Declaration of Pamela Lipscomb on Authentication of Publication
`
`1.
`
`1, Pamela Lipscomb, am a librarian, and the Director of Library and
`
`Research Services at Arent Fox LLP, located at 1717 K Street NW, Washington, DC
`
`20006—5344.
`
`1 have worked as a librarian at Arent Fox since 1994. Through the course
`
`of my employment, I have become well informed about the operations of the Arent Fox
`
`library system, which follows standard library practices.
`
`2.
`
`This Declaration relates to the dates of receipt and availability of the
`
`following: United States Pharmacopeia and National Formulary (USP 36-NF 31)
`
`Vol 1. (2013).
`
`3.
`
`Standard 0 era tin
`
`racedares or materials at Arent Fax LLP Libraries.
`
`When a reference is received by the Library, it is checked in, added to library holdings
`
`records, and made available to readers as soon after its arrival as possible. The
`
`procedure normally took a few days or at most 2 to 3 weeks.
`
`4.
`
`Exhibit A to this Declaration is true and correct copy of the cover, USP
`
`Authenticity Certificate, and copyright pages of United States Pharmacopeia and
`
`National Formulary (USP 36-NF 31) Vol 1. (2013) from Arent Fox’s collection.
`
`Exhibit A also includes an excerpt of pages 54 to 55 and 930 to 933 of that volume,
`
`showing the chapters entitled <51> Antimicrobial Efleciiveness Testing and <1191>
`
`Siabiiiifv Considerations in Dispensing Practice.
`
`5.
`
`Exhibit B to this Declaration is a true and correct copy of the accounting
`
`system record for check number 1 17519 for payment to the United States Pharmacopeia
`
`Nalox1066
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`Page 1 of 14
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`

`

`Declaration of Pamela Lipscomb on Authentication of Publication
`
`Convention, Inc. for the United States Pharmacopeia and National Formulary (USP 36-
`
`NF 31) Vol 1. (2013) ordered for the Arent Fox Library by my staff in September 2012.
`
`6.
`
`Exhibit C to this Declaration is a true and correct copy of the cataloguing
`
`system record of the Arent Fox Library for its copy of the United States Pharmacopeia
`
`and National Formulary (USP 36-NF 31) Vol I. (2013). As shown in the “Date” field of
`
`this Exhibit (highlighted in yellow), Arent Fox’s Library owned this book and had it
`
`catalogued in the system as of November 28, 2012.
`
`7.
`
`Based on the information in Exhibit C, it is clear that the volume was
`
`received by the library shortly after September 1 l, 2012, catalogued, and available to
`
`library patrons on or before November 28, 2012.
`
`8.
`
`I declare that all statements made herein of my own knowledge are true and
`
`that all statements made on information and belief are believed to be true; and further
`
`that these statements were made with the knowledge that willful false statements and the
`
`like so made are punishable by fine or imprisonment, or both, under Section 1001 of
`
`Title 18 of the United States Code.
`
`Date: December 18, 2018
`
`(\L’Q
`
`Arent Fox LLP
`1717 K Street NW
`
`Washington, DC 20006—5344
`
`Pamela Lipscomb
`Director of Library and Research Services
`
`Nalox1066
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`Nalox—l Pharmaceuticals, LLC
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`Page 2 of 14
`
`

`

`
`
`
`
`2013
`
`
`
`USP 36
`
`NF 31
`
`
`
`LLB. Pharmacopeia
`
`National Formulary
`
`
`
`Volume ’I
`
`- General Notices
`- FrontMatter
`TableofContents
`
`
`Generakchirpters'ffit
`
`' GenerafChaptETS -
`
`ReferenceTables
`
`- DietarySupplements
`
`o NFMonographs
`
`Combined Index
`
`SP U5. PHARMACOPEIA
`U re The Standard onuaJ'ii‘ys'“
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`

`__ _ a,_ a..."
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`AU IIIENI ICITY EEIIEIIIIEJ‘EI
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`“USP us. PHARMACOPEIA
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`”‘9 s"G'ITCIIQII‘I:I GI Qua-III? 3”
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`2m 3
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`Volume 1
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`
`USP 36 me WEED STATES pHAamameeaa
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`
`
`—Ir...__.—_-=.a..—......._
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`”31% NAVIONAL FORMULARY
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`By authority 0! the United States Pnornmcoper'of Convention
`Prepared by the Councit of Experts and Its Expert Committees
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`Otficr‘o.’ from May t, 2013
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`The. designation on the cover of thrs pubiication, ”USP NF 2013,” is for ease of
`iclenti’ri(.'ati0n only. The pubiication Contains two separate compendia: The United
`States t‘normocoper‘o, Thirty—Sixth Revision, and The Nationot Formw'ory, Thirty~First
`Edition.
