2000
`
`US P 24
`NF 19
`
`THE UNITED STATES PHARMACOPEIA
`THE NATIONAL FORMULARY
`
`By authority of the United States Pharmacopeial
`Convention, Inc., meeting at Washington, D.C.,
`March 9-12, 1995. Prepared by the Committee of
`Revision and published by the Board of Trustees
`
`Official from January 1, 2000
`
`UNITED STATES PHARMACOPEIAL CONVENTION, INC.
`12601 Twinbrook Parkway, Rockville, MD 20852
`
`Page 1
`
`SHIRE EX. 2080
`KVK v. SHIRE
`IPR2018-00293
`
`

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`NOTICE AND WARNING
`
`Concerning U.S. Patent or Trademark Rights
`The inclusion in the Pharmacopeia or in the National Formulary of a monograph on any drug in
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`other person may exercise the same without express permission, authority, or license secured
`from such patent or trademark owner.
`
`Concerning Use of USP or NF Text
`Attention is called to the fact that USP and NF text is fully copyrighted. Authors and others
`wishing to use portions of the text should request permission to do so from the Secretary of the
`USPC Board of Trustees.
`
`The United States Pharmacopeial Convention, Inc.
`D 1999
`12601 Twinbrook Parkway, Rockville, MD 20852.
`All rights reserved
`ISSN 0195-7996
`ISBN 1-889788-03-1
`
`Printed by National Publishing, Philadelphia, PA
`
`Page 2
`
`

`

`134
`
`Amphetamine /Official Monographs
`
`twined from the Assay preparation and the Standard preparation,
`respectively.
`
`Amphetamine Sulfate
`
`C~ I ~~ HJ2 • ~SO~
`
`(C9H„N)Z • HzSO, 368.49
`Benzeneethanamine, oc-methyl-, sulfate (2:1), (±)-.
`[60-13-9].
`(±)-a-Methylphenethylamine sulfate (2:1)
`Amphetamine Sulfate, dried at 105° for 2 hours, con-
`tains not less than 98.0 percent and not more than 100.5
`percent of (C9H13N)Z•HZSO,,.
`Packaging and storage—Preserve in well-closed containers.
`USP Reference standards (11)—USP Dextroamphetamine Sulfate
`RS.
`IdenHfication—
`A: Dissolve about 100 mg in 5 mL of water, add 5 mL of 1 N
`sodium hydroxide, cool to about 10°, add 1 mL of a mixture of 1
`volume of benzoyl chloride and 2 volumes of absolute ether, insert
`the stopper, and shake for 3 minutes. Filter the precipitate, wash
`with about 10 mL of cold water, and recrystallize from diluted
`alcohol: the crystals of the benzoyl derivative of amphetamine so
`obtained, after drying at 80° for 2 hours, melt between 131° and
`135°, the procedure for Class I being used (see' Melting Range or
`Temperature (741)).
`B: A solution (1 in 10) responds to the tests for Sulfate (191).
`Loss on drying (731)—Dry it at 105° for 2 hours: it loses not
`more than 1.0% of its weight.
`Residue on ignition (281): no[ more than 0.2%.
`Dextroamphetamine—A solution (1 in 50) is optically inactive.
`Ordinary impurities (466)—
`Test solution: methanol.
`Standard solution: methanol.
`Eluant: a mixture of methanol and ammonium hydroxide (50:
`1).
`Visualization: 1.
`Organic volatile impurities, Method / (467): meets the require-
`ments.
`Assay—
`Standard preparation—Prepare as directed under Amphetamine
`Assay (331).
`Assay preparation—Dissolve about 125 mg of Amphetamine
`Sulfate, previously dried and accurately weighed, in 25 mL of hy-
`drochloric acid solution (1 in 100) in a 50-mL volumetric flask,
`dilute with the solvent to volume, and mix. Pipet 2.0 mL of the
`solution into a 100-mL beaker containing 3 g of purified siliceous
`earth, and mix until a fluffy mixture is obtained.
