigned to categories which cannot be readily
`compared, and products meeting the requirements of
`one national compendium need not necessarily meet
`those of another.
`Scope-Although many products have been tested
`in the laboratories of the Food and Drug Directorate
`following the USP, NF, and B.P. procedure, few
`ever failed to comply. Pharmacopeial tolerances
`appear generally to be too wide and unappreciative
`of advances made during recent years in pharma-
`ceutical manufacturing technology. Solid dosage
`forms of considerably smaller weight variations than
`those specified as pharmacopeial standards are
`produced with modern tableting machines.
`Consider, for example, a batch of digoxin
`tablets, (USP requirements: assay f8%; assay
`for content uniformity f15%) formulated to weigh
`100 mg. and contain 0.25 mg. of digoxin each,
`which had been prepared from a perfectly homo-
`geneous and accurately dosed granulation but,
`manufactured under adverse conditions of com-
`pression, just met USP specifications for weight
`variation. A cardiac patient, maintained at a 0.25-
`mg. daily dose of the drug and dispensed 20 such
`tablets, could conceivably receive only four-fifths
`of the potent medication one day, and 1.5 times as
`much the following day (0.2 mg. and 0.3 mg.,
`respectively).
`I t has been argued that weight variation is not
`an essential criterion of product quality-what
`is
`important is drug content. Little if any signifi-
`cance need be attached to differences in weight
`between tablets from a given batch or even from
`batch to batch as long as there is present in each
`the required amount of active ingredient.2 Ad-
`mittedly, the drug content of a tablet cannot be
`deduced from the weight variation test.
`I t can
`only be derived from quantitative analyses of
`individual dosage forms. Such assays have already
`found recognition as pharmacopeial
`standards,
`and as their usefulness through application in
`pharmaceutical quality control is becoming more
`apparent, the need for retaining official weight varia-
`tion tolerances much longer has been questioned.
`As a pharmacopeial standard the test has, how-
`ever, many virtues. Weight variation is easily
`determined. Requiring only a balance, the test
`provides a reliable means of gauging tablet uni-
`formity in terms of tablet weight within a given
`batch as well as from batch to batch. Applied
`readily to all tablets, large and small, with prac-
`
`2 It has so far not yet been established whether the physi-
`ological availability of a medication from a tablet is totally
`independent of tablet weight for any type of formulation.
`Lozinski for example has shown that dicoumarol tablets of
`identicai formulation’ and drug content, but larger size,
`displayed markedly reduced therapeutic efficacy. [Con.
`Med. Assoc. J., 83. 177(1960).]
`
`manufacturing . ”
`AQUESTIVE EXHIBIT 1033 page 0003
`
`Journal of Pharmaceutical Sciences
`TABLE IV-WEIGHT VARIATION TOLERANCES“
`(PHARMACOPOEA NORDICA 111)
`
`Av.
`Tablet
`Wt., mg.
`<80
`
`>80
`
`Tolerances
`Based on 30 Determinations
`27 tablets (goyo of sample) may differ
`from av. wt. by &lo% and 3 tablets
`(l0yo of sample) may differ from av.
`wt. by f200/ob
`27 tablets (90% of sample) may differ
`from av. wt. by f (4 mg. +5% of
`av. wt.) and 3 tablets (10% of sample)
`may differ from av. wt. by f (8 mg.
`+lo% of av. wt.)
`a Applicable to compressed, uncoated tablets. Tolerance
`also applicable to coated and uncoated tablets not prepared
`by compression, regardless of weight.
`
`tically the same degree of accuracy and precision,
`it is a dependable indicator of good pharmaceutical
`manufacturing practices and production technology.
`Uniform specifications of methodology and com-
`pliance and more realistic tolerances reflecting the
`precision with which tablet weight can be con-
`trolled by means of modern tableting equipment
`would greatly enhance its universal value in pharma-
`ceutical quality control.
`Drug Content
`As a rule, pharmacopeial assays for active
`ingredients are based on analyses of aliquots ob-
`tained from a given number of tablets reduced to a
`fine powder.
`USP XVII and NF XII-Methods-(a)
`Composite
`or, in most instances, 20 tablets
`Assays-Ten
`are required for physicochemical assays of drug
`content. They are finely powdered and aliquots
`of the triturate examined in accordance with the
`method of analysis specified in the corresponding
`monograph.