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`THE UNITED STATES PHARMACOPEIAL CONVENTION
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`12601 Twinbrook Parkway, Rockville, MD 20852
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`ii
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`USP 36
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`SIX-MOl‘IlTH IMPLEMENTATION GUIDEUNE
`
`ihe United States Pharmorowio Notional FOl'riitIl'GI'jx and Its supplements become official six months IIlILr beino released to
`the pLIbiic. The USP—NF whict Is released on Novei‘n'oei
`| of each year becomes official on May'I of the loIIoI-Iiing year. This
`six- month implementation liming glVCS users more time to bring their methods and procedures Into cornI.)lIance III-ith new
`and revised USP—NF requirements.
`The table below describes the official: dates of the USP—I\I'F' and Its supplements. The 2011 USP .35 NF 50 and Its supple»
`menls interim Revision Announceriients (er-lsi and ReVIs'I on Bulletins to that edition will be official until Iklay '| 2013, at which
`lime the USP 36—Ni’ 31 becomes official.
`
`
`_Eilblicetipn ..
`Hill" _lé—NF J!
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`__.. ..
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`._ 1-.
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`R_el_ea_s_e_Date
`November 1 2012
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`._.._
`Official _[_)___ate
`90 I 1
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`August '1, 2013
`December 1, )[313
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`'_9ff_icia_l_l.ln_1tii_
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`\riIIy 1_. 2014 (exceptuas so'IFrseI‘Ft‘i by fiL'1J|)|9F‘I'I‘=11‘sIHI‘AK nIIrl
`_Rg'msiurt Kin!" ms]
`NILy 1 201-1 [eXLe pt as s:We".seoed by SeLGrII‘ Suppieriient IRAs,
`and Revenue 8-:II'I_'e__ Iris;-
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`I June I, 2013
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`' First SII'prilIIIII-erir it: the
`_Uw iri—Nf
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`SL’COJTd SIIIrJIIJteIiIeWI.‘ to me
`IisI'I M air 'I-'
`USP 3 7 NF 12
`
`
`
`i May 1, 2015 [except as superseded by supplements, lilrts. and
`I’I'L'I'I'I'Lir: Buf'I'Ifi-I'Is'}
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`.51.
`The table below gives the details oi the ”(As that Will apply to USP 36- NF
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`JRA. _.
`..._
`..._
`E'E Posting fiat-e
`.._' Comma”mt Duepage
`TWA Pasting Date
`IRA Officlal eqte
`_391.l_}_..
`ldimair 2.2013
`"\‘laI'CL_3..=.I.?£U|3.._...
`.. flat .3? 20L.“- .
`July ‘I 2.52.1.3
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`39(2)
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`1 _2_UI’> __
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`I"."ii"l‘,' $I, 2013
`ulv 26 '20! .§__
`September | 2013
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`_398)
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`1 Menu | 2013
`Jylv 31 2013
`_Sepierntrer 2? 2915
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`Willy :, EON; _ ___|
`Revision Builetins published on the USP website become official on the date speCIerd In the Revrsiun BIII'ieI‘I-II
`
`|
`i November I, 2013
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`II
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`May I, 2014
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`NOTICE AND WARNING
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`Concerning U 5'. Patent or Trademark Rights—The inclusion in The United States Piieriiiocoeeie III in the national FeirrIIIlLIry of a
`monograph on any drug in Iespect to which patent or trademark Iights may exist shall not be cleemeci and is not intended
`as a grant of or authority to exercise anv right 01 privilege pIotected by such patent oI tiaclerhiark All such rights and
`[JI'lVIiE‘gL‘S are vested in the patent or trademark owner and no other person may eJLerCIse the same without expiess
`permission, authority, or license secured from such patent or trademark owner.
