1 B
`
`iowaiver Monographs for Immediate Release Solid
`Oral Dosage Forms: Diclofenac Sodium and
`Diclofenac Potassium
`
`B. CHUASUWAN,1,2 V. BINJESOH,1,3 J.E. POLLI,1 H. ZHANG,4 G.L. AMIDON,5 H.E. JUNGINGER,6 K.K. MIDHA,7
`V.P. SHAH,9 S. STAVCHANSKY,9 J.B. DRESSMAN,10 D.M. BARENDS11
`
`1Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland
`
`2Research and Development Institute, The Government Pharmaceutical Organization, Bangkok, Thailand
`
`3Faculty of Pharmacy, Rangsit University, Pathumtani, Thailand
`
`4AstraZeneca Pharmaceuticals LP, Wilmington, Delaware
`
`5College of Pharmacy, University of Michigan, Ann Arbor, Michigan
`
`6Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand
`
`7University of Saskatchewan, Saskatoon, Saskatchewan, Canada
`
`8International Pharmaceutical Federation FIP, The Hague, The Netherlands
`
`9Pharmaceutical Division, College of Pharmacy, University of Texas at Austin, Austin, Texas
`
`10Institute of Pharmaceutical Technology, J.W. Goethe University, Frankfurt, Germany
`
`11RIVM—National Institute for Public Health and the Environment, Bilthoven, The Netherlands
`
`Received 23 May 2008; accepted 3 July 2008
`
`Published online 27 August 2008 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.21525
`
`ABSTRACT: Literature data are reviewed regarding the scientific advisability of allow-
`ing a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release
`(IR) solid oral dosage forms containing either diclofenac potassium and diclofenac
`sodium. Within the biopharmaceutics classification system (BCS), diclofenac potassium
`and diclofenac sodium are each BCS class II active pharmaceutical ingredients (APIs).
`However, a biowaiver can be recommended for IR drug products of each salt form, due to
`their therapeutic use, therapeutic index, pharmacokinetic properties, potential for
`excipient interactions, and performance in reported BE/bioavailability (BA) studies,
`provided: (a) test and comparator contain the same diclofenac salt; (b) the dosage form of
`the test and comparator is identical; (c) the test product contains only excipients present
`in diclofenac drug products approved in ICH or associated countries in the same dosage
`form, for instance as presented in this paper; (d) test drug product and comparator
`dissolve 85% in 30 min or less in 900 mL buffer pH 6.8, using the paddle apparatus at
`75 rpm or the basket apparatus at 100 rpm; and (e) test product and comparator show
`dissolution profile similarity in pH 1.2, 4.5, and 6.8. ß 2008 Wiley-Liss, Inc. and the American
`Pharmacists Association J Pharm Sci 98:1206–1219, 2009
`
`A project of the International Pharmaceutical Federation
`FIP, Groupe BCS, www.fip.org/bcs. This article reflects the
`scientific opinion of the authors and not the policies of regulat-
`ing agencies, the International Pharmaceutical Federation
`(FIP) and the World Health Organization (WHO).
`
`(Telephone: 31-30-
`to: D.M. Barends
`Correspondence
`2744209; Fax: 31-30-2744462; E-mail: dirk.barends@rivm.nl)
`
`Journal of Pharmaceutical Sciences, Vol. 98, 1206–1219 (2009)
`ß 2008 Wiley-Liss, Inc. and the American Pharmacists Association
`
`1206
`
`JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 4, APRIL 2009
`
`LUPIN EX. 1009
`Lupin v. iCeutica
`US Patent No. 8,999,387
`
`Page 1
`
`

`
`BIOWAIVER MONOGRAPH FOR DICLOFENAC
`
`1207
`
`Keywords: absorption; bioequivalence; biopharmaceutics classification system
`(BCS); diclofenac; permeability; solubility; regulatory science
`
`INTRODUCTION
`
`A biowaiver monograph of diclofenac is present-
`ed based on literature data and new experimental
`data. Risks are evaluated in basing a BE as-
`sessment on in vitro study results (i.e., ‘‘biowaiv-
`ing’’), rather than in vivo study results, for the
`approval of new IR solid oral dosage forms
`containing diclofenac sodium and diclofenac
`potassium, for example, plain IR tablets, disper-
`sable tablets and powders for oral solutions. This
`risk evaluation considers diclofenac sodium and
`diclofenac potassium biopharmaceutical and clini-
`cal properties, as they pertain to reformulated
`products and new multisource products. This
`evaluation concerns drug products containing
`diclofenac as the only API and does not concern
`combination drug products. This evaluation does
`not concern delayed release products or any other
`modified release formulations of diclofenac.
`The purpose and scope of this series of mono-
`graphs have been previously discussed.1 Briefly,
`the aim is to evaluate all pertinent data available
`from literature sources for a given API to assess
`the risks associated with a biowaiver. For these
`purposes, risk is defined as the probability of
`making an incorrect biowaiver decision, as well as
`the resulting consequences of such a decision in
`terms of public health and individual patient
`risks. On the basis of these considerations, a
`recommendation can be made as to whether a
`biowaiver is advisable or not. This systematic
`approach to recommend for or to advise against a
`biowaiver is described in the recently published
`World Health Organization (WHO) Guideline.2
`These monographs do not intend to simply apply
`the WHO, FDA3 and/or EMEA Guidance,4 but aim
`to apply these guidances and further serve as a
`critical validation of these regulatory documents.