`Procedure—Proceed as directed under Amphetamine Assay
`(331). Calculate the quantity, in mg, of (C9H„N)~•H_SO, in the
`poRion of Amphetamine Sulfate taken by the formula:
`0.25C[(A~37 — A~„eo)~~Ar_s~ — Aszeo)~+
`in which C is the concentration, in µg per mL, of U3P Dextro-
`amphetamine Sulfate RS in the Standard preparation, and the other
`terms are as defined therein.
`
`USP 24
`
`Packaging and storage—Preserve in well-closed containers.
`USP Reference standards (11)—USP Dextroamphetamine Sulfate
`RS.
`Identification—Macerate a quantity of powdered Tablets, equiva-
`lent to about 50 mg of amphetamine sulfate, with 10 mL of water
`for 30 minutes, and filter into a small flask. To the filtrate add 3
`mL of 1 N sodium hydroxide. Cool to about 10° to 15°, add 1 mL
`of a mixture of 1 volume of benzoyl chloride and 2 volumes of
`absolute ether, insert the stopper, and shake well for 3 minutes.
`Filter the precipitate, wash with about 15 mL of cold water, and
`recrystallize twice from diluted alcohol: the crystals of the benzoyl
`derivative of amphetamine so obtained, after drying at 80° for 2
`hours, melt between 131° and 135°, the procedure for Class 1 being
`used (see Melting Range or Temperature (741)).
`Dissolution, Procedure for a Pooled Sample (711)—
`Mediesm: water; 500 mL.
`Apparatus 1: 100 rpm.
`Time: 45 minutes.
`Mobile phase—Dissolve 1.1 g of sodium i-heptanesulfonate in
`575 mL of water. Add 25 mL of dilute glacial acetic acid (14 in
`100) and 400 mL of methanol. Adjust by the dropwise addition of
`glacial acetic acid to a pH of 33 ± 0.1, if necessary, filter, and
`degas the solution. Make adjustments if necessary (see System Suit-
`a6ility under Chromatography (621)).
`Chromatographic s}~stem (see Chromatography (621)~The liq-
`uid chromatograph is equipped with a 254nm detector and a 3.9-
`mm X 30-cm column that contains packing Ll. The flow rate is
`about 1 mL per minute. Chromatograph replicate injections of the
`Standard solution, and record the peak responses as directed for
`Procedure: the relative standard deviation is not more than 2.0%.
`Procedure—Inject a volume (about 500 µL) of a filtered poRion
`of the solution under test into the chromatograph, record the chro-
`matogram, and measure the response for the major peak. Calculate
`the quantity of (CyH„N),•H,SO, dissolved in comparison with a
`Standard solution having a known concentration of USP Dextro-
`amphetamine Sulfate RS in [he same medium and similarly
`chromatographed.
`Tolerances—Not less than 75% (Q) of [he labeled amount of
`(C9H13N), • H,SO, is dissolved in 45 minutes.
`Uniformity of dosage units X905): meet the requirements.
`Assay—
`Standard preparation—Prepare as directed under Amphetamine
`Assay (331).
`Assay preparation—Weigh and finely powder no[ less than 20
`Tablets. Transfer an accurately weighed portion of the powder,
`equivalent to about S mg of amphetamine sulfate, to a 100-mL
`beaker, add 2 mL of hydrochloric acid solution (1 in 100), swirl
`gently to wet the powder thoroughly, warm on a steam bath for
`about 1 minute, with occasional gentle swirling, and cool. Add 3 g
`of purified siliceous earth, and mix until a fluffy mixture is obtained.
`Procedure—Proceed as directed under Amphetamine Assay
`(331). Calculate the quantity, in mg, of (C9H,3N):•H,SO, in the
`portion of Tablets taken by the formula:
`OA 1CI(A~n_s~ — Arn_ao)~~A.r~~ — Ar_so)),
`in which C is the concentration, in µg per mL, of USP Dextro-
`amphetamine Sulfate RS in the Standard preparation.