`
`Loric'erriinci UsII oi USP or N!- Text— "Attention is called to the fact that lI'B'P t-illfi NF text Is fllliV copyrighte d. Authors and
`others Wishing totuse portions of the te:It should request permission to do so lrorn the Secretaiy of the USPC Board of
`Trustees
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`Copyright ’5‘ 201)1 'llie Uniletl States Pharmacopeial Convention
`12601 Twinbrook Parkway, Rockville, MD 20852
`
`All rights reserved.
`1531101957996
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`ISBN: 9?8-1—936424-1?-2
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`Printed in the United States by Llnileti Book i’ress,
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`'nc., Baltimore,
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`

`

`USP 36
`
`PRODUCT CATEGORIES
`
`For the purpose of testing, com endial articles have been
`divided into four categories (see
`able 1). The criteria of
`antimicrobial effectiveness for these products are a function
`of the route of administration.
`
`Table 1. Compendlal Product Categories
`Product Description
`Injections, other parenterals including
`emulsions, otic products, sterile nasal
`products, and ophthalmic products made
`with a ueous bases or vehicles.
`2
`Topically used products made with aqueous
`bases or vehicles, nonsterile nasal products,
`l0 MUCOUS membranes.
`Oral products other than antacids, made with
`agueous bases or vehicles.
`Antacids made with an aqueous base.
`
`1
`
`3
`
`4
`
`and emulsions, including those applied
`
`-
`
`.
`
`
`
`
`54 (41) Weights and Balances /Appardtus
`
`quantities below 20 mg. (For weights of 10 g or less, the
`requirements of class 1 are met by USP XX! class M.)
`Class 2 weights are used as workin standards for calibra-
`tion, built-in weights for analytical ba ances, and laboratory
`weights for routine anal tical work. {The requirements of
`class 2 are met by USP Xi class S.)2
`Class 3 and class 4 wei hts are used with moderate—preci—
`sion laboratory balances. %Class 3 requirements are met b
`USP XXi class 5-1,- class 4 requirements are met by USP X i
`class P.)2
`-
`A weight class is chosen so that the tolerance of the
`weights used does not exceed 0.1% of the amount
`weighed. Generally, class 2 may be used for quantities
`greater than 20 mg, class 3 for quantities of
`reater than
`50 m , and class 4 for quantities of greatert an 100 mg.
`WEiEio ts should be calibrated periodically, preferably against
`an a solute standard weight.
`
`Microbiological Tests
`
`(51) ANTIMICROBIAL
`- EFFECTIVENESS TESTING
`
`Antimicrobial preservatives are substances added to non-
`sterile dosa e forms to protect them from microbiological
`growth or
`rom microorganisms that are introduced inadver-
`tently during or subsequent to the manufacturing rocess.
`In the case of sterile articles packaged in multiple— ose con—
`tainers, antimicrobial preservatives are added to inhibit the
`growth of microorganisms that may be introduced from re—
`peatedly withdrawing individual doses.
`Antimicrobial preservatives should not be used as a substi-
`tute for ood manufacturing practices or solely to reduce
`the viab e microbial population of a nonsterile product or
`control the presterilizatlon bioburden of multidose formula-
`tions durin manufacturing. Antimicrobial preservatives in
`compendia dosage forms meet the requirements for Added
`Substances under ingredients and Processes in the General
`Notices.
`All useful antimicrobial agents are toxic substances. For
`maximum protection of patients, the concentration of the
`preservative shown to be effective in the final packaged
`product should be below a level that may be toxic to
`uman beings.
`The concentration of an added antimicrobial preservative
`can be kept at a minimum if the active ingredients of the
`formulation possess an intrinsic antimicrobial activity. Anti-
`microbial effectiveness, whether inherent in the product or
`whether produced because of the addition of an antimicro—
`bial preservative, must be demonstrated for all injections
`packaged in multiple-dose containers or for other products
`containing antimicrobial preservatives. Antimicrobial effec-
`tiveness must. be demonstrated for multi
`le-dose topical and
`oral dosage forms and for other dosa e orms such as
`o hthalmic, otic, nasal, irrigation, an
`dialysis fluids (see
`P ormaceuticdl Dosage Forms (1151)).
`This chapter provides tests to demonstrate the effective—
`ness of antimicrobial protection. Added antimicrobial pre—
`servatives must be declared on the label. The tests and crite-
`ria for effectiveness apply to a product in the original,
`unopened container In which it was distributed by the
`manufacturer.
`
`2 Note that the designations S and P no longer designate weight classes but
`rather weight grades, that Is, design limitations such as range of density of
`materials, surface area, surface finish, corrosion resistance. and hardness.