`Biowaiver monographs have already been pub-
`lished for acetaminophen (INN: paracetamol),5
`acetazolamide,6 aciclovir,7 amitriptyline,8 ateno-
`lol,1 chloroquine,9 cimetidine,10 ethambutol,11
`ibuprofen,12 isoniazid,13 metoclopramide, predni-
`solone,14 prednisone,15 pyrazinamide,16 propra-
`nolol,1 ranitidine,17 and verapamil.1 They are also
`available on-line at www.fip.org/bcs. Although
`diclofenac is not on the present WHO List of
`
`Essential Medicines,18 it was considered appro-
`priate to include this widely used and important
`API in this series.
`
`Literature Review
`
`Published information was obtained from PubMed
`up to November 2007. Key words used were:
`diclofenac potassium, diclofenac sodium, NSAID,
`indication,
`therapeutic index, solubility, poly-
`morphism, partition coefficient, pKa, absorption,
`permeability, distribution, metabolism, excretion,
`excipients, bioequivalence and dissolution.
`
`GENERAL CHARACTERISTICS
`
`Name and Structure
`
`The chemical name of diclofenac is 2-[(2,6-
`dichlorophenyl)amino]-benzeneacetic
`acid.
`Its
`structure is shown in Figure 1.
`
`Therapeutic Indication, Side Effect and
`Therapeutic Index
`
`Diclofenac is a well-known nonsteroidal anti-inflam-
`matory drug (NSAID) with anti-inflammatory,
`analgesic and antipyretic properties, comparable or
`superior to other NSAIDs.19 Diclofenac shows
`preferential
`inhibition of
`the cyclooxygenase-2
`
`Figure 1. Structure of diclofenac, where M¼ Kþ
`or Naþ for potassium or sodium salt, respectively.
`
`DOI 10.1002/jps
`
`JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 4, APRIL 2009
`
`Page 2
`
`

`
`1208
`
`CHUASUWAN ET AL.
`
`(COX-2) enzyme.20 Diclofenac sodium is mainly
`indicated in the treatment of osteoarthritis, rheu-
`matoid arthritis and ankylosing spondylitis. Diclo-
`fenac potassium is claimed to dissolve faster, and
`hence absorbed faster, than the sodium salt and is
`recommended for the treatments that need short
`onset of action, mainly for its analgesic properties.
`Diclofenac potassium is also indicated for the
`treatment of primary dysmenorrheal and mild to
`moderate pain.21,22 As with other NSAIDs, diclofenac
`is known to increase the risk of gastrointestinal
`bleeding and cardiovascular side effects.21,22 How-
`ever, diclofenac has a relatively high therapeutic
`index in comparison to other NSAIDs.23
`
`PHYSICOCHEMICAL PROPERTIES
`
`Salts, Esters, Polymorphs, Hydrates
`
`Diclofenac is usually formulated as the sodium or
`potassium salt, but other salts are also used, such
`as hydroxyethylpyrrolidine salt for oral prepara-
`tions, and diethylammonium and diethylamine
`for topical preparation.24 This monograph refers
`to drug products containing the sodium or
`potassium salt of diclofenac only. Most ‘‘plain’’
`tablets contain the potassium salt, whereas most
`dispersable dosage forms
`contain diclofenac
`sodium, see Tables 1 and 2. In this monograph,
`the term diclofenac without indicating the salt
`form refers to the sodium and potassium salts.
`Trihydrates and tetrahydrates exist for both of
`diclofenac potassium and diclofenac sodium,25,26
`but in pharmacopoeial drug products only the
`anhydrate is used.27,28
`
`Solubility
`
`Solubility values for diclofenac sodium taken from
`the literature29 are shown in Table 3 and
`experimentally determined solubilities of diclofe-
`nac potassium are show in Table 4, respectively,
`together with the dose to solubility ratios (D/S) for
`several tablet strengths.
`
`Polymorphism
`
`Reports of diclofenac potassium or diclofenac
`sodium polymorphs were not
`found in the
`literature.
`
`Partition Coefficient
`
`Partition coefficient in n-octanol/aqueous buffer
`(log D) are reported to be 1.4 and 1.1 for pH 6.8 and
`
`7.4, respectively.30–32 The experimental
`log P
`(n-octanol/water) and C log P values of diclofenac
`are 4.40 and 4.71, respectively,33,34 which are
`larger than the corresponding values of 1.72 and
`1.35 for the highly permeable marker drug
`metoprolol.35
`
`pKa
`The pKa of diclofenac is about 3.80 at 258C.36,37
`
`Strengths of Marketed Drug Products
`
`Dosage form strength is expressed in mg of salt
`present, not equivalent of the free acid. In the
`United States (US) and in the EU, Marketing
`Authorizations (MAs), that is, registrations, exist
`for IR solid oral dosage forms for 12.5, 25, and
`50 mg diclofenac salt, see Tables 1 and 2. Higher
`strengths of these drugs have been marketed, but
`only as delayed release solid forms or combination
`oral products; however, such products are outside
`the scope of this monograph.