`
`Amphotericin B
`
`Amphetamine Sulfate Tablets
`Amphetamine Sulfate Tablets contain not less than
`93.0 percent and not more than 107.0 percent of the
`labeled amount of (CvH13N)2 • HZSO4.
`
`C„H„NO„ 924.08
`Amphotericin B.
`Amphotericin B.
`
`Page 3
`
`

`

`4824 Theophylline /Official Monographs
`
`Uniformity of dosage units (905): meet the requirements.
`Assay—
`Mobile phase—Prepare a solution containing a mixture of
`water, methanol, and glacial acetic acid (64:35:1).
`Standard preparation—Dissolve an accurately weighed quan-
`tity of USP Theophylline RS in methanol to obtain a solution
`having a known concentration of about 400 µg per mL.
`Assay preparation for hard Capsules—Remove, as completely
`as possible, the contents of not less than 20 Capsules, weigh,
`and mix. Transfer an accurately weighed portion of the powder,
`equivalent to about 100 mg of anhydrous theophylline, to a
`250-mL volumetric flask, add about 150 mL of methanol, and
`shake to dissolve. Dilute with methanol to volume, mix, and
`filter, using a membrane filter.
`Assay preparation for soft Capsules—Cut open 20 Capsules,
`and place them in a 200-mL volumetric flask. Add 50 mL of
`6 N ammonium hydroxide, shake to dissolve the contents, add
`water to volume, mix, and filter, discarding the first 20 mL of
`the filtrate. Transfer an accurately measured portion of the fil-
`trate, equivalent to about 100 mg of anhydrous theophylline,
`to a 250-mL volumetric flask, add methanol to volume, mix,
`and filter through a membrane filter.
`Chromatographic system (see Chromatography (621))—The
`liquid chromatograph is equipped with a 254-nm detector and
`a 4-mm x 30-cm column that contains packing Ll .The flow
`rate is about 2 mL per minute. Chromatograph three replicate
`injections of the Standard preparation, and record the peak re-
`sponses as directed for Procedure: the relative standard deviation
`is not more than 2%.
`Procedure—Separately inject equal volumes (about 20 µL) of
`the Standard preparation and the Assay preparation into the
`chromatograph, record the chromatograms, and measure the
`responses. Calculate the quantity, in mg, of anhydrous theo-
`phylline in the portion of Capsule contents taken by the
`formula:
`
`0.25C(ru / rs)
`
`in which C is the concentration, in µg per mL, of USP Theo-
`phylline RS in the Standard preparation, and ru and rs are the
`peak responses obtained from the Assay preparation and the
`Standard preparation, respectively.
`
`Theophylline Extended-Release
`Capsules
`
`Theophyliine Extended-Release Capsules con-
`tain not less than 90.0 percent and not more
`than 110.0 percent of the labeled amount of an-
`hydrous theophylline (C,HgNaOz).
`Packaging and storag~Preserve in well-closed containers.
`Labeling—The labeling indicates whether the product is in-
`tended for dosing every 12 or 24 hours, and states with which
`in vitro Dissolution Test the product complies.
`USP Reference standards (11 ~
`USP Theophylline RS
`Identification—
`A: Transfer a quantity of Capsule contents, equivalent to
`about 100 mg of anhydrous theophylline, to a suitable conical
`flask. Add 150 ml of methanol, and sonicate until the insoluble
`material is dispersed into fine particles. Shake by mechanical
`means for 15 minutes, and filter into a 250-mL volumetric flask.
`Dilute with water to volume, and mix. Pipet 5 mL of this solu-
`tion into a 200-mL volumetric flask, dilute with 0.1 N hydro-
`chloric acid to volume, and mix: the UV absorption spectrum of
`the solution so obtained exhibits maxima and minima at the
`
`USP 35
`
`~
`
`U
`
`same wavelengths as that of a similar solution of USP Theophyl-
`line RS, concomitantly measured.
