U.S. Pharmacopeia National Formulary 2018: USP 41 NF

1339 Pages·2018·480.7 MB·English

by  The United States Pharmacopeial Convention

2018
N F 36 THE NATIONAL FORMULARY
Volume 3
By authority of the United States Pharmacopeial Convention
Prepared by the Council of Experts and its Expert Committees
Official from May 1, 2018
The designation on the cover of this publication, “USP NF 2018,” is for ease of
identification only. The publication contains two separate compendia: The United
oars Pharmacopeia, Forty-First Revision, and The National Formulary, Thirty-Sixth
Edition.
THE UNITED STATES PHARMACOPEIAL CONVENTION
12601 Twinbrook Parkway, Rockville, MD 20852

USP 41| THE UNITED STATES PHARMACOPEIA
SIX-MONTH IMPLEMENTATION GUIDELINE
The United States Pharmacopeia—National Formulary and its supplements become official six months after being released to
the public. The USP-NF, whic is released on November 1 of each year, becomes official on May 1 of the following year. This
six-month implementation timing gives users more time to bring their methods and proceduresinto compliance with new
and revised USP-NF requirements.
The table below describes the official dates of the USP-NF and its supplements. The 2017 USP 40-NF 35, and its supple-
ments, Interim Revision Announcements (IRAs) and Revision Bulletins to that edition, will be official until May 1, 2018, at which
time the USP 41—-NF 36 becomes official.

Publication Release Date Official Date Official Until

USP41-NF 36 November 1, 2017 May 1, 2018 May 1, 2019 (except as superseded by supplements, /RAs, and
Revision Bulletins)

First Supplement to the February 1, 2018 August 1, 2018 May 1, 2019 (except as superseded by Second Supplement, IRAs,
USP 41-NF 36 and Revision Bulletins)

Second Supplement to the June 1, 2018 December 1, 2018 May 1, 2019 (except as superseded by /RAs and Revision Bulletins)
USP 41-NF 36

USP42-NF 37 November 1, 2018 May 1, 2019 May 1, 2020 (except as superseded by supplements, /RAs, and
Revision Bulletins)

Thetable below gives the details of the /RAs that will apply to USP 41—-NF 36,

IRA. PF Posting Date Comment Due Date IRA Posting Date IRA Official Date

4401) January 2, 2018 March 31, 2018 May 25, 2018 july 1, 2018

44(2) March 1, 2018 May 31, 2018 July 27, 2018 September 1, 2018

44(3) May 1, 2018 july 31, 2018 September 28, 2018 November 1, 2018

44(4) July 2, 2018 September 30, 2018 November 23, 2018 Januar1y, 2019

44(5) Septembe4r, 2018 November 30, 2018 January 25, 2019 March 1, 2019

44(6) November 1, 2018 January 31, 2019 March 29, 2019 May 1, 2019

Revision Bulletins published on the USP website become official on the date specified in the Revision Bulletin.
NOTICE AND WARNING
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.
Copyright © 2017 The United States Pharmacopeial Convention 12601 Twinbrook Parkway, Rockville, MD 20852
All rights reserved.
ISSN: 0195-7996
ISBN: 978-1-936424-70-2
Printed in the United States by United Book Press, Inc., Baltimore, MD
Concerning U.S. Patent or Trademark Rights—The inclusion in The United States Pharmacopeia or in the National Formulary of a
monograph on any drug in respect to which patent or trademark rights may exist shall not be deemed, and is not intended
as, a grant of, or authority to exercise, any right or privilege protected by such patent or trademark. All such rights and
privileges are vested in the patent or trademark owner, and no other person may exercise the same without express
permission, authority, or license secured from such patent or trademark owner.
USP 41-NF 36 Contents iii

Contents
VOLUME 1 Guide to General Chapters .......... 13

USP 41
Mission Statement and Preface...... vii

People 2015-2020 Revision Cycle ..... xi Monographs
Officers «ss iss 4 104 saweweemesmeenavteeaee xi Official Monographs for USP 41, A-l......... 19