`
`PHARMACOKINETIC PROPERTIES
`
`The majority of pharmacokinetic data concerns
`diclofenac sodium. Literature reports indicate that
`diclofenac sodium and diclofenac potassium are
`similar in terms of extent of oral absorption, pattern
`of distribution, metabolism, and elimination.38
`
`Absorption and Permeability
`
`Diclofenac is 100% absorbed after oral adminis-
`tration, compared to intravenous administration,
`based on urine recovery studies.21,22 Only about
`60% of drug reaches the systemic circulation
`due to first pass metabolism.39,40 In some fasting
`volunteers, measurable plasma levels are ob-
`served within 10 min of dosing with diclofenac
`potassium, although peak plasma levels are
`generally achieved after 0.33–2 h.21 For enteric-
`coated diclofenac sodium tablets, drug is released
`once the tablet reaches the duodenum, with
`subsequent rapid absorption.30,41,42 Absorption
`of diclofenac occurs throughout the intestinal
`tract.43–46 Diclofenac shows linear pharmacoki-
`netics. The absolute BA of diclofenac potassium
`after oral administration did not differ signifi-
`cantly when 1 12.5- and 2 12.5-mg were dose
`in a randomized, three-way, crossover study in
`
`JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 4, APRIL 2009
`
`DOI 10.1002/jps
`
`Page 3
`
`

`
`BIOWAIVER MONOGRAPH FOR DICLOFENAC
`
`1209
`
`Table 1. Excipientsa Present in Diclofenacb IR Solid Oral Drug Productsc With a Marketing Authorization (MA) in
`Germany (DE), Denmark (DK), Finland (FI), France (FR), The Netherlands (NL), Norway (NO), Spain (ES), Sweden
`(SE), United Kingdom (UK) and the United States (US)d, and the Minimal and Maximal Amount of that Excipient
`Present Pro Dosage Unit in Solid Oral Drug Products With an MA in the USAe
`
`Excipient
`
`Drug Products Containing that
`Excipient With an MA Granted by
`the Named Country
`
`Range Present in
`Solid Oral Dosage
`Forms With an MA
`in the USA (mg)
`
`Croscarmellose sodium
`Crospovidone
`dimeticone
`Glycerol
`Glycerol dibehenate
`Hypromellose
`
`Lactose
`
`Lecithin
`Macrogol
`
`Macrogol stearate
`Magnesium stearate
`
`DK(1) NO(2) SE(3)
`Benzoic acid
`Calcium hydrogen phosphate DE(4) DK(5–12) FI(13,14) NO(15,16) SE (17,18) UK(19)
`Calcium phosphate
`DE(20) DK(21) FI(22) NL(23) NO(24) SE (25,26) US(27,28)
`Carmellose sodium
`DK(29) FI(30) NO(31) SE (32)
`Cellulose
`DE(20,33–36) DK(1,29,37) ES(38,39) FI(30,40)
`FR (41) NL(23,42,43) NO(2,31,44,45) SE
`(3,25,26,32,46,47) US(27,28,48,49)
`FI(40) US (48)
`DE(50,51)
`DE(33)
`DK(29) FI(30,40) NO(31) SE (32)
`DE(50,51)
`DE(34–36,50,51) DK(1,29,37) ES(38) FI(30,40) FR
`(41) NO(2,31) SE (3,32) US (28,48)
`DE(34–36) DK(1,29,37) ES(38,39) FI(30,40) FR (41)
`NL(42,43) NO(2,31,44,45) SE (3,32,46,47) US (28,48,49)
`DE(4) DK(5–12) FI(13,14) NO(15,16) SE (17,18)
`DE(20,33–36,50,51) DK(1,37) ES(38) FR (41) NL(23) NO(2)
`SE (3,25,26) US (27,28,48)
`DK(1) NO(2) SE (3)
`DE(4,20,33–36,50,51) DK(1,5–12,21,29,37) ES(38,39)
`FI(13,14,22,30,40) FR (41) NL(23,42,43) NO(2,15,16,
`24,31,44,45) SE (3,17,18,25,26,32,46,47) UK(19) US
`(27,28,48,49)
`DE(35,36) DK(37) FR (41)
`Maltodextrin
`DE(50,51)
`Mannitol
`Octamethylcyclotetrasiloxane DK(1) NO(2) SE (3)
`Polydextrose
`US (48)
`Polysorbateg
`DK(37)
`Polysorbate 80
`DE(35,36) FR (41)
`Poly(vinylalcohol)
`DE(4) DK(5–8) FI(13,14) NO(15,16) SE (17,18)
`Potassium hydrogen
`DE(50,51)
`carbonate
`Povidone
`
`Silica
`
`Simethicone
`Sodium hydroxide
`Sodium lauryl sulphate
`Sodium starch glycolate
`
`Sorbic acid
`
`DE(4,20,33–36) DK(5–12,21,37) ES(38,39) FI(13,14,22) FR (41)
`NL(23,42,43) NO(15,16,24,44,45) SE(17,18,25,26,46,47)
`UK (19) US (27,28)
`DE(4,20,34–36) DK(5–12,21,29,37) ES(38,39) FI(13,