`B: The retention time of the major peak in the chromato-
`gram of the Assay preparation corresponds to that in the chro-
`matogram of the Standard preparation, as obtained in the gSSQy,
`Dissolution (711)—{NOTE—The following tests, which were as-
`signed numbers chronologically, are placed in groups corre-
`sponding to product dosing intervals. Thus, individual tests do
`not necessarily appear in numerical order.]
`FOR PRODUCES LABELED FOR DOSING EVERY 12 HOURS—
`TEsr t—If the product complies with this test, the labeling
`indicates that it meets USP Dissolution Test 1. Proceed as di-
`rected for Method B under Apparatus 1 and 2, Delayed-Release
`Dosage Forms, except to use Acceptance Table 2.
`Medium: pH 1.2 simulated gastric fluid (without pepsin)
`for the first hour; pH 6.0 phosphate buffer (see Buffer Solutions
`in the section Reagents, Indicators, and Solutions); 900 mL.
`Apparatus 2: 50 rpm.
`Procedure—Determine the amount of C,HeNaOz dissolved
`from UV absorbances at the wavelength of maximum absorb-
`ance at about 271 nm on filtered portions of the solution under
`test, diluted with Medium, if necessary, in comparison with a
`Standard solution having a known concentration of USP Theo-
`phylline RS in the same Medium.
`Times and Tolerances The percentage of the labeled amount
`of C,HsN,Oz dissolved at the times given conforms to Accep-
`tance Table 2.
`
`Time (hours)
`1
`2
`4
`6
`8
`
`Amount dissolved
`between 3% and 15°~
`between 20%and 40'Yo
`between 50% and 75%
`between 65% and 100%
`not less than 80%
`
`TEST z—If the product complies with this test, the labeling
`indicates that it meets USP Dissolution Test Z.
`pH 4.5 Phosphate buffer—Dissolve 6.8 g of monobasic potas-
`sium phosphate in 750 mL of water, mix, and dilute with water
`to 1000 mL. Adjust with either 1 N hydrochloric acid or 1 N
`sodium hydroxide to a pH of 4.5 ± 0.05.
`Medium: pH 4.5 Phosphate buffer,• 900 mL.
`Apparatus 2: 75 rpm.
`Procedure—Proceed as directed under Test 1.
`Times and Tolerances The percentages of the labeled
`amount of C,HaNaOz dissolved at the times specified conform
`to Acceptance Table 2.
`
`Time (hours)
`Amount dissolved
`1 between 10% and 30°~
`2 between 30°x6 and 55°r6
`4 between SSS'o and 80°x6
`8 not less than 80°x6
`
`TEsr 3—If the product complies with this test, the labeling
`indicates that it meets USP Dissolution Test 3. Proceed as di-
`rected for Method 8 under Apparatus 1 and 2, Delayed-Release
`Dosage Forms, except to use Acceptance Table 2.
`Medium: pH 1.2 simulated gastric fluid (without pepsin)
`for 1 hour; pH 7.5 simulated intestinal fluid (without enryme);
`900 mL.
`Apparatus 2: 50 rpm.
`Procedure—Proceed as directed under Test 1.
`Times and Tolerances—The percentage of the labeled amount
`of C,HsN40z dissolved at the times given conforms to Accep-
`tonce Table 2.
`
`ins
`rep
`Dc
`
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`tic
`0.~
`
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`a E
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`Page 4
`
`

`

`USP 35
`
`Official Monographs / Theophylline 4825
`
`Time (hours)
`1
`2
`3
`4
`7
`
`Amount dissolved
`between 1 °~b and 17%
`between 30% and 60%
`between 50% and 9046
`not less than 65%
`not less than 859%
`
`TEsr a-If the product complies with this test, the labeling
`indicates that it meets USP Dissolution Test 4. Proceed as di-
`rected for Method A under Apparatus 1 and 2, Delayed-Release
`Dosage Forms, except to use Acceptance Table 2.
`Medium: pH 3.0 phosphate buffer prepared by adjusting
`0.05 M potassium phosphate buffer with phosphoric acid to a
`pH of 3.0 ± 0.05, for the first 3'/z hours, followed by the addi-
`tion of 5.3 M sodium hydroxide to adjust to a pH of 7.4 ±
`0.05; 900 mL.