`( b ) Single Dosage Assays (Content Uniformity)-A
`representative sample consisting of 30 tablets is
`obtained from a given lot, and 10 of these are
`analyzed individually by the method of assay
`specified in the relevant monograph. At the an-
`alyst’s discretion the degree of dilution of solutions
`and/or the volume of aliquots used may be adjusted
`so that the concentration of the drug in the final
`solution will be comparable to that obtained for
`the assay described in the corresponding mono-
`graph.
`Compliance-(a) Composite Assays-Experimental
`results, indicative of the drug content of an aliquot
`from a number of tablets, are expressed in terms
`of the percent of labeled amount of drug claimed
`to be present in a single tablet. Tolerances are
`specified in individual monographs and vary de-
`pending on the nature of the product examined and
`the analytical method applied.
`(See under Assays
`of Bulk Drugs and Compressed Tablets.)
`( b ) Single Dosage Assays-Requirements which
`must be met are shown in Table V.
`B.P. 1963-Method-It
`is essentially that adopted
`for composite assays by the United States Pharma-
`copeia, with tolerances “framed to allow for all
`permissible variations including that of the active
`ingredient itself and that due to the process of
`
`

`

`Vol. 56, No. 12, December 1967
`TABLE V-SINGLE DOSAGE ASSAYS FOR CONTENT
`(USP XVII, NF XII)
`UNIFORMITY OF TABLETS
`
`1625
`TABLE VII-DRUG CONTENT O F TABLETS
`
`(STATE PHARMACOPOEIA U.S.S.R. IX)
`
`No. of
`Tablets
`- Requirements
`Analyzed
`(Out of 30)
`I
`I1
`If one result exceeds
`10 All results must be
`within 85115%
`limits
`specified
`of av. of toler-
`under I, each of
`ances specified
`remaining 20 tab-
`in official mono-
`lets must be with-
`graph
`in limits specsed
`under 10
`
`A rare “flyer” will thus not cause rejection of an entire
`batch.
`
`Compliance-Experimental results are expressed
`as previously defined.
`In circumstances where the
`required number of tablets cannot be obtained, a
`smaller number, but not less than five, may be
`assayed by the official method. To allow for sam-
`pling errors in such instances tolerances are widened
`progressively, as shown in Table VI.
`The corrections are to be applied to tablets for
`which tolerances ranging from 90-110% have been
`specified. For limits exceeding these values, pro-
`portionately larger allowances are to be made.
`Reasons for extending consistently upper limits
`more than the corresponding lower ones are not
`stated.
`for
`Pharmacopde Francaise VIII-Monographs
`tablets have not been included in this edition and
`generally applicable specifications for drug content
`and content uniformity are not described.
`State Pharmacopoeia U.S.S.R.
`IX-Specimens
`are prepared by grinding one or more tablets to
`a fine powder. The amount of sample required for
`analysis, the assay procedure to be followed, and
`tolerances permitted are specified in official mono-
`graphs. Tablets for which such monographs are
`not given must meet the requirements shown in
`Table VII.
`examination of a
`Pharmacopoea Nordica-The
`specified aliquot obtained as a rule from the tritura-
`tion of at least 10 tablets is required.
`In general,
`drug content may vary by not more than *lo%
`from label claims. The tolerances are considered
`to take into account variations arising from manu-
`facture and storage as well as analytical method-
`ology.
`Canadian Food and Drugs Act and Regulations
`(ir)--MethodSchedule B of the Canadian Food
`and Drugs Act and Regulations lists seven pharma-
`copeial compendia officially recognized by the Food
`and Drug Directorate. They include, at present,
`the Pharmacopoea
`Internationalis,
`the British
`
`Active Ingredient
`Per Tablet, mg.
`>loo
`<loo
`
`Tolerance, %
`f 5
`f 10
`
`Pharmacopoeia, the United States Pharmacopeia,
`the Codex Francais, the Canadian Formulary, the
`British Pharmaceutical Codex, and the National
`Formulary. Methods specified in these reference
`texts are endorsed by the Food and Drug Directorate
`as valid standards of pharmaceutical quality con-
`trol, unless an “official method,” i.e., a method of
`analysis or examination designated as such by the
`Director-General for use in the administration of
`the Act, is the method to be applied.
`Compliance-Tolerances
`set forth in any of the
`pharmaceutical compendia cited above are ac-
`cepted for products thus identified. For non-
`official drugs “put up in tablet or any other indi-
`vidual dosage or dispensing form other than in
`ampoules or vials, variations within the limits stated
`in the following table as determined by an ac-
`ceptable method” are permitted (Table VIII).