`14,22,30,40) FR (41) NL(23,42,43) NO(15,16,24,31,44,45) SE
`(17,18,25,26,32,46,47) UK (19) US (27,28,48)
`DK(1) NO(2) SE (3)
`DE(33)
`DE(50,51) US (48)
`DE(4,20,33,35,36) DK(1,5–12,21,37) ES(38,39) FI(13,14,22)
`FR (41) NL(23,42,43) NO(2,15,16,24,44,45) SE
`(3,17,18,25,26,46,47) UK (19) US (27,28)
`DK(1) NO(2) SE (3)
`
`DOI 10.1002/jps
`
`JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 4, APRIL 2009
`
`No data
`104–850
`21–362
`2.2–160
`4.6–1385f
`
`2–180
`4.4–792f
`3.7
`0.14–198f
`5.7–14
`0.8–86
`
`23–1020f
`
`5–15
`0.12–500f
`
`0.15–401f
`
`0.16–80
`33–454
`No data
`3.8–8.1
`No data
`2.2–418f
`0.7–20
`12
`
`0.17–75
`
`0.65–99
`
`0.0004–5.7
`0.74–6.7
`0.65–50
`2–876f
`
`0.94
`
`(Continued)
`
`Page 4
`
`

`
`1210
`
`CHUASUWAN ET AL.
`
`Table 1. (Continued )
`
`Excipient
`
`Starch
`
`Starch, pregelatinized
`Sucrose
`Talc
`
`Triacetin
`Xanthan gum
`
`Drug Products Containing that
`Excipient With an MA Granted by
`the Named Country
`
`DE(4,20,33–36) DK(1,5–12,21,29,37) ES(38,39)
`FI(13,14,22,30,40) FR (41) NL(23,42,43)
`NO(2,15,16,24,31,44,45) SE (3,17,18,25,26,32,46,47)
`UK(19) US (27,28)
`US (49)
`DE(20,33) NL(23) SE (25,26) US (27)
`DE(4,20,33,34) DK(1,5–12) ES(38) FI(13,14) NL(23)
`NO(2,15,16) SE (3,17,18,25,26)
`US (48)
`DE(4) DK(5–12) FI(13,14) NO(15,16) SE (17,18)
`
`Range Present in
`Solid Oral Dosage
`Forms With an MA
`in the USA (mg)
`
`0.44–1135f
`
`6.6–600
`12–900
`0.26–220f
`
`0.72–15
`14
`
`1.
`2.
`3.
`4.
`5.
`6.
`7.
`8.
`9.
`10.
`11.
`12.
`13.
`14.
`15.
`16.
`17.
`18.
`19.
`20.
`21.
`22.
`23.
`24.
`25.
`26.
`27.
`28.
`29.
`30.
`31.
`32.
`33.
`34.
`35.
`36.
`37.
`38.
`39.
`
`Eeze, filmovertrukne tabletter
`Ezze 25 mg filmdrasjerte tabletter
`Eeze 25/50 mg, filmdragerade tabletter
`Diclac1 Dolo 12.5 mg Filmtabletten (Mono)
`Diclofenac Rapid ‘‘Actavis’’, filmovertrukne tabletter
`Diclofenac Rapid ‘‘Copyfarm’’, filmovertrukne tabletter
`Diclon Rapid, filmovertrukne tabletter
`Diclopax, filmovertrukne tabletter
`Fenaclo, filmovertrukne tabletter
`Dictavis, filmovertrukne tabletter
`Diclium, filmovertrukne tabletter
`Fenacta, filmovertrukne tabletter
`Diclofenac Rapid Actavis 25/50 mg tabletti, kalvopa¨ a¨ llysteinen
`Diclofenac Rapid Copyfarm 25/50 mg tabletti, kalvopa¨ a¨ llysteinen
`Diclofenackalium Actavis 25/50 mg tabletter, filmdrasjerte
`Diclofenackalium Copyfarm 25/50 mg filmdrasjerte tabletter
`Diklofenak T Actavis 25/50 mg filmdragerade tabletter
`Diklofenak T Copyfarm 25 mg och 50 mg filmdragerade tabletter
`Diclofenac potassium 12.5 mg tablets
`Voltaren1 K Migra¨ ne 50 mg u¨ berzogene Tabletten (Mono)
`Voltaren Rapid, overtrukne tabletter
`Voltaren Rapid 25/50 mg tabletti, pa¨ a¨ llystetty
`Cataflam 25/50, omhulde tabletten 25/50 mg
`CATAFLAM 50 mg drasjerte tabletter
`Diklofenak T Sandoz 25/50 mg, tabletter
`Voltaren T 25/50 mg, dragerade tabletter
`Cataflam1 tablet 50 mg, sugar-coated [Novartis Pharmaceuticals Corporation]
`Diclofenac potassium tablets 50 mg, film-coated [TEVA Pharmaceuticals USA]
`Diclofenac ratiopharm Rapid, filmovertrukne tabletter
`Diclomex Rapid 25/50 mg tabletti, kalvopa¨ a¨ llysteinen
`DiclofenacKalium ratiopharm tabletter, filmdrasjert
`Diclofenac T ratiopharm 25/50 mf filmdragerade tabletter
`Diclofenac PB 50 mg Tabletten (Mono)h
`Diclodoc1 50 Tabletten (Mono)h
`Optalidon1 Zahnschmerz mit Diclofenac Filmtabletten (Mono)
`Voltaren1 Dolo 12. mg Filmtabletten (Mono)
`Voltaren Dolo, filmovertrukne tabletter
`DICLOFENACO PENSA 50 mg comprimidos EFGh
`Voltalgial 12.5 mg comprimidos
`
`JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 4, APRIL 2009
`
`(Continued)
`
`DOI 10.1002/jps
`
`Page 5
`
`

`
`BIOWAIVER MONOGRAPH FOR DICLOFENAC
`
`1211
`
`Table 1.