`Apparatus 2: 50 rpm.
`Procedure-Proceed as directed under Test 1.
`Times and Tolerances The .percentage of the labeled amount
`of C,HeN40z dissolved at the times given conforms to Accep-
`tance Table 2.
`
`Time (hours)
`1
`2
`3.5
`S
`
`Amount dissolved
`between 13% and 38%
`between 25% and 50%
`between 37~/o and 65%
`between 85%and 11 S%
`
`7E57 5-If the product complies with this test, the labeling
`indicates that it meets USP Dissolution Test 5.
`Medium, Apparatus, and Procedure-Proceed as directed
`under Test 4.
`Times and Tolerances-The percentage of the labeled amount
`of C,HsN40z dissolved at the times given conforms to Accep-
`tance Table 2.
`
`Amount dissolved
`Time (hours)
`1 between 10% and 30%
`between 30% and 60%
`3.5
`5 between 50% and 80°r6
`7 not less than 65%
`not less than 80%
`10
`
`TEsr 7-If the product complies with this test, the labeling
`indicates that it meets USP Dissolution Test 7.
`Phosphate buffer-Dissolve 40.8 g of monobasic potassium
`phosphate in 6 L of water, add 667 mg of octoxynol 9, mix,
`and adjust with dilute hydrochloric acid or sodium hydroxide to
`a pH of 4.5.
`Medium: Phosphate buffer,• 900 mL.
`Apparatus 2: 50 rpm.
`Procedure-Proceed as directed under Test 1.
`Times and Tolerances-The percentages of the labeled
`amount of C,HeN40z dissolved at the times specified conform
`to Acceptance Table 2.
`
`Amount dissolved
`Time (hours)
`1 between 10% and 40%
`2 between 35% and 70%
`4 between 60°x6 and 90%
`8 not less than 85%
`
`TEST s-If the product complies with this test, the labeling
`indicates that it meetr USP Dissolution Test 8.
`Medium: pH 7.5 simulated intestinal fluid (without en-
`zyme); 900 mL.
`
`Apparatus 1: 100 rpm.
`Procedure-Proceed as directed under Test 1.
`Times and Tolerances-The percentages of labeled amount of
`C,HsN40z dissolved at the times specified conform to Accep-
`tance Table 2.
`
`Time (hours)
`1
`2
`4
`6
`8
`
`Amount dissolved
`between 3% and 30°rb
`between 15% and SO%
`between 45% and 80%
`not less than 70%
`not less than 85°r6
`
`rEsr 9-If the product complies with this test, the labeling
`indicates that it meets USP Dissolution Test 9.
`Medium 1: 0.1 N hydrochloric acid; 900 mL.
`Medium 2: simulated intestinal fluid (without enryme);
`900 mL.
`Apparatus 1: 50 rpm.
`Determine the amount of theophylline dissolved at the times
`specified, using Medium 1 for the first hour and Medium 2 for
`the next five hours.
`Procedure-Proceed as directed under Test 1.
`Times and Tolerances The percentage of the labeled amount
`of C,HaNaOz dissolved at the times given conforms to Accep-
`tance Table 2.
`
`Time (hours)
`1
`2
`3
`4
`6
`
`Amount dissolved
`between 5% and 15%
`between 25°r6 and 45%
`between 50% and 65%
`not less than 70%
`not less than 85%
`
`TEsr ~o-If the product complies with this test, the labeling
`indicates that it meets USP Dissolution Test 10. Proceed as di-
`rected for Testa.
`Times and Tolerances-The percentage of the labeled amount
`of C,HaNaOz dissolved at the times given conforms to Accep-
`tonce Table 2.
`
`Time (hours)
`1
`2
`4
`8
`
`Amount dissolved
`between 6% and 27%
`between 25% and 50%
`between 65% and 85%
`not less than 80%
`
`FOR PRODUCES LABELED FOR DOSING EVERY 24 HOURS-
`TEST 6-If the product complies with this test, the labeling
`indicates that it meets USP Dissolution Test 6.