`
`TABLE VIII-LIMITS O F VARIABILITY FOR
`NONOFFICIAL SOLID ORAL DOSAGE FORMS
`(CANADIAN FOOD AND DRUGS
`ACT AND REGULATIONS)
`
`Amt. of Drug Per Tablet
`gr.
`mg.a
`>324
`>5
`0 . 5 -5
`32.4-324
`0.02-0.5
`3 . 2 4 3 2 . 4
`0.01-0.02
`0 , 6 6 3 . 2 4
`<o. 01
`<0.65
`a Equivalents not given in original table.
`
`Limits, %
`94-106
`93-107
`92-108
`91-109
`90-110
`
`( a ) “glyceryl tri-
`Two exceptions are made:
`nitrate shall contain not less than 85% and not
`more than 115% of
`the labelled amount,” and
`( b ) “if the drug consists of several ingredients, the
`amount of each ingredient so dispensed shall be
`not less than 90% and not more than 110% of the
`amount calculated from the label description.”
`Similarities and Differences-Tablet drug content
`and content uniformity depend on a number of
`processes associated with tablet manufacture, e.g.,
`compounding, mixing, drying, slugging, dispersion,
`compression, etc. Pharmacopeial standards have
`been established to control these processes, permit
`
`TABLE VI-ASSAY TOLERANCES FOR TABLETS INCLUDED I N B.P. 1963
`
`
`BASED ON ANALYSIS OF LESS THAN 20 SPECIMENS
`
`--
`
`,--
`
`Wt. of Drug
`in Tablet, mg.
`< 120
`120-300
`>300
`
`Lower
`0.2
`0 . 2
`0 . 1
`
`Tablets Used for Analysis, No.
`15
`10
`Extend Limits Specified in Monographs by Following Percentages-
`Upper
`Lower
`Upper
`Lower
`0 . 3
`0 . 7
`0 . 8
`1 . 6
`0 . 5
`0 . 6
`0 . 3
`1 . 2
`0.4
`0 . 2
`0 . 2
`0.8
`
`5
`
`-
`
`-7
`
`Upper
`1 . 8
`1 . 5
`1.0
`
`AQUESTIVE EXHIBIT 1033 page 0004
`
`i
`
`

`

`1626
`
`determination of the amount of active ingredient
`present in a given product, and gauge the uni-
`formity with which the drug is incorporated into
`individual dosage units.
`the
`Methodology-The USP and N F require
`examination of a specified aliquot obtained as a
`rule from the trituration of 20 tablets. The B.P.
`accepts assay values derived from the analysis of
`aliquots from a smaller number of tablets as well,
`and endorses results obtained with as few as 5
`tablets if only that many are available. The French
`pharmacopeia does not include monographs for
`solid dosage forms, and guidelines concerning general
`techniques and methodologies are, likewise, not
`described.
`Assays given in the Russian pharmacopeia are
`not based on the examination of an aliquot from a
`definite number of tablets, but on direct analysis
`of a specified amount of sample material representing
`a fraction of one or several tablets. The Pharma-
`copoea Nordica, in general, requires the use of at
`least 10 tablets. The Canadian Food and Drugs
`Act and Regulations endorse any acceptable method,
`i.e., any method of analysis or examination sanc-
`tioned by the Director-General for use in the ad-
`ministration of the Act.
`It should be emphasized in this connection that
`different methods of analysis displaying different
`degrees of selectivity and sensitivity may be
`specified for the same preparation
`in different
`pharmacopeias. Single dosage assays have so
`far been adopted only by the United States Pharma-
`copeiaa and the National F o r m ~ l a r y . ~
`Compliance-Tolerances
`are stated
`in official
`monographs and marked variations exist between
`different pharmacopeial standards
`(see under
`Assays of Bulk Drugs and Compressed Tablets).
`Limits are generally a function of the weight of
`active ingredient claimed to be present in a single
`dosage unit. The greater the amount of active
`ingredient per tablet, the smaller the variation
`permitted. Unlike any other pharmacopeia, the
`B.P. allows for a further extension of tolerances if
`assays are based on less than 20 tablets. No
`reference is made in the USP, B.P., or NF to
`tolerances for products for which official mono-
`graphs have not been described. The Russian
`pharmacopeia, on the other hand, specifies tol-
`erances for such preparations as well. Products
`containing more than 100 mg. of active ingredient
`may vary by +5% and those containing less than
`this amount by +lo% from label claims. The
`Canadian Food and Drugs Act and Regulations
`also cover nonofficial products, specifying five
`concentration ranges and corresponding tolerances.