`
`(Continued)
`
`Excipient
`
`Drug Products Containing that
`Excipient With an MA Granted by
`the Named Country
`
`Range Present in
`Solid Oral Dosage
`Forms With an MA
`in the USA (mg)
`
`Diclofenac Rapid ratiopharm 25/50 mg tabletti, kalvopa¨ a¨ llysteinen
`40.
`VOLTARENDOLO 12.5 mg cp enr
`41.
`Voltaren K, omhulde tabletten 12.5 mg
`42.
`Otriflu, omhulde tabletten 12.5 mg
`43.
`CATAFLAM 12.5 mg tabletter, filmdrasjerte
`44.
`Otriflu 12.5 mg tabletter, filmdrasjerte
`45.
`Otriflu 12.5 mg filmdragerade tabletter
`46.
`Voltaren T 12.5 mg filmdragerade tabletter
`47.
`Diclofenac potassium tablets USP, 50 mg film-coated [Mylan Pharmaceuticals Inc.]
`48.
`Diclofenac potassium tablets 50 mg, film-coated [Sandoz Inc.]
`49.
`Diclo-CT akut 12.5 mg Filmtabletten (Mono)
`50.
`Diclofenac-ratiopharm1 Schmerztabletten 12.5 mg Filmtabletten (Mono)
`51.
`aColourants, flavors and ingredients present in the printing ink are not included. Coating substances are excluded if in the SmPC
`the constituents of core and coating are stated separately.
`bDiclofenac potassium and diclofenac sodium. Unless otherwise indicated the reported drug products contain diclofenac
`potassium.
`acDrug products containing more than one API are excluded. Soluble tablets, dispersible tablets and powders and tablets to
`prepare an oral solution are reported in Table 2.
`dSources of data: DE, www.rote-liste.de (assessed September 25, 2007); DK, www.dkma.dk (assessed September 20, 2007); FI,
`www.nam.fi (assessed September 25, 2007); FR, www.vidal.fr (assessed September 24, 2007); NL, www.cbg-meb.nl. (assessed
`September 20, 2007); NO, www.legemiddelverket.no (assessed September 24, 2007); ES, www.agemed.es (assessed September 21,
`2007); SE, www. lakemedelsverket.se (assessed September 25, 2007); UK, www.mhra.gov.uk (assessed February 7, 2008); USA,
`http://dailymed.nlm.nih.gov (assessed February 6, 2008).
`feFDA’s Inactive Ingredient Database: http://www.fda.gov/cder/iig/iigfaqweb.htm#purpose (version date November 1, 2007).
`fThe reported upper range value is unusually high. The authors doubt its correctness.
`gWithout specified grade.
`hContains diclofenac sodium.
`
`10 subjects.39 The systemic absorption of diclofe-
`nac as a function of the dose is proportional within
`the range 25–150 mg,39,44 which suggests that the
`low drug solubility at low pH is not limiting
`absorption.
`Administration with food can extend the lag
`time (tlag) of drug absorption, thereby increasing
`the time to maximum concentration (tmax) and
`decreasing the maximum concentration (Cmax).
`Food does not have a significant effect on the
`extent of oral absorption of diclofenac sodium or
`diclofenac potassium.22,38,47,48 Diclofenac’s rapid
`and complete absorption suggests a high perme-
`ability through the intestinal membrane.43,44 This
`observation of high permeability throughout the
`intestinal tract is also supported by reports of
`rapid absorption of diclofenac from effervescent
`tablets45 and the high permeability of diclofenac
`in the colon after administration of the drug as a
`suppository.46
`In a Caco-2 cell monolayer experiment, the
`permeability of diclofenac from apical-to-basolat-
`eral ( PA–B) and basolateral-to-apical ( PB–A) direc-
`
`tions were 20.2  106 and 21.3 106 cm/s,
`respectively, while metoprolol permeability was
`43.4  0.7 106 and 34.1  0.6 106 cm/s in the
`respectively.49 Metoprolol
`is
`two directions,
`90–95% absorbed from the intestinal tract and
`is often used as a reference for the lower limit of a
`highly permeable drug.3,35,50 In an artificial
`membrane model, Pam of diclofenac, metoprolol
`and propanolol were 53.3  106, 5.67  106, and
`13.7  106 cm/s, respectively.51
`
`Distribution
`
`The apparent volume of distribution is 1.3 L/kg for
`diclofenac potassium21 and 1.4 L/kg for diclofenac
`sodium.22 Circulating diclofenac is known to be
`greater than 99% bound to human serum protein,
`primarily to albumin.30,52 However, this binding
`has been described as pharmacokinetically insig-
`nificant due to the rapid association–dissociation
`of diclofenac to albumin, such that the drug
`readily dissociates and permeates across the
`vascular membrane to the tissues.38
`
`DOI 10.1002/jps
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`

`
`1212
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`CHUASUWAN ET AL.