`Medium: 0.05 M pH 6.6 phosphate buffer (see Buffer Solu-
`tions in the section Reagents, Indicators, and Solutions); 1000
`mL.
`Apparatus 1: 100 rpm.
`Procedure-Proceed as directed under Test 1.
`Times and Tolerances-The percentages of the labeled
`amount of C,HBN40z dissolved at the times specified conform
`to Acceptance Table 2.
`
`Time (hours)
`1
`2
`4
`5
`8
`
`Amount dissolved
`between 5% and 15%
`between 12% and 30°x6
`between 25% and 50°x6
`between 30% and 60%
`between 55% and 75%
`
`Page 5
`
`

`

`4826 Theophylline /Official Monographs
`
`USP 3
`
`L
`
`Uniformity of dosage units (905): meet the requirements.
`Procedure for content uniformity—Using a mortar and pestle,
`triturate the contents of 1 Capsule with 20 mL of water. With
`the aid of water, transfer the mixture to a 100-mL volumetric
`flask. Add 25 mL of 6 N ammonium hydroxide, shake or soni-
`cate for about 45 minutes, and cool to room temperature. Di-
`lute with water to volume, and mix. Filter a portion of the
`mixture, discarding the first 20 mL of the filtrate. Dilute a por-
`tion of the filtrate quantitatively, and stepwise if necessary, with
`water to obtain a solution containing about 12 µg of theophyl-
`line per mL. Concomitantly determine the absorbances of this
`solution and a Standard solution of USP Theophylline RS, simi-
`larly prepared, having a known concentration of about 12 µg
`per mL, in 1-cm cells, at the wavelength of maximum absorb-
`ance at about 270 nm, with a suitable spectrophotometer, us-
`ing water as the blank. Calculate the quantity, in mg, of
`C,HsNaOz in the Capsule taken by the formula:
`
`(TC / D)(Au l As)
`
`in which T is the labeled quantity, in mg, of theophylline in the
`Capsule; C is the concentration, in µg per mL, of USP Theophyl-
`line RS in the Standard solution; D is the concentration, in µg
`per mL, of theophylline in the solution from the Capsule, based
`on the labeled quantity per Capsule and the extent of dilution;
`and A„ and AS are the absorbances of the solution from the
`Capsule and the Standard solution, respectively.
`Assay—
`Buffer solution, Mobile phase, Internal standard solution, and
`Standard preparation—Prepare as directed in the Assay under
`Theophylline.
`Assay preparation~uantitatively transfer the contents of 10
`Capsules to a 500-mL volumetric flask, and add 100 mL of
`water and 50 mL of 6 N ammonium hydroxide. Heat on a hot
`plate, with occasional stirring, just to boiling. Remove from the
`hot plate, and sonicate for about 1 minute while still hot. Cool
`to room temperature, dilute with water to volume, mix, and
`centrifuge. Transfer an accurately measured aliquot portion of
`this concentrate, equivalent to about 10 mg of theophylline, to
`a 100-mL volumetric flask. Add 20.0 mL of Internal standard
`solution, dilute with Mobile phase to volume, and mix.
`Chromatographic system—Proceed as directed in the Assay
`under Theophylline, except for flow rate, which may be 1.0 to
`2.0 mL per minute.
`Procedure—Proceed as directed for Procedure in the Assay
`under Theophylline. Calculate the quantity, in mg, of C,HeNaOz
`per Capsule taken by the formula:
`
`5000(C / l~(Ru / Rs)
`
`in which C is the concentration, in mg per mL, of USP Theo-
`phylline RS in the Standard preparation; V is the volume, in mL,
`of concentrate taken for the Assay preparation; and Ru and Rs
`are the response ratios of the theophylline peak to the internal
`standard peak obtained from the Assay preparation and the
`Standard preparation, respectively.
`
`Theophylline Oral Solution
`
`Theophylline Oral Solution contains not less
`than 95.0 percent and not more than 105.0 per-
`cent of theophylline (C,H8N402).