`
`
`
`'
`
`_
`
`TESTORGANISMS
`Use cultures of the following microorganisms': Candida ai—
`bi'cans (ATCC No. 10231 ), Aspergilius ni er (ATCC No.
`16404), Escherichia coli (ATCC No. 873 ), Pseudornonas
`aeru inosa {ATCC No. 9027), and Staphyiococcus aureus
`(AT C NO. 6538). The viable microorganisms used in the
`test must not be more than five passages removed from the
`ori
`inal ATCC_culture. For urposes of the test, one
`assa e
`is
`efined as the transfer oForganisms from an estab ishe
`culture to fresh medium. All transfers are counted. In the
`case of organisms maintained by seed-lot techniques, each
`cycle of freezing, thawing, and revival in fresh medium is
`taken as one transfer. A seed-stock techni ue should be
`used for Ion -term storage of cultures. Cu tures received
`from the AT C should be resuscitated according to direc-
`tions. if grown in broth, the cells are pelleted by centrifuga-
`tion. Resuspend in 1i20th the volume of fresh maintenance
`broth, and add an equal volume of 20% (va in water) ster-
`ile
`lycerol. Cells
`rown on a ar may be scraped from the
`su ace into the “93% glycero broth. Dispense small aliquots
`of the suspension into sterile vials. Store the vials in liquid .
`nitrogen or in a mechanical freezer at no more than —50°.
`When a fresh seed-stock vial is required, it may be removed
`and used to inoculate a series of working cultures. These
`working cultures may then be used periodically (each day in
`the case of bacteria and yeast) to start the inoculum culture.
`
`MEDIA
`
`All media used in the test must be tested for growth pro-
`motion. Use the microorganisms indicated above under Test
`Organisms.
`-
`
`PREPARATION OF INOCULUM
`
`Preparatory to the test, inoculate the surface of a suitable
`volume of solid agar medium from a recently revived stock
`culture of each of the specified microorganisms. The culture
`conditions for the inoculum culture are described in Table 2
`in which the suitable media are Soybean—Casein Digest or
`Sabouraud Dextrose Agar Medium (see Microbial Enumera-
`tion Tests (61) and Tests for Specified Microorganisms (62)).
`To harvest the bacterial and C. ulbimns cultures, use ster-
`ile saline TS, washing the surface growth, collectin -it in a
`suitable vessel, and adding sufficient sterile saline
`S to ob—
`tain a microbial count of about 1I><108 colony-forming units
`
`Boulevard, Manassas, VA 2 110-2209 (httpfliwwwatccorg).
`1 Available from American Type Culture Collection, 10801 University
`
`
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`

`

`USP 36
`
`Microbiological Tests .3 {51) Antimicrobial Effectiveness Testing 55
`
`_
`
`
`
`
`
`
`Table 2. IEulture Conditions ioir Inacuium Preparation
`Incubation
`Inoculum
`l Microbial Recovery
`I
`
`___ “Suitable Medium
`__
`_ Temperattlre__
`|n_c_uh_atio_t_1 Time
`!_
`__ _lnl_:_u_bag_i:|nn_TiIr_I_e _
`._ _ ___ _0I;ga_ni__sm _ __ __
`“:25 + 2.5"
`Iii to 24 hours
`I
`5 tr. 5 days
`Soybean—Casein Digesr Broth,
`|
`fscheirrliio coir
`
`._
`_..
`.
`.__
`‘
`.
`.
`microns £3.32)
`..c. ._.
`.- semen—costeflsoesteoe. _._. a. -l .__s._
`..
`-_
`
`3 to 5 days
`=
`l‘seodonior'os oerogiric-so
`Soybean-Casein Digest Broth,
`52 b i 2 5'
`18 to 24 hours
`l
`I
`1.. (EEC it‘ll-.2023).
`_
`.. Soybean (Lew-“DIE?“ Agar.
`_ _
`..
`._.
`_.
`In........
`_ h._ _. ___
`I Sropnyiocc-I'cui omens
`Soybea n—Casmn Digest. Broth;
`3? S i- 25'
`18 to ”24"hours
`3 to 5 days
`'_.