`
`Table 2. Excipientsa Present in Diclofenacb IR Soluble Tablets, Dispersable Tablets and Powders for Oral Solutionc
`With a Marketing Authorization (MA) in Germany (DE), Denmark (DK), Norway (NO), Spain (ES), Sweden (SE) and
`United Kingdom (UK)d, and the Minimal and Maximal Amount of that Excipient Present Pro Dosage Unit in Solid
`Oral Drug Products With an MA in the USAe
`
`Excipient
`
`Castor oil hydrogenated
`Cellulose
`Citric acid
`Croscarmellose sodium
`Crospovidone
`Glycerol dibehenate
`Lactose
`Magnesium stearate
`Mannitol
`Potassium hydrogen carbonate
`Povidone
`Silica
`Sodium starch glycolate
`Starch
`Talc
`
`Drug Products
`Containing that Excipient
`With an MA Granted by
`the Named Country
`
`DE(1–4) DK(5) ES(6) UK (7)
`DE(1–4,8,9) DK(5) ES(6) UK (7)
`DE(8,9)
`DE(1–4) DK(5) ES(6) UK (7)
`DE(8,9) ES(10)
`DK(11) NO(12) SE (13)
`DE(8,9)
`DE(8,9) ES(10)
`DK(11) NO(12) SE (13)
`DK(11) NO(12) SE (13)
`DE(1–3) ES(6)
`DE(1–4,8,9) DK(5) ES(6) UK (7)
`DE(1–4) DK(5) ES(6) UK (7)
`DE(8,9)
`DE(1–4) DK(5) ES(6) UK (7)
`
`Range Present in
`Solid Oral Dosage Forms
`With an MA in the USA (mg)
`
`0.93–37.6f
`4.6–1385f
`2.6–78
`2–180
`4.4–792f
`5.7–14
`23–1020f
`0.15–401f
`33–454
`12
`0.17–75
`0.65–99
`2–876f
`0.44–1135f
`0.26–220f
`
`1.
`2.
`3.
`
`Diclofenac AbZ 50 mg Trinktabletten (Mono)g
`Diclofenac-CT 50 mg Trinktabletten (Mono)g
`Diclofenac-ratiopharm1 50 mg Disperstabletten Tabletten zur Herstellung einer
`Suspension zum Einnehmen (Mono)g
`Voltaren1 Dispers Tabletten (Mono)g
`4.
`Voltaren, opløselige tabletterg
`5.
`DICLOFENACO RCA 50 mg comprimidos dispersables EFGg
`6.
`Voltarol Dispersible Tablets 50 mgg
`7.
`Diclac1 Dispers Tabletten (Mono)g
`8.
`Diclo dispers1 Tabletten zur Herstellung einer Suspension zum Einnehmen (Mono)g
`9.
`DICLOFENACO NORMON 50 mg Comprimidos Dispersables EFGg
`10.
`Voltaren Rapid, pulver til oral opløsningh
`11.
`CATAFLAM 50 mg dosepulver til mikstur, oppløsningh
`12.
`Voltaren 50 mg pulver till oral lo¨sning, dospa˚ seh
`13.
`aColourants, flavors and ingredients present in the printing ink only are not included.
`bDiclofenac potassium and diclofenac sodium. The salt form present is indicated for each product.
`cDrug products containing more than one API are excluded.
`dSources of data: DE, www.rote-liste.de (assessed October 24, 2007); DK, www.dkma.dk (assessed October 24, 2007); NO,
`www.legemiddelverket.no (assessed September 20, 2007); ES, www.agemed.es (assessed October 24, 2007); SE, www. lakemedels-
`verket.se (assessed October 24, 2007); UK, www.medicines.org.uk (assessed February 7, 2008).
`eFDA’s Inactive Ingredient Database, http://www.fda.gov/cder/iig/iigfaqweb.htm#purpose (version date November 1, 2007).
`fThe reported upper range value is unusually high. The authors doubt its correctness.
`gContains diclofenac sodium.
`hContains diclofenac potassium.