`The classification is an unrealistic one in the light
`of modern technology, and efforts to revise it are
`now being made.
`Scope-It
`is generally recognized that tablet
`weight variation does not necessarily reflect drug
`content variation. While tablets satisfying phar-
`macopeial specifications for weight variation are
`readily made by means of modern machines, it
`
`a Applicable to tablets of chlorprornazine hydrochloride.
`digoxin, ergonovine maleate, hydrocortisone, rnethylergono-
`vine maleate, metyrapone, phenobarbital, prednisolone,
`prednisone, and prochlorperazine maleate.
`4 Applicable to tablets of amphetamine phosphate, am-
`phetamine
`sulfate, hetarnethasone, cortisone acetate,
`dexamethasone, dextroamphetamine phosphate, methyl-
`prednisolone, methyltestosterone, and syrosingopine.
`
`Journal of Phnrmceutical Sciences
`
`is most difficult to produce truly homogeneous
`tablet granulations and to feed solid blends con-
`tinuously into the tableting machine for compaction
`into truly uniform dosage forms. The smaller the
`concentration of the active ingredient present, the
`more difficult it becomes to attain product uni-
`formity. Tablets containing potent drugs,
`i.e.,
`tablets whose safety and efficacy demand careful
`control, are, therefore, particularly prone to com-
`positional variations.
`Several studies relating tablet weight and drug
`content have been published during recent years.
`They covered both practical and theoretical aspects
`associated with the production of solid dosage
`forms (8, lo), principles of mixing solids and their
`application to pharmacopeial standards for content
`uniformity in the absence of single dosage assays
`(11, 12), the effect of sampling and bulk mix hetero-
`geneity on tablet variation (13), reproducibilities
`of assay and drug recovery from dosage forms
`(14), the nature and scope of sampling techniques
`(15), the application of automated equipment to
`single-tablet assays (16), and the effect of tableting
`technology on the relationship between
`tablet
`weight variation and percent composition (17, 18).
`Relevant investigation on commercial products
`were carried out in the laboratories of the Canadian
`Food and Drug Directorate (19) and are continuing
`(20, 21). The following experiments may serve
`to illustrate some of
`the problems encountered
`during the course of these studies.
`Ten tablets of hydrocortisone (5 mg.)6 were taken
`at random from a bottle of 100 and analyzed in ac-
`cordance with the USP procedure (tolerances allowed
`9&110%). Theywere found to be below labeled
`strength (87.3%). Another analyst repeated the
`assay using a second lot of 10 tablets selected,
`likewise, at random from
`the same container.
`His results showed that the product complied
`(91.8%). Concerned about the discrepancy, a
`third analyst decided to assay 10 tablets indi-
`vidually. He obtained an average assay value of
`100.87, on the basis of results varying from 68.47,
`to 151.2%.
`In each case, the 10 tablets used for
`analysis met perfectly the requirements of
`the
`weight variation test.
`Because they are based on the examination of
`sample composites obtained from randomly selected
`tablets, pharmacopeial assays cannot be relied
`upon to provide infallible criteria for uniformity of
`tablet drug content. The weakness inherent in
`these methods is their inconsistency in relating
`experimental design to data utilization. They
`express product dosage on an individual tablet
`basis but are, themselves, based on sample com-
`posites of many tablets. Such analyses may not
`only average out minor compositional variations
`between tablets, as originally believed, but also
`mask major deviations
`reflecting substandard
`“pharmaceutical workmanship.” The greater the
`number of tablets used for such analyses, the greater
`the possibility of masking variation in active in-
`gredient due to imperfections in mixing all com-
`ponents during formulation, which process is con-
`sidered a most critical one (9, 11, 12). On statistical
`grounds, the variation in drug content of an indi-
`vidual tablet taken from a number of tablets may
`
`5 Average weight of tablets 104.4 mg.; maximum deviation
`from mean 5.4 mg.
`
`AQUESTIVE EXHIBIT 1033 page 0005
`
`

`

`Vol. 56, No. 12, December 1967
`
`1627
`
`be as large as the square root of this number multi-
`plied by the limit set for the composite assay.
`That is, an individual tablet taken at random from
`a group of 20 tablets for which drug content limits
`of SO-llO%, i.e., flOyo have been set, may deviate
`from the standard by as much as d%l X 10 =
`44.7%. Conversely, if all tablets should be within
`the range of 9(rllO%, i.e., +lo% of label claim,
`the limit of variability for the composite assay
`based on 20 tablets should be no more than 10 f
`4% = 2.25%.
