Petitioner Amerigen Pharmaceuticals Ltd.
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1013 - Page 1
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`

`
`Petitioner Amerigen Pharmaceuticals Ltd.
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1013 - Page 2
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`

`
`Petitioner Amerigen Pharmaceuticals Ltd.
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1013 - Page 3
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`

`
`Petitioner Amerigen Pharmaceuticals Ltd.
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1013 - Page 4
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`

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`
`component. that will pharmacologically antagonize an
`unfavorable property or properties exhibited by the basic
`agent. Salts of N -cyclohexylsulfamic acid are an example
`of the practical application of this approach. N-Cyclo-
`hexylsulfamic acid salts, better known as cyclamates, have
`a characteristic sweet, pleasing taste. Although presently
`under investigation by the FDA for potentially carcino-
`genic properties, salts incorporating this compound can
`render unpleasant or bitter—tasting drugs acceptable. For
`example.
`the cyclamates of dextromethorphan and
`chlorpheniramine exhibit. gfeatly improved bitterness
`thresholds compared to corrunonly occurring salts (31).
`Furthermore, their stability in aqueous solution was de-
`scribed as good when maintained at a pH not greater than
`4.
`
`N-Cyclohexylsulfarnic acid salts of thiamine hydro-
`chloride and lincomycin also have been synthesized. Thi-
`amine N -cyclohexylsulfamate hydrochloride was reported
`to have a more pleasant taste than other thiamine salts
`while having an equal or greater stability (32). Lincomycin
`cyclamate, shown t.o possess an enhanced thermal stability
`over its hydrochloride, was prepared {B3} to test the hy-
`pothesis that reduced lincomycin absorption in the pres-
`ence of small quantities ofcyclamates was due to a simple
`metathetic reaction. However, this assumption was found
`not to be true. An extensive study of the preparation and
`characterization of cyclamic acid salts of several widely
`used classes ofdrugs including antihistamines. antibiotics.
`antitussives, rnyospasinolytics, and local anesthetics was
`reported (34, 135}.
`Various salts of penicillin and basic amine compounds
`have been formulated in an effort to produce a long-acting,
`nonallergenic Form of penicillin. Since antihistamines
`appear to mitigate the syniptomatology of penicillin re-
`acl.ions in some patients, coadministration of the two has
`been advocated. The preparation of the henzhydralamine
`salt of penicillin was an attempt. to produce a repository
`form of penicillin with antiallergic properties (36). Blood
`levels achieved with this salt were comparable to those of
`penicillin G potassium; however, it.s antiallergic properties
`were not evaluated- In fact, the investigators noted that
`antihistamines can actually cause sensitization at times
`and stated that. “despite their occasionally l'avorable in-
`fluence on the svmptorns of penicillin sensitivity, they
`contribute directly to the potential of drug sensitivity when
`co-administered with penicillin."
`Silver salts of sulfanilarnide, penicillin, and other anti-
`biotics have been prepared and represent cases where the
`species {ions} are complementary. When aqueous solutions
`of the salts were applied topically to burned tissue, they
`yielded the combined benefits of the oligodynarnic action
`of silver and the advantages of the. antibacterial agents
`(37).
`
`The use of 8-substituted xanthines, particularly the
`8-substituted theophyllines. as salt—forming agents was
`lirst reported in the preparation ofa series ofantihislamine
`salts (38-41). Synthesis of these xanthine salts was an at-
`tempt. to find a drug to counteract the drowsiness caused
`by the antihistamines with the stimulant properties of the
`xanthines. When an electroncgative group is introduced
`into the xanthine molecule at the 8-position, the elec-
`tron—drawing capacity of the substituent results in the
`creation of an acidic hydrogen at position 7. Thus. these
`
`-I
`
`/I Jon-rriol of .{'I.lI[I.l'l'Ti('l,(,'L-'Hl‘!IL'«'I.f .5(‘lii?n.L'r'.s
`
`moderately strong acidic compounds can undergo salt
`formation with various organic bases.
`The 8—l1alotheophyllines were the first group of san-
`thines studied as potential salt-forming agents. Since the
`report on the preparation of the 8-chlorotheophylline salt
`of diphenhydramine (42), synthesis of the 8-ha_lotheo-
`phyllinates of a number of organic bases has been at-
`tempted. The 8-chlorotheophylline salts of quinine,
`ephedrine, and strychnine were prepared and character-
`ized (43). These salts were less water soluble than the
`corresponding free alkaloidal bases. In a similar report, the
`8-chlorotheophyllinates of
`three synthetic narcotics.
`meperidlne, levorphanol, and metopon, were prepared
`(44).