`
`Metabolism
`
`Excretion
`
`Diclofenac undergoes extensively hepatic bio-
`transformation involving aromatic hydroxyla-
`tions and conjugations.53,54 Five diclofenac
`metabolites have been identified.22,41,54 One
`metabolite has a very weak pharmacological
`activity.22
`
`Approximately 65% of diclofenac is excreted in the
`urine, largely as metabolites, and 35% in bile as
`conjugates of unchanged diclofenac and metabo-
`lites.22 Very little drug is eliminated in the
`unchanged form in urine.44 The terminal half-life
`of unchanged diclofenac is approximately 2 h.22,30
`
`JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 4, APRIL 2009
`
`DOI 10.1002/jps
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`

`
`Table 3. Solubility of Diclofenac Sodium from Literature Data19 and the Corresponding Dose/Solubility (D/S)
`Ratio’s for Three Tablet Strengths
`
`BIOWAIVER MONOGRAPH FOR DICLOFENAC
`
`1213
`
`pH
`
`1.2
`2.0
`3.0
`4.1
`4.5
`5.5
`5.8
`6.0
`6.8
`7.0
`7.4
`7.8
`8.0
`
`Medium
`
`0.1 N HCl
`0.01 N HCl
`0.001 N HCl
`Acetate buffer
`Acetate buffer
`Acetate buffer
`Phosphate buffer
`Phosphate buffer
`Phosphate buffer
`Phosphate buffer
`Phosphate buffer
`Phosphate buffer
`Phosphate buffer
`
`Solubility (mg/mL) (23 28C)
`
`12.5 mg
`
`0.0012
`0.0017
`0.28
`0.0033
`0.0036
`0.036
`0.14
`0.15
`0.67
`1.36
`5.15
`12.00
`12.14
`
`12500c
`7353c
`45
`3788c
`3472c
`347c
`89
`83
`19
`9
`2
`1
`1
`
`aCritical limit: <250 mL.2–4
`bHighest tablet strength of IR solid oral dosage forms on USA and EU market.
`cExceeds critical limit.
`
`D/Sa (mL)
`
`25 mg
`
`25000c
`14706c
`89
`7576c
`6944c
`694c
`179
`167
`37
`18
`5
`2
`2
`
`50 mgb
`
`50000c
`29412c
`179
`15152c
`13889c
`1389c
`357c
`333
`75
`37
`10
`4
`4
`
`DOSAGE FORM PERFORMANCE
`
`Excipients and/or Manufacturing Variations
`
`over, diclofenac is not on the list of except APIs
`from in vivo BE studies by the Dutch Regulatory
`Authorities.56
`
`Excipients present in diclofenac sodium and
`diclofenac potassium IR solid oral drug products
`with an MA in the US and some European
`countries are shown in Table 1. These products
`are ‘‘plain’’
`tablets and are intended to be
`swallowed intact. In Table 2, the same informa-
`tion is shown for IR soluble tablets, dispersible
`tablets and powders for oral solution. In view of
`the MAs, it is presumed that these drug products
`successfully met the in vivo BE criteria. Unlike
`other APIs, diclofenac products were not
`exempted from in vivo BE studies for some time
`by the German Regulatory Authorities.55 More-
`
`In Vivo Bioequivalence
`
`demonstrated BE among
`studies
`Several
`diclofenac potassium IR products.39,52,57,58 In a
`randomized, single dose, two-way crossover study
`in 66 subjects, a 12.5 mg diclofenac potassium
`tablet formulation was shown to be bioequivalent
`in terms of log transformed Cmax, AUC0t and
`AUC0–1 to its reference, Voltarol Dolo 12.5 mg
`tablets (Norvatis, Basel, Switzerland).57 Dissolu-
`tion profiles of test product were reported to be
`similar to the reference products marketed in
`various European countries.57
`
`Table 4. Solubility of Diclofenac Potassium at Room Temperature and the Corresponding Dose/Solubility (D/S)
`Ratio’s for Three Tablet Strengths
`
`pH
`
`4.5
`6.8
`7.4
`
`Medium
`
`Solubility (mg/mL)a
`
`12.5 mg
`
`Acetate buffer
`Phosphate buffer
`Phosphate buffer
`
`0.0014 (0.0001)
`0.7167 (0.0165)
`2.341 (0.016)
`
`8929d
`17
`5
`
`aBetween brackets: standard deviation of mean.
`bCritical limit: <250 mL2–4.
`cHighest tablet strength of IR solid oral dosage forms on USA and EU market.
`dExceeds critical limit.
`
`D/Sb (mL)
`
`25 mg
`
`17857d
`35
`11
`
`50 mgc
`
`35714d
`70
`21
`
`DOI 10.1002/jps
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`

`
`1214
`
`CHUASUWAN ET AL.
`
`In another single dose study in 24 healthy
`volunteers, a diclofenac potassium 50 mg sachet
`formulation containing excipients such as potas-
`sium hydrogen carbonate, mannitol, aspartame,
`saccharin sodium, glyceryl dibehenate, and fla-
`vors proved to be bioequivalent to the reference
`tablet formulation Voltfast in terms of AUC0–1,
`although Cmax was twofold larger from the
`sachet formulation.58 No dissolution studies were
`performed because the test formulation is a
`powder for oral solution.