Board (Of Trustees«a's ow sxscmssnsienmoMnsEatWtew9y xi
COUNEII OF EXPerts:.. 2. ncinaincomveaycrsaairnat,lwse xi Index
FADGIE COMINITEES (5oe ccmereee6r4nmamarS xii Combined Index to USP 41 and NF 36....... I-1
In Memoriam 1... 0.0... ceceee xviii
Members of the United States
VOLUME 2
Pharmacopeial Convention,
as of May 31, 2017................ xix

2016 Recognition of Monograph
and Reference Material Donors ... xxvi Notices

General Notices and Requirements ........... ix
Articles of Incorporation . xvi
USP Governance ................... xxix
Guide to General Chapters .......... xix
Bylaws 2.6... eee ees xxix

Rules and Procedures .............-.000- xxix
Monographs
USP Policies: «2s 44.4 2 2 ¢%'s B92 paaethtandllinals Xxix
Official Monographs for USP 41, J-Z....... 2303

Admissions .....................055 Xxxiii
Index
Articles Admitted to USP 47 by
SUDPIEMIENE,cnn cee ene ee ee ee a wo ieeneiassenns xxxiii Combined Index to USP 47 and NF 36....... I-1
New Articles Appearing in USP 47 That Were Not
Included in USP 40 Including
Supplements 0 ce svcev54sssesaeR3ey XXxiv VOLUME 3
Articles Included in USP 40 But Not

Included in USP 47 2.0... cece eee nee XXxiV
Annotated List. sci css eeecssaeaassssawe XXXVi Notices

General Notices and Requirements ........... ix

Notices
General Notices and Requirements ........... 3 Guide to General Chapters .......... xix
iv Contents USP 41-NF 36
Global Health SOWWUONS: ss sweeekemReeaLbeabansa4gae 5748
Official Monographs ................00. 4415 Butler SolWHONS vcvwowwew erences es auas 5748

Colorimetric Solutions ..............-. 5749
Dietary Supplements Test SOlUHONS accyeeceewegeeeryeusaeas 5750
Official Monographs’ s iu. ss eis cease enemys 4417 Volumetric Solutions ..............005 5761
Chromatographic Columns.............. 5774
NF 36

Reference Tables
Containers for Dispensing Capsules and
Admissions
Tablets... eeeeee eee 5781
Articles Admitted to NF 36 by Supplement .. 5167
Description and Relative Solubility of USP
New Articles Appearing in NF 36 That Were Not and NF AMIGIES! sis¢ecconygcoaaaEyRs 5791
Included in NF 35 Including
Approximate Solubilities of USP and
Supplements ........ 000-00. e eee 5167
NF Articles... 0... cece 5851
New Articles Appearing in NF 36 ......... 5167
Atomic Weights cuqwadeesbesseescede 5859
Annotated List o oo.¢ ean ws ane a svicacwmesnnaes 5168
Half-Lives of Selected Radionuclides ....... 5860

Alcoholometric Table...............0005 5861
Excipients
Intrinsic Viscosity Table ..............04. 5863
USP and NF Excipients, Listed by

CAMQOOIY «seu eeu s e485 8s semeewRwee¢ 5169

General Chapters
Monographs See page xix for detailed contents
Official Monographs for NF 36 ........... 5179 General Tests and Assays..............45 5915

General Requirements for Tests and Assays .. 5915
Index
Apparatus for Tests and Assays ........... 5954
Combined Index to USP 41 and NF 36....... I-1
Microbiological Tests « so cosewsisGu.sssens 5959
Biological Tests and Assays .............. 5991
VOLUME 4 Chemical Tests and Assays ............-. 6094
Physical Tests and Determinations......... 6327

Notices
Index
General Notices and Requirements ........... ix
Combined Index to USP 41 and NF 36....... 1-1

Guide to General Chapters .......... xix

VOLUME 5
Reagents, Indicators, and

Solutions ....................00-
Notices
Reagent Specifications...............005 5664
General Notices and Requirements ........... ix
Indicators and Indicator Test Papers ....... 5745
USP 41-NF 36 Contents v
am]
7
Guide to General Chapters ..........xix Dietary Supplements.............-.0005 8153 $