`(ATCC No 6538}
`Hwbean-Casem Digest Agar
`__
`_
`_
`. Londidci tilts-cons
`Sabouraud Dextrose Agar;
`22 5 L 2.5"
`44 to 52 hours
`3 to 5 days
`____
`_
`__
`__
`__(ATCC No.
`l__023'_|}
`Sabomaud DextIosc- Br_oth _
`_
`_
`_
`_
`__
`___ _ _
`iIAsIuergiiI'us Hit}?!
`' SJbOUraud Dextrose Adar,
`22.5 t 2 5"
`6 to If) days
`3 to 2 days
`
`IATCC No 16404}
`Sahouraud I.)e):tr0§l:' Broth
`_
`.
`..._
`_ i...___ _.. .__.__... ._ _._... _
`
`..
`
`_
`
`_
`
`plating. These conditions are delermineii in the validation
`study for that sample based upon the conditions of media
`and microbial recovery Incubation times listed in Tobie 2.
`Using the calculated concentrations of cfu per not present at
`the start of the test, calculate the change In logs; values of
`the concentration of cfu per not for each rrIIcroOIganism at
`the applicable test intervals and express the changes in
`terms of log reductions
`
`CRITERIA FOR ANTIMICROBIAL
`EFFECTIVENESS
`
`The requirements for antimicrobIal effectiveness are met if
`the criteria specified under labia 3 are met (see Significant
`Figures and Tolerances under General Notices). No Increase Is
`defined as not more than 0.5 log. I unit higher than the
`previous value measured.
`
`Table 3. Criteria for Tested Microorganisms
`
`
`For Category i Produrrt
`| Not less than 1 0 log reduction from
`J
`the Initial calculated count at 2 days.
`'_
`nol less than 3.0 log reduction from
`l'
`the initial count at l4 days, and no
`I
`Increase from the l4 days“ count at
`_|
`28 days.
`___
`_
`_l'
`Yeast and Molds.
`II' No Increase trom the initial calculated
`|
`i mentor. ti deified:
`For Curacao 2 Products
`I Not less than 2 0 log reduction from
`i
`the initial count at 14 days, and no
`|
`increase from the 14 days' count at
`l
`23 clavs
`_
`_
`__
`__
`i—
`I No Increase from the. Initial calculated
`! Yeast and Molds-
`
`f—
`count at I4 and )3 days.
`For fetenoiv
`Products
`['_u
`—. —_
`.
`_.
`_
`_
`i Not less than 1.0 log reduction from
`the Irutial count at 14 days, and no
`Increase lIom '_he 14 days" count at
`2.5 (tats
`.
`. _..
`| No increase from the Initial calculated
`.
`count at 14 ar_I_d28 dL
`l-or Careuor} 4__f'_ioq‘-.I_crs
`_
`I No increase fioni the irIILIai calculated
`I Count _a_t_l‘! an_d__2_8_$j£__
`
`ll i
`
`J_ Bat'EFfild'.
`
`
`
`4
`
`__
`
`i
`
`||| l| |
`
`Yeast and Molds
`
`|
`
`_
`
`I Bacteria, Yeast,
`|_ and Molds
`
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`
`(cfu) per mL. To harvest the cells of £1. niger, use sterile
`saline TS contain. ng 0. 05% of polysorbate 80 and add suffi—
`CIent sterile saline 13 to obtain a count of about 1 x106 cfu
`)er m|..
`I Alternatively. the stock culture organlsms may be grown
`in a Suitable liquid medium (I.e., Soybean—Casein Digest
`Broth or Sabouraud Dextrose Broth) and the cells harvested
`by centrifugation, then washed and resus ended in sterile
`saline TS to obtain a microbial count of a soul 1 x 105 clu
`per mL. [NOTt—The estimate or Inoculum concentration
`may be performed by turbidimetric measurements for the
`challenge microor anrsrns Refrigerate the suspension if
`It
`not. used within 2 tours]
`Determine the number of do per mL in each suspension,
`using the conditions of media and microbial recover
`incu-
`bation times listed in Torrie 2 to confirm the initial c u per
`mL estimate. This value serves to calibrate the size of inocu—
`Ium used 'In the test. The bacterIal and yeast suspensions are
`to be used WIthIn 24 hours of harvest, but the fungal prepa-
`ration may be stored under refrigeration for tip to 7 days.