`Atropine sulfate tablets B.P., for example, may
`contain as little as 0.25 mg. of the potent anti-
`cholinergic and no less than 80 such tablets are
`required for the official assay. Yet, theoretically, a
`sample composite complying with the official B.P.
`standard of drug content (90-110%) may consist
`of
`individual tablets, some of which could con-
`tain as little as 10% or as much as 190% of the
`required amount. More pertinent information
`concerning the extent of
`tablet variation can be
`obtained by carrying out several composite assays
`and calculating standard deviations of individual
`tablets from the standard deviations of the com-
`posites. However, direct criteria of drug content
`uniformity are provided only by single-tablet as-
`says, as described in the United States Phar-
`macopeia and the National Formulary, respectively
`(see Table V). Admittedly, such a scheme of
`quality control increases the time and cost of drug
`analysis, but it permits a more reliable appraisal
`of true product uniformity and its application to
`tablets containing potent chemotherapeutic agents
`should be of major concern to governmental and
`industrial laboratories alike.
`The principle of pharmacopeial standards for
`monitoring intertablet dosage variation has been
`favorably received and accepted by the pharma-
`ceutical industry in Canada and the United States!
`A t present, analytical methods for determining
`content uniformity
`involve spectrophotometric
`techniques only, and provided tablet formulations
`are amenable to such determinations, accurate
`measurements are readily made. Other equally
`sensitive methods are being developed in order to
`obtain single-tablet assays for as many products
`as possible. It should be in the pharmaceutical
`manufacturer's interest to produce only simple
`dosage forms which can readily be subjected to
`quantitative analysis.
`
`Tablet Disintegration
`Tests for gauging the disintegration of
`tablets
`under controlled conditions are described in most
`official compendia. Although not necessarily in-
`dicators of
`therapeutic efficacy, they are widely
`applied in pharmaceutical quality control.
`Apparatus can be obtained commercially, and
`methodology
`is simple. Most pharmacopeias
`require that the tablet be placed in a tube (trans-
`parent plastic or glass) of precise dimensions fitted
`at its lower end with a wire gauze of specified mesh.
`The tube, suspended in a fluid kept a t constant
`
`temperature, is raised and lowered at a uniform
`rate throughout a specified distance for a given
`period of time.
`The tablet is considered disintegrated when,
`except for fragments of insoluble coating, only a
`soft mass having no palpable firm core remains
`above the gauze. The time required to reach this
`stage is called the disintegration time. Depending
`on the type of product and the pharmacopeial
`standard selected, a plastic disk of definite weight,
`shape, and size may be placed above the tablet
`in the tube either for the duration or throughout
`certain phases of the test.
`Commercial units meeting official requirements
`are available and permit testing of as many as
`6 tablets a t a time.
`USP XVII and NF XII--Apparatus-Vessel
`for
`basket rack assembly: a suitable vessel, preferably
`a 1-L. beaker. Temperature of medium: 37 f
`length, 7.75 f 0.25 cm.;
`2". Tube dimensions:
`inside diameter, 21.5 mm.; wall thickness, 2 mm.
`Wire mesh: nominal width of aperture 0.075 in.
`(1.90 mm.). Disk: material, transparent plastic,
`sp. gr. 1.18-1.20;
`thickness, 9.5 f 0.15 mm.;
`diameter, 20.7 + 0.15 mm.; perforations, five,
`each 2-mm. wide; notches, four having V-shaped
`planes. Movement: rate, 30 f 2 c.p.m.; distance,
`5-6 cm. Wire mesh position: high point, not less
`than 2.5 cm. below surface of fluid; low point, not
`less than 2.5 cm. from bottom of vessel.
`Methodology and Compliance-These
`marized in Table IX.
`B.P. 1963-Appavatus-Vessel:
`depth not less
`than 15 cm. Temperature of medium: 37 31 2".
`length, 8-10 cm.;
`Tube dimensions:
`inside di-
`ameter, 28 mm.; wall thickness, 2-3 mm.; volume,
`200-250 ml. Wire mesh:
`nominal width of
`aperture 0.0661 in. (1.68 mm.). Disk: material,
`plastic; thickness, 2 mm.; diameter, 26 mm.;
`weight, 1.9-2.1 Gm. Guide ring: 27 mrb. 0.d.
`Movement: rate, 30 c.p.m. (by hand or mechan-
`ically); distance, 7.5 cm.; high p