=
General Chapters Index 2
See page 63 for detailed contents Combined Index to USP 47 and NF 36....... 1 a
General Information ................000. 6699
USP 41 General Notices vii

General Notices and
Requirements
Applying to Standards, Tests,
Assays, and Other Specifications
of the United States Pharmacopeia
1. Title and Revision....................... ix 6.50. Preparation of Solutions ................8. xiv
£200, Units Necessary to Complete a Test ......... xiv
70. WUSincecene «uae oo en MemREEO6NaECTAF i
2. Official Status and Legal 680: Equipment 2222220xiv
Reco ne AGS TB GAG + eeanene 2 « comme # © omnes ww ix
2.10. Official Text... 22.2... eee eee ix
2.20. Official Articles . 2... 0... ccc eee eee eee ix 7 Ae etanee Requirements comeueaa sees OF
2.30. Legal RECOQNIBION) w.00 06 ee a ee warneaado ix 7:20. Rounding Rules.....0.0.2c.--ll-l., sa
3. Conformance to Standards............. ix —
3.10. ppplcgeileg Of Standards « «2 «x aexcowver46ai%g& ix 8. eanie eeeDet ineithons iE 2 SUH Ao beled 2 nv
3.20. Indicating Conformance..............00005 x 820. About ........
8.30. Alcohol Content
4. Monographs and General Chapters .... xi 8.40. Atomic Weights
4.10. Monographs ...... 2.0.ce0ee.ee.e.ee xi 8.50. Blank Determinations ..............00005 xv
4.20. General Chapters... 0... 0.0.eee0ee.ee0e xi 8.60, Concomitantly «sss en 22 eeoenmems9e02yes xvi
8.70. Desiccator ... i
5. Monograph Components ............... ect aeeit :
5.10. Molecular Formula... ........ 0200000000. 8.100Nel “ol aa
5.20. Added Substances ......0.00.0.es.ea.s 3.110. NUM
5.30. Description and Solubility. ..............4. 3.120. Odor -
S-A0. Identificationinns. «.35 6 i naa osepee9 6noee 8.130. Percent...
BBO. ASSAY, woro342n31e3,8n§Heeaens 8.140.Pe “ hE ge Concenttations...........0200. ;
5.60. Impurities and Foreign Substances 3.150.Pressure CNCCNMSUCNS etsrEEGeRTeEEY “v
5.70. Performance Tests .. 0... 0... eee eee eee iii 3.160.Re ton Tine ccc teea
5.80. USP Reference Standards ........ ......00. iii rag R eece rcp © FH EN sian ae aa ene ey aM
8.170. Specific Gravity... 0... ee eeexvi
8.180. Temperatures 1... eee eeexvi
6. Testing Practices and Procedures ..... xiii 8.190. Time... i
6.10. Safe Laboratory Practices .........-...000.xiii 8.200. Transfer. . .
6.20. Automated Procedures. ..........-..0.00.xiii 8.210. Vacuum
6.30. Alternative and Harmonized Methods and 8.220. Vacuum Desiccator ..............-00005 xvi
Procedures:s.< <3 24274 cuswmebeeedaeeessxiii 8.230. Water 2... ee eee xvi
6.40. Dried, Anhydrous, Ignited, or Solvent- 8.240. Weights and Measures ............0.0005 xvi
Free Basis... 2... eeeeeeeexiii

cepIbtNeM SELICID)
viii General Notices USP 41
9. Prescribing and Dispensing............ xvi 10. Preservation, Packaging, Storage,