`
`is
`
`PROCEDURE
`
`The test can be conducted either in five original contain-
`ers if sufficient volume of producl is available in each con—
`tainer and the product container can be entered aseptically
`(i. e., needle and syIInge through an elastomeric rubber
`stopper}, or in five sterile capped bacteriological containers
`of suitable size Into chh a sufficient volume of product has
`been transferred. inoculate each container with one of the
`pre ared and standardized Inoculurnr and mix. The volume
`of t e suspension inoculum used is between 0.5% and
`1 0% of the volume of the product. The concentration of
`test microelganisms thatis added to the product [Categories
`i 2 and 3) are such that the final conCEIitratIon of the test
`pIeparation afteI inoculation Is between 1 x105 and 1 ‘2 10°
`cfu per ml. of the product. For Category 4 products
`(antacids) the final concentration of the test pre aration af—
`ter inoculation is between 1 y '10-‘- and 1 210‘1 c u per ml of
`the product
`The initial concentration of viable microorganisms in each
`test preparation is estimated based on the concentration of
`micioor amsrns in each of the standardIzed inoculum as de-
`teIrnIne
`bv the plate- count method.
`incubate the inoculated containers at 22 5-+ 2.;‘ " .Sarnple
`each containei at the appropriate Intervals specifiedIn table
`3. Record any changes observed In appearance at these in-
`tervals. Determine by the plate—count procedure the number
`of ciu present in each test
`reparation for the applicable
`intervals (see Procedure un er I'vtIcIobI'oI Enumeinoon Tests
`{61) and Tests for Specified MIcroorgonisrns {62‘-) incor orate
`an inactivator (neutralizer) of the specific antimicrohia in
`the plate count or In the appropriate dilution prepared for
`
`

`

`930 (l ”I 84} Sensitization Testing / General Information
`
`USP 36
`
`Preparations (795)), The stability and clinical effect 0f manu-
`factured dosage forms can be greatly compromised by
`seemingly negligible alterations or inap rofpriate prescription
`compounding. Pharmacists should estaglis
`and maintain
`compounding conditions that include the ensurin of drug
`stability to help prevent therapeutic failure and a verse
`responses.
`tabilitymsrobility is defined as the extent to which a
`product retains, within specified limits, and throughout its
`period of storage and Use (i.e., its shelf-life), the same
`properties and characteristics that it possessed at the time oi
`its manufacture. Five types of stability generally recognized
`are shown in the accompanying table.
`
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`Criteria for Acceptable Levels of stability
`Type of
`Condlflons Maintained Throughout the
`
`-
`% Shelf Life of the Drug Product
`;
`Chemical
`Each active ingredient retains its chemical in-
`tegrity and labeled potency, within the spec-
`
`ilied limits.
`.
`The original physical properties, including ap-
`Physical
`pearance, palatability, uniformity, dissolu-
` l
`tion, and suspendability. are retained.
`4
`Sterility or resistance to microbial growth Is
`Microbiological
`retained according to the specified require-
`menu. Antimicrobial agents that are present
`retain effectiveness within the specified lim-
`its. __
`The therapeutic effect remains uncha-Ilged.
`No significant increase in toxicity occurs.
`
`FACTORS AFFECTING PRODUCT STABILITY
`
`Each in redient, whether therapeutically active or phar-
`maceutica Iy necessary, can allect the stability of drug sub-
`stances and dosage forms. The primary environmental fac
`tors that can reduce stability include exposure to adverse
`temperatures, light, humidity, oxygen, and carbon dioxide.
`The major dosage form factors that influence drug stability
`include particle size (especially in emulsions and suspen—
`sions), pH, solvent system composition (i.e., percentage of
`"free” water and overall polarity), compatibility of anions
`and cations, solution ionic stren th, primary container, spe-
`cific chemical additives, and mo ecular binding and diffusion
`of drugs and excipients.
`In dosage forms, the iollowin re-
`actions usually cause loss of active drug content, and t ey
`usually do not provide obvious visual or olfactory evidence
`of their occurrence.
`Hydrolysis—Esters and ,O-Iactams are the chemical bonds
`that are most likely to hydrolyze in the presence of water.
`For example, the acetyl ester in aspirin Is h drolyzed to ace-
`tic acid and salicylic acid in the presence olmoisture, but in
`a dry environment the hydrolysis of aspirin is negligible. The
`aspirin hydrolysis rate increases in direct proportion to the
`water vapor pressure in an environment.