`Packaging and storage—Preserve in tight, light-resistant
`containers, and avoid exposure to excessive heat.
`Labeling—Label it to indicate the alcohol content (if present).
`
`USP Reference standards (11)—
`USP Theophylline RS
`
`i
`
`a mixture of chloroform, meth;,
`
`Identification—
`A: Thin-Layer Chromatographic Identification Test (201)—
`Test solution Transfer a portion of Oral Solution, equivalent
`to about 100 mg of theophylline, to a reparatory funnel. Ex- ~
`tract with two 25-mL portions of chloroform, collecting the ex-
`tracts in a 100-mL volumetric flask. Dilute with methanol to
`volume, and mix.
`Standard solution—Prepare a solution of USP Theophylline Its
`in methanol containing about 1 mg per mL.
`Application volume: 20 µL.
`Developing solvent system:
`anol, and acetic acid (89:10:1).
`Procedure~pply the Standard solution and the Test solution;
`as directed in the chapter, and dry the plate in a current of
`~`
`cool air. Place the plate in a suitable chromatographic chamber
`lined with filter paper and previously equilibrated with the De-
`veloping solvent system. Upon removing the plate from the
`chamber, dry with a current of warm air in a suitable hood.
`B: The retention time of the major peak in the chromato-
`gram of the Assay preparation corresponds to that in the chro-
`matogram of the Standard preparation, as obtained in the Assoc;
`Microbial enumeration tests (61) and Tests for specified''
`microorganisms (62~It meets the requirements of the tests
`for absence of Salmonella species and Escherichia coli. The total
`aerobic microbial count does not exceed 100 cFu per mL, and
`the total combined molds and yeasts count does not exceed SQ
`cfu per mL.
`pH (791):
`between 4.3 and 4.7.
`Alcohol content, Method II (611) (if present):
`between
`90.0% and 115.0% of the labeled amount of CzH50H is found,•,
`using acetone as the internal standard.
`Assay—
`Mobile phase—Prepare a filtered and degassed mixture of
`water, methanol, and acetic acid (76.5:22.5:1) containing 200.
`mg of sodium 1-octanesulfonate in each 1000 mL of solution. ,
`Make adjustments if necessary (see System Suitability under
`Chromatography (621)).
`System suitability preparation—Dissolve accurately weighed
`quantities of USP Theophylline RS and caffeine in water to
`obtain a solution containing about 0.68 mg of each per mL.
`Standard preparation—Dissolve an accurately weighed quan-
`tity of USP Theophylline RS in water to obtain a solution having
`a known concentration of about 0.68 mg per ml.
`Assay preparation Transfer an accurately measured volume
`of Oral Solution, equivalent to about 68 mg of theophylline, to
`a 100-mL volumetric flask. Dilute with water to volume, and
`mix.
`Chromatographic system (see Chromatography (621)~The
`liquid chromatograph is equipped with a 254-nm detector and
`a 4.0-mm x 30-cm column that contains packing Ll .The flow
`rate is about 2.0 mL per minute. Chromatograph the System
`suitability preparation, and record the peak responses as directed
`for Procedure: the relative retention times are about 0.6 for the-
`ophylline and 1.0 for caffeine; the resolution, R, between theo-
`phylline and caffeine is not less than 2.0; the tailing factor is
`not more than 2; and the relative standard deviation for repli-
`cate injections is not more than 2.0%.
`Procedure—Separately inject equal volumes (about 10µL) of
`the Standard preparation and the Assay preparation into the
`chromatograph, record the chromatograms, and measure the
`responses for the major peaks. Calculate the quantity, in mg, ofi+
`theophylline (C,HsNaOZ) in the portion of Oral Solution taken
`by the formula:
`
`y
`
`3
`
`i ooc~r~ / rs~
`in which C is the concentration, in mg per mL, of USP Theo-
`phylline RS in the Standard preparation; and r~ and rs are the
`peak responses obtained from the Assay preparation and the
`Standard preparation, respectively.
`
`Page 6
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