`Neuvonen59 reported no significant change in
`the pharmacokinetics of diclofenac when coadmi-
`nistered with magnesium hydroxide, but this
`study was carried out with enteric coated tablets
`and hence of very limited value for IR dosages
`forms.
`
`Dissolution and In Vitro/In Vivo Correlation
`
`For diclofenac potassium tablets, the USP30
`dissolution specification is not less than 80% (Q)
`of the labeled amount to be dissolved within
`60 min in 900 mL simulated intestinal fluid
`(without enzyme) at 50 rpm in the paddle
`apparatus.27 The Ph.Eur and the BP do not
`contain monographs for IR diclofenac tablets. No
`in vitro/in vivo correlations were identified in the
`literature for diclofenac IR solid oral dosage forms.
`
`DISCUSSION
`
`Solubility
`
`Tables 3 and 4 show the dose/solubility ratio (D/S)
`of each salt at pH 6.0 and above to be less than the
`critical
`limit of 250 mL for highly soluble
`according to the present BCS Guidances.2,3,60
`The solubility reported by Kincl et al.29 at pH 3.0
`in 0.001 N HCl appears unexplainably high. All
`other data show diclofenac to be below pH 4.5 (or
`pH 5.8, depending on the tablet strength) to be not
`highly soluble. Although most solubility data have
`been collected at room temperature, it is unlikely
`that solubility values would be much different at
`378C to change the interpretation in terms of the
`BCS classification.
`
`Absorption and Permeability
`
`The complete 100% absorption classifies diclofe-
`nac as highly permeable.2,3,60 This classification is
`
`supported by in vitro data. Some reports indicate
`that a permeability coefficient of more than
`1 106 cm/s in Caco-2 model is considered to
`imply high permeability and/or complete absorp-
`tion.49,61,62 Others report that a permeability
`coefficient over 10 106 cm/s implies high
`permeability11 or >70% absorption in humans.63
`Diclofenac exceeds both criteria. The artificial
`membrane permeability data and the partitioning
`data further support the classification of di-
`clofenac as being highly permeable.
`
`BCS Classification
`
`According to all Guidances, the data presented
`above classify diclofenac in BCS Class II.2–4 Using
`the disposition characteristics of the API as an
`estimate for its permeability, Wu and Benet64
`assigned diclofenac to Class II in a Biopharma-
`ceutics Drug Disposition Classification System
`(BDDCS).
`
`Risk for Drug Products to be Bioinequivalent
`
`Tables 1 and 2 show excipients and their quantity
`limits used in diclofenac IR products with MAs in
`a number of countries. By virtue of their MAs, it
`may be assumed that these drug products passed
`in vivo BE studies. Hence, it is inferred that none
`of the excipients tabulated in these tables has had
`a significant effect on the extent nor the rate of
`diclofenac absorption. It is worthy of note that
`some drug products contain sodium lauryl sulfate,
`which has been reported to improve drug dissolu-
`tion of poorly soluble drugs.65 However, it appears
`that even if there was improved dissolution,
`sodium lauryl sulfate did not lead to the drug
`product to be bioinequivalent. It is deduced that
`these excipients in these reported limits do not
`cause interactions that result in bioinequivalence
`for diclofenac.
`We conclude that the low solubility of diclofenc
`at pH values of 4.5 and below does not pose a
`substantial risk for bioinequivalence. This may be
`the result of diclofenac high permeability, as
`well as the dynamic character of the uptake
`processes.66
`
`Surrogate Techniques for In vivo BE Testing
`
`The rate-limiting step in the absorption of
`diclofenac from a drug product is gastric empty-
`ing, disintegration in vivo or dissolution in vivo.
`Comparative in vitro dissolution testing in
`
`JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 4, APRIL 2009
`
`DOI 10.1002/jps
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`
`

`
`discriminatory media is a sensible technique to
`detect significant differences in disintegration
`in vivo or dissolution in vivo between a test drug
`product and comparator. In vitro dissolution
`testing in SIF (pH 6.8) without enzyme is
`suggested by USP and FDA for IR diclofenac
`potassium drug products as the quality control
`test.27,67 SIF without pancreatin and SIF without
`pancreatin with 1% (w/v) Tween 20 has been
`suggested as discriminatory dissolution media for
`diclofenac sodium prolonged release tablets.68
`Dissolution in these media can be considered as
`discriminatory dissolution test for IR dosage
`forms. The BCS Guidance prescribes comparative
`in vitro dissolution testing between test and com-
`parator in pH 1.2, 4.5, and 6.8 buffers and also
`provides criteria for the assessment of dissolution
`profile similarity.2–4 In media pH 1.2 and pH 4.5, no
`dissolution is expected, providing evidence that no
`dissolution enhancers are present.
`Since diclofenac permeability is high, intestinal
`absorption is not limiting. An excipient interac-
`tion with the permeation process is unlikely. This
`risk of interaction is even lower if the test product
`contains excipients that are known to exert no
`such influence, that is, the excipients tabulated in
`Tables 1 and 2.
`
`Patient’s Risks Associated With Bioinequivalence
`
`Bioinequivalence with respect to AUC can cause
`subtherapeutic