`The amide bond also hydrolyzes, though generally at a
`slower rate than comparable esters. For example, procainr-
`(an ester) will hydrolyze upon autoclaving, but procaina-
`mide will not. The amide or peptide bond in peptides and
`proteins varies in the lability to hydrolysis.
`The lactam and azomethine (or imine) bonds in behind-
`azepines are also labile to hydrolysis. The major chemical
`accelerators or catalysts of hydrolysis are adverse pH and
`specific; chemicals (eg, dextrose and copper in the case of
`ampicillin hydrolysis).
`Epimerization—Members of the tetracycline family are
`most likely to incur epimerization. This reaction occurs rap-
`idly when the dissolved drug is exposed to a pH of an inter
`mediate range (higher than 3), and it results In the steric
`
`NaioxlO66
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`Nalox—l Pharmaceuticals, LLC
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`Page 9 of 14
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`Therapeutic
`Toxicological
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`rearrangement of the dimethylamino group. The epimer of
`
`PRELIMINARY TESTING
`
`The maximally nonirritating dose and minimally irritating
`concentrations should be determined using separate groups
`of animals. This could be done as described for Preliminary
`Testing in the Mouse for Swelling Test.
`
`INDUCTION PHASE
`
`The fur of the abdomen and thorax of to mice per group
`should be shaved. Then 100 uL of test article (at the mini-
`maliy irritating concentration) should be applied to the test
`areas on days 0, 2, 4, 7, and 11. Control animals receive
`100 pL of vehicle alone on the same schedule.
`
`CHALLENGE PHASE
`
`This phase should occur 4 da 5 after the final application
`of the induction Phase. Twenty— ive pl. of test artic e (at the
`maximally nonirritating concentration) should be applied to
`each ear of each animal in the test and control groups.
`
`OBSERVATIONS
`
`Ear thickness for both ears of each animal should be re-
`corded alter 24 and 48 hours postchallenge. The measure-
`ments should be made with a caliper (a Spring-loaded cali—
`per is
`referable). The percent increase in ear thickness
`shoul be calculated for each ear by subtracting the pre—
`treatment measurement. from the post—treatment measure-
`ment, dividing the result by the pretreatment measurement,
`then multiplying by 100. The response oi the test grou
`versus the control group should be compared statistica y.
`(The Mann-Whitney U test could be used for the compari—
`son.)
`The results of individual animals should also be calculated.
`if an increase in ear thickness for an animal from the test
`group is at least 50% greater than the largest increase of a
`control animal, that is indicative of sensitization. As an over-
`all evaluation, should the results ol the stud provide a sig-
`nificant result of the statistical test at p < 0.
`l for the con—
`trol versus test group comparisons, or ii at least two test
`animals have ear thickness increases in excess of 50% of the
`maximum control thickness changes and the group compar-
`aruc e.
`isonlshowed a p c 0.05, sensitization is indicated for the test
`
`(1191) STABILITY
`CONSIDERATIONS IN
`
`DISPENSING PRACTICE
`
`NOTEilnasmuch as this chapter is lor purposes of general
`information only, no statement in the chapter is intended to
`modify or supp ant any of the specific requirements perti-
`nent to l’harmacopeial articles, which are given elsewhere in
`this Pharmaco eia.
`Aspects of
`rug product stability that are of primary con-
`cern to the pharmacist in the dispensing oi medications are
`discussed herein.
`PharmaCIsts should avoid ingredients and conditions that
`could result In excessive physical deterioration or chemical
`decomposition of drug preparations, especially when com-
`pounding tsc-c- PIIuIrricIceutrcol Compounding—Nonsterile
`
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`USP 36
`
`General information /(1191) Stability Considerations in Dispensing Practice 931
`
`The influence of pH on the physical stability oi two phase
`systems, especially emulsions,
`is also important. For exam
`ple, intravenous fat emulsion is destabilized by acidic pH.
`Interionic (lonNtalonN-J Compatibility-"The compatibil-
`ity or solubility of oppositely charged ions depends mainly
`on the number of chart es
`er ion and the molecular size of
`the ions.
`in general, po yva ent ions of opposne char e are
`more likely to be incompatible. Thus, an incompatibi ity is
`likely to occur upon the addition of a large ion with a
`charge opposite to that of the drug,
`Solid State Stability—Solid state reactions are relatively
`slow; thus, stability of dru s in the solid state is rarely a
`dispensing concern. The
`egradation rate of dry solids is
`usually characterized by first—order kinetics or a sigmoid
`curve. Therefore, solid drugs with lower meltin point temw
`peratures should not be combined with other c emicals that
`would form a eutectic mixture.