`
`Pharmacological and clinical studies involving the 8-
`hromotheophylline pyrilamine salt revealed the unusual
`diuretic properties associated with the S8-halotheophylline
`portion of the compound (45, 46}. This finding initiated
`an investigation into the preparation of a soluble 8-bro
`motheophylline salt of high diuretic activity. With readily
`available amines, over 30 salts were synthesized and
`screened for diuretic activity (47). When tested against
`theophylline salts of the same amines, the 8-bromotheo
`phyllinates showed greater activity in every case.
`With the successful formation of 8-halotheophyllinates
`of organic bases, Morozowich and Hope (48) proposed that,
`if the halogen moiety was replaced with a more electro-
`negative substituent such as a nitro group, a more acidic
`compound would be formed. Presumably, more stable salts
`would result and precipitation of the free xanthine deriv-
`ative in the stomach would be less likely to occur. On this
`premise, they successfully prepared pharmacologically
`effective 8-nitrotheophyllinates of several pharmaceuti-
`cally useful bases.
`Duesel et al. (19), in their study of choline theophylli-
`nate, prepared the 8-chloro-. 8—bromo-, and 8-nitrotheo
`phylline salts of choline. Oral toxicity studies in mice
`showed that the LD.-an of the 8-nitrotheophyllinate was
`much greater than that of either 8-halul.heoph_vlline. In
`fact, it remained nonlethal at doses as high as 5 g.
`Polygalacturonic acid, a derivative of pectin, has been
`used to prepare quinidine salts exhibiting reduced toxicity
`[49, 50). The compound possesses special dernulcent
`properties and inhibits mucosal irritation. The rationale
`for use of this agent is to reduce the ionic shock to the GI
`mucosa resulting from the flood of irritating ions liberated
`by rapid dissociation of the conventional inorganic quin-
`idine salts. Studies have shown that it is four times less
`toxic orally than the sulfate. This difference was attributed
`to the slower release of quinidine from the pol_vgalactu-
`ronate.
`
`Other compounds reported to be potentially useful as
`pharmaceutical salt forms are listed in Table III.
`
`PHYSICOCHEMICAL STUDIES
`
`Biological activity of a drug molecule is influenced by
`two factors: its chemical structure and effect at a specific:
`site and its ability to reach—and then he removed from—
`the site ofaction. Thus, a knowledge ofthe physicochem
`lcal properties ot' a compound that influence its absorption.
`distribution, metabolism, and excretion is essential for a
`complete understanding of the onset and duration of ac-
`
`Table H‘l—
`
`Hal I
`
`Acel.vlan:inot
`N-Acelyl-I.-a
`N -A ct-lylcvsl
`Arlatnanloic 2
`l"\rlipi1:3Cl[l
`N .-’\ll«i_vlsuil‘aI
`
`Anlhrncguinoi
`firrnlnogalarlas
`:‘\rginine
`
`Aspartale
`Bolaine
`Hisiil-carhm<_\
`['.arnitine
`-1-C‘.hluro—m—II
`l'}ei.-anoate
`[Jiacclyl sulfa
`[lilaenz_vIet.hy|
`Tlielhvloinine
`l"liguaiac_v| ph
`llioctyl sull'n.r-'.
`Pmb: mic {pan
`
`l“-'l‘l.l[?l.ll5t'- l.£i-G‘
`
`Gin:-.1 use l-pllu
`l'i-pho:-.ph_ori
`1.-tilulamine
`H_vdrr:_\;ynnph
`3—l-1-lrnidagmlg
`lsrnialllalirnlaln
`Lau ryl su ll'aI.e
`Lys: ne
`Mel l1.'!I'|l:Rtlll-L].
`N- Met liylgluc
`
`N -iVlet.hy|pipe
`l\1lnrphollne
`3-N.’-]}}l‘l1.llF1l(~‘.rlI
`fl:-I ant u1l.{-‘
`Pr: uhe ne:.-iii
`'l‘a1111lc:Jt-id
`Theobromine.
`H,-l.5-"l'rimt‘lh(
`
`’l'romel haminr
`
`tion, the rel
`ministratior
`in a reviei
`“different se
`logically; the
`properties."
`panded upoi
`nature of th
`salts of the s
`ciahly. their
`The salt fr
`
`cocheinical [
`dissolution r
`These propc
`rnulation ch
`pharrnaceutl
`extensive pr.
`properties of
`suitable forn:
`
`concerning s
`tion studiesi
`salt form on
`under invest
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1013 - Page 5
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1013 - Page 5
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`
`Jdergo salt
`
`mp of Xan-
`s. Since the
`nhylline salt
`3—halotheo-
`as been at.-
`
`)f quinine,
`lcharacter—
`le than the
`_-report, the
`narcotics,
`e prepared
`
`ving the 8-
`.he unusual
`
`heophylline
`1g initiated
`uble 8-bro-
`
`Vitii readily
`esized and
`
`ted against
`3ro1notheo~
`ass.