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9.10 Use of Metric Units... 2. eeeeeu ea eee anes xvii and Labeling ........................
9.20 Changes in Volume.... 0.2.c0ec6eee.eeexviii 10.10, Packaging and Storage a .
10.20. Labeling»... 2... 2. eee ee eee eee
USP 41 General Notices ix
The General Notices and Requirements section (the General USB flash drive versions of USP-NF. These versions also are
Notices) presents the basic assumptions, definitions, and de- superseded by Accelerated Revisions as described above.
fault conditions for the interpretation and application of the In the event of anyclisparity between the print or USB
United States Pharmacopeia(USP) and the National Formulary flash drive versions and the USP-NF Online, the USP-NF On-
(NF). line will be deemed to apply.
Requirements stated in these General Notices apply to all 2.20. Official Articles
articles recognized in the USP and NF (the “compendia”) An official article is an article that is recognized in USP or
and to all general chapters unless specifically stated NF. An article is deemed to be recognized and included in a
otherwise. compendium when a monograph for the article is published
1. TITLE AND REVISION in the compendium and an official date is generally or spe-
The full title of this publication (consisting of five volumes cifically assigned to the monograph.
and including its Supplements), is The Pharmacopeia of the The title specified in a monograph is the official title for
United States of America, Forty-First Revision and the Na- such article. Other names considered to be synonyms of the
tional Formulary, Thirty-Sixth Edition. These titles may be ab- official titles may not be used as substitutes for official titles.
breviated to USP 41, to NF 36, and to USP 41-NF 36. The Official articles include both official substances and official
United States Pharmacopeia, Forty-First Revision, and the Na- products. An official substance is a drug substance, excipient,
tional Formulary, Thirty-Sixth Edition, supersede all earlier re- dietary ingredient, other ingredient, or component ofa fin-
visions. Where the terms “USP,” “NF,” or “USP—NF’ are used ished device for which the monograph title includes no indi-
without further qualification during the period in which cation of the nature of the finished form.
these compendia are official, they refer only to USP 41, NF An official product is a drug product, dietary supplement,
36, and any Supplement(s) thereto. The same titles, with no compounded preparation, or finished device for which a
further distinction, apply equally to print or electronic pres- monograph is provided.
entation of these contents. Although USP and NF are pub- 2.30. Legal Recognition
lished under one cover and share these General Notices, they The USP and NF are recognized in the laws and regula-
are separate compendia. tions of many countries throughout the world. Regulatory
This revision is official beginning May 1, 2018 unless oth- authorities may enforce the standards presented in the USP
erwise indicated in specific text. and NF, but because recognition of the USP and NF may
Supplements to USP and NF are published periodically. vary by country, users should understand applicable laws
Accelerated Revisions, published periodically on the Offi- and regulations. In the United States under the Federal
cial Text section of USP’s website (http://www.usp.org/usp- Food, DruG), and Cosmetic Act (FDCA), both USP and NF are
nf/official-text), are designed to make revisions official more recognized as official compendia. A drug with a name rec-
quickly than through the routine process for publishing ognized in USP-NF must comply with compendial identit
standards in the USP-NF. Interim Revision Announcements are standards or be deemed adulterated, misbranded, or both.
Accelerated Revisions to USP and NF that contain official re- See, eg FDCA § 501(b) and 502(e)(3)(b); also FDA regula-
visions and their effective dates. tions, 21 CFR § 299.5(a&b). To avoid being deemed
Revision Bulletins are Accelerated Revisions to official text adulterated, such drugs must also comply with compendial
or postponements that require expedited publication. They standards for strength, quality, and purity, unless labeled to
generally are official immediately unless otherwise specified show all respects in which the drug differs. See, e.g., FDCA
in the Revision Bulletin. § 501(b) and 21 CFR § 299.5(c). In addition, to avoid being
Errata are Accelerated Revisions representing corrections deemed misbranded, drugs recognized in USP-NF must also
to items erroneously published. Announcements of the avail- be packaged and labeled in compliance with compendial
ability of new USP Reference Standards and announcements standards. See FDCA § 502(g).
of tests or procedures that are held in abeyance pending A dietary supplement represented as conforming to speci-
availability of required USP Reference Standards are also fications in USP will be deemed a misbranded food if it fails
available on the “Official Text” tab of USP’s website. to so conform. See FDCA § 403(s)(2)(D).
2. OFFICIAL STATUS AND LEGAL RECOGNITION Enforcement of USP standards is the responsibility of FDA
2.10. Official Text and other government authorities in the U.S. and elsewhere.
Official text of the USP and NF is published in the USP-NF USP has no role in enforcement.
Online (www.uspnf.com) in the edition identified as “CUR-
RENTLY OFFICIAL” and in Accelerated Revisions that super-
Change to read:
sede the USP-NF Online as described below.
Routine revisions are published in the USP-NF Online and
3. CONFORMANCE TO STANDARDS
become official on the date indicated, usually six months
after publication. Accelerated Revisions supersede the 3.10. Applicability of Standards
USP-NF Online and become official on the date indicated. Standards for an article recognized in the compendia
Links to Accelerated Revisions on the USP website can be (USP-NF) are expressed in the article’s monograph, applica-
found in any superseded monograph or general chapter in ble general chapters, and General Notices. The identity,
the USP-NF Online. strength, quality, and purity of an article are determined by
Print and USB flash drive versions of the USP and NF also the official tests, procedures, and acceptance criteria, and
are available. Routine revisions are provided with the same other requirements incorporated in the monograph, in ap-
timing as the USP-NF Online. Official text published in Sup- plicable general chapters, or in the General Notices. “Appli-
plements supersedes that in the previously published print or cable general chapters” means general chapters numbered