`When moisture is present, the solid drug decomposition
`may change to zero—order chemical kinetics because the rate
`is controlled by the relatively small fraction of the drug that
`exists in a saturated solution, which is located (usually im-
`perceptibly) at the surface or in the bulk of the solid drug
`product.
`Temperature—in general, the rate of a chemical reaction
`increases exponentially for each it)” increase in temperature
`This relationship has been observed for nearly all drug hy—
`drolysis and some drug oxidation reactions. The actual fac—
`tor of rate increase depends on the activation energy of the
`particular reaction. The activation energy is a function of the
`specific reactive bond and the drug formulation (eg, sol-
`vent, pH, additives). As an example, consider a hydrolyzable
`drug that is exposed to a 20° increase in temperature, such
`as t at from cold to controlled room temperature (see Geri-
`erol Notices and Requirements). The shelf life of the drug at
`controlled room temperature should be expected to de-
`crease to one-fourth to one—twenty-filth of its shelf life under
`refrigeration.
`The pharmacist should also be aware that inappropriately
`cold temperatures may cause harm. For example, refrigera-
`tion may cause extreme viscosity in some liquid drugs and
`cause supersaturation in others. Freezing may either break
`or cause a large increase in the droplet size of emulsions; it
`can denature proteins; and in rare cases, it can cause less
`soluble polymorphic states of some drugs to form.
`
`STABILITY STUDIES IN MANUFACTURING
`
`The scope and design of a stability study vary accordin
`to the product and the manufacturer concerned. Ordinari y
`the formulator of a product first determines the effects of
`temperature, light, air, pH, moisture, trace metals, and com-
`monly used excipients or solvents on the active ingredi-
`ent(s). From this information, one or more formulations of
`each dosage form are prepared, packaged in suitable con-
`tainers, and stored under a variety of environmental condi-
`tions, both exa geratecl and normal. At appropriate time
`intervals, samp es of the product are assayed for potency by
`use of a stability-indicating method, observed for physical
`changes, and, where app icable, tested for sterility and or
`for resistance to microbial growth and for toxicity and
`bioavailability. Such a study, in combination with clinical
`and toxicological results, enables the manufacturer to select
`the optimum formulation and container and to assign rec-
`ommended storage conditions and an expiration date for
`each dosage form in its package.
`
`Responsibility of Pharmacists
`
`Pharmacists help to ensure that the products under their
`supervision meet acceptable criteria of stability by (1) dis—
`pensing oldest stock first and observing expiration dates, {2)
`storing products under the environmental conditions stated
`in the individual monographs, labeling, or both, (3) observ—
`
`tetracycline, epitetracycline, has little or no antibacterial ac
`tivity.
`Decarbox lation—Some dissolved carbox lic acids, such
`as p-aminosa ic lic acid, iose carbon dioxide rom the car-
`boxyl group w en heated. The resulting product has re-
`duced pharmacological potency.
`Jtil<c3to decarboxylation can occur in some. solid antibiotics
`that have a carbonyl group on the fi—carbon of a carboxylic
`acid or a carboxylate anion. Such decarboxylations will oc-
`cur in the following antibiotics: carbenicillin sodium,
`aCl
`cargeniciilin free acid, ticarcillin sodium, and ticarcillin free
`ehydratiowAcid—catalyzed dehydration of tetracycline
`forms epianhydrotetracycline, a product that both lacks an-
`tibacterial activity and causes toxicity.
`Oxidation—The molecular structures most likely to oxi-
`dize are those with a hydrox I group directly bonded to an
`aromatic ring (e.g., phenol
`erivatives such as catecho-
`lamines and morphine), conju ated dienes (eg, vitamin A
`and unsaturated free fatty aci
`s), heterocyclic aromatic
`rings, nitroso and nitrite derivatives, and aldehydes (eg, fla—
`vorings). Products of oxidation usually lack therapeutic activ-
`ity Visual identification of oxidation, for example, the
`c iange from colorless epinephrine to its amber colored
`products, may not be visible in some dilutions or to some
`9 “es.
`)0xidation is catalyzed by pH values that are higher than
`optimum, polyvalent heavy metal ions (e.g., cop