PEPENM SEIU ID)
GENERAL NOTICES AND
REQUIREMENTS
x General Notices USP 41
below 1000 or above 2000 that are made applicable to an 3.10.10. Applicability of Standards to Drug Products,
article through reference in General Notices, a monograph, Drug Substances, and Excipients
or another applicable general chapter numbered below The applicable USP or NF standard applies to any article
1000. Where the requirements of a monograph differ from marketed in the United States that (1) is recognized in the
the requirements specified in these General Notices or an compendium and (2) is intended or labeled for use as a
applicable general chapter, the monograph requirements drug or as an ingredient in a drug. Such articles (drug prod-
apply and supersede the requirements of the General Notices ucts, drug substances, and excipients) include both human
or applicable general chapters, whether or not the mono- drugs (whether dispensed by prescription, “over the
graph explicitly states the difference. counter,” or otherwise), as well as animal drugs. The appli-
General chapters numbered 1000 to 1999 are for infor- cable standard applies to such articles whether or not the
mational purposes only. They contain no mandatory tests, added designation “USP” or “NF” is used. The standards
ww assays, or other requirements applicable to any official arti- apply equally to articles bearing the official titles or names
C7
cle, regardless of citation in a general chapter numbered derived by transposition of the definitive words of official
Ro
=] below 1000, a monograph, or these General Notices. Gen- titles or transposition in the order of the names of two or
°
eral chapters numbered above 2000 apply only to articles more 4drug substancesausrs; in official titles, or where there
ra
that are intended for use as dietary ingredients and dietary is use of synonyms with the intent or effect of suggesting a
3 supplements. General chapter citations in NF monographs significant degree of identity with the official title or name.
-
v refer to USP general chapters. 3.10.20. Applicability of Standards to Medical Devices,
= Early adoption of revised standards in advance of the offi-
Dietary Supplements, and Their Components and
Vv
cial date is allowed by USP unless specified otherwise at the Ingredients
fe)
time of publication. Where revised standards for anexisting An article recognized in USP or NF shall comply with the
article have been published as final approved “official text” compendial standards if the article is a medical devter com-
(as approved in section 2.10 Official Text) but have not yet ponent intended for a medical device, dietary supplement,
reached the official date (six months after publication, un- dietary ingredient, or other ingredient that is intended for
less otherwise specified; see “official date”, section 2.20. Of- incorporation into a dietary supplement, and is labeled as
ficial Articles), compliance with the revised standard shall not conforming to the USP or NF.
preclude a finding or indication of conformance with com- Generally, dietary supplements are prepared from ingredi-
pendial standards, unless USP specifies otherwise by prohib- ents that meet USP, NF, or Food Chemicals Codex standards.
iting early adoption in a particular standard. Where such standards do not exist, substances may be used
The standards in the relevant monograph, general chap- in dietary supplements if they have been shown to be of
ter(s), and General Notices apply at all times in the life of the acceptable food grade quality using other suitable
article from production to expiration. It is also noted that procedures.
the manufacturer’s specifications, and manufacturing prac-
3.10.30. Applicability of Standards to the Practice of
tices (e.g., Quality by Design, Process Analytical Technology,
Compounding (New)
and Real Time Release Testing initiatives), generally are fol-
USP compounding practice standards, Pharmaceutical
lowed to ensure that the article will comply with com-
Compounding—Nonsterile Preparations (795) and Pharmaceu-
pendial standards until its expiration date, when stored as
tical Compounding—Sterile Preparations (797), as appropriate,
directed. Every compendial article in commerce shall be so
apply to compounding practice or activity regardless of
constituted that when examined in accordance with these
whether a monograph exists for the compounded prepara-
assays and test procedures, it meets all applicable pharma-
tion or these chapters are referenced in such a monograph.
copeial requirements (General Notices, monographs, and
In the United States, (795) and (797) are not applicable to
general chapters). Thus, any official article is expected to
drugs compounded by entities registered with FDA as out-
meet the compendial standards if tested, and any official
sourcing facilities as definedty FDCA § 503B, because such
article actually tested as directed in the relevant monograph
facilities are required to comply with FDA’s current good
must meet such standards to demonstrate compliance.
manufacturing practice requirements.pent te prepa-
Some tests, such as those for Dissolution and Uniformity of
rations, including drug products compounded by outsourc-
Dosage Units, require multiple dosage units in conjunction
ing facilities, may also be subject to applicable monographs;
with a decision scheme. These tests, albeit using a number
see section 2.20 Official Articles and section 4.10
of dosage units, are in fact one determination. These proce-
Monographs.
dures should not be confused with statistical sampling
3.20. Indicating Conformance
plans. The similarity to statistical procedures may seem to
A drug product, drug substance, or excipient may use the
suggest an intent to make inference to some larger group of
designation “USP” or “NF” in conjunction with its official
units, but in all cases, statements about whether the com-
title or elsewhere on the label only when (1) a monograph
pendial standard is met apply only to the units tested. Re-
is provided in the specified compendium and (2) the article
peats, replicates, statistical rejection of outliers, or extrapola-
complies with the identity prescribed in the specified
tions of results to larger populations, as well as the necessity
compendium.
and appropriate requency of batch testing, are neither
When a drug product, drug substance, compounded
specified nor proscribed by the compendia; such decisions
preparation, or excipient differs from the relevant USP or NF
are based on the objectives of the testing. Frequency of
standard of strength, quality, or purity, as determined by
testing and sampling are left to the preferences or direction
the application of the tests, procedures, and acceptance cri-
of those performing compliance testing, and other users of
teria set forth in the relevant compendium, its difference
USP-NF, including manufacturers, buyers, or regulatory
shall be plainly stated on its label.
authorities.
When a drug product, drug substance, compounded
Official products are prepared according to recognized
preparation, or excipient fails to comply with the identity
prne/ples of good manufacturing practice and from ingredi-
prescribed in USP or NF or contains an added substance that
ents that meet USP or NF standards, where standards for
interferes with the prescribed tests and procedures, the arti-
such ingredients exist (for dietary supplements, see section
cle shall be designated by a name that is clearly distinguish-
3.10.20 Applicability of Standards to Medical Devices, Dietary
ing and differentiating from any name recognized in USP or
Supplements, and Their Components and Ingredients).
NF.
Official substances apepaed according to recognized
A medical device, dietary supplement, or ingredient or
principles of good manufacturing practice and from ingredi-
component of a medicaldevice or dietary supplement may
ents complying with specifications designed to ensure that
use the designation “USP” or “NF” in conjunction with its
the resultant substances meet the requirements of the com-
official title or elsewhere on the label only when (1) a mon-
pendial monographs.
ograph is provided in the specified compendium and (2)