`
`nphyllinates
`iiposed that,
`ore electro-
`mere acidic
`estable salts
`thine deriv-
`cur. On this
`acologically
`Iarrnaceuti-
`
`theophylli—
`5-nitrotheo—
`ice in mice
`-'llinate was
`ohylline. In
`3 5 g.
`n, has been
`_ced toxicity
`cleinulcent.
`rte rationale
`:k to the GI
`ns liberated
`
`‘genie quin-
`r times less
`.5 attributed
`:elygalactu-
`
`_ly useful as
`lll.
`
`fluenced by
`at a specific
`‘wed from-—
`
`1ysicochein—
`5 absorption,
`sential for a
`ration of ac-
`
`Tahle lII—Potentially Useful Salt Forms of Pharmaceutical Agents
`
`Salt-Forming Agent
`
`Compound Modified
`
`Nlcadificatitrn
`
`itc-ts-rem-e
`
`.-\cr».ty|aminoacetic acid
`.'\"—Acetyl—I.—asparagine
`N-Acel._vlcysti:1e
`atrlarnantoic acid
`.-tdipic acid
`ti‘-Alkylstrllamntes
`
`r\nt.hraquinone— l,5—disulI'onic acid
`Ara bogalactan sulfate larabino}
`Argininc
`
`Aspartale
`Betnine
`lrlisl133-carbu)xycl1romon~5—yloxy)alkanes
`Carnitinc
`at-{‘h|orn—m -toluenesulfonic acid
`Decanoate
`llincetyl sulfate
`Ilibenaylethylenediamine
`Dietliylamine
`lligiiaiat-yl phosphate
`lliortyl sulfosuccinate
`Fimhonic ipamoic) acid
`
`Fructose. 1,6-cliphosphoric acid
`
`tllucose 1 -phosphoric acid, glucose
`['l-[)l'!05|.')l1¢1]‘l(.‘ acid
`I.-tiltltamine
`l-lyrlrmcynaphthoate
`2-l-l-lmidaitolyllethylarnine
`lsoliutanolarnine
`Lauryl sulfate
`|.._\.rsine
`
`.-irlelhonesulfonic acid
`:'\'-i\«'lcl.hylglt1carninc
`
`.’\'-Vlet hylpiperazine
`."vir:rpholine
`‘_’-'\lirphtlialenesoltonic acid
`Uctan--etc
`Prolienecicl
`'i'.-mnir acid
`'|'heubroInine acetic acid
`It,4.5-'l‘riniethoxybenaoatc
`
`'l"romcthaminc
`
`Doxycycline
`Erythromycin
`Doxycycline
`Alkylbiguanides
`Piperazine
`Ampicillin
`Lincomycin
`Cephalexin
`Various alkaloids
`Cephalosporins
`orvSulfoben'Ly]penicillin
`Erythromycin
`Tetracycline
`T-(Aminoall<ylltheophyllines
`Metforrnin
`Propoxyphene
`l-leptaminol
`Thiamine
`Ampicillin
`Cephalosporins
`Tetracycline
`Vincamine
`Kanamycin
`2—Phenyl-3~niethylmorpholinc
`'l"et.racycline
`Erythromycin
`'l‘etrac_vcline
`Erythromycin
`Erythromyciri
`Bephenium
`Prostaglaiidin
`Tbeophylline
`Vincamine
`or-Sulfobenzylpenicillin
`Cephalosporins
`F‘ralidoxin1e(2- PAMt
`cr-Sulfobenzylpcnicillin
`Cephalosporinfi
`Phcnylbtit-azone
`Cephalosporins
`Propoxyphene
`l-leptaminol
`Pivampicillin
`Various amines
`Propmryphene
`Tetracycline
`Heptaminol
`Aspirin
`Dlnoprost. lprostaglanrlin l7‘;,,J
`
`Solubility
`t-hrltibility, activity, stability
`Combined effect useful in pneumonia
`Prolonged action
`Stability. toxicity, or:.{anoleptio propcrtie.-e
`Absorption {oral}
`Solubility
`F-baliility, absorption
`Prolonged act ion
`'l"osi:.-it_V
`.°~t.abilit.y, l1_vgrosropicit.y, Loxit-it_\'
`Solubility
`Gastric alJsorpt ion
`Act’.ivit_v_. prolonged prnph_vlan::t.ic effect
`Tr-xittity
`Organoleptic properth-_-s
`Prolonged at-tion
`.‘-Stability. hygroscopicity
`Prolonged action
`Reduced pain on injection
`Activity’
`Organoleptic properties
`Toxicity
`Toxicity
`.‘~1o|obilit_v
`5-iolubility
`l‘inlubilit_v
`l'n'nlubilii._v
`Solubility. activity. stability
`Toxicity
`Prolonged &(‘l.l<tI'|
`Stability
`Urganoleptic properties
`'l‘:otictty, stability. hygroscopic-ity
`
`htsslubi I it);
`"l‘oxiciI.y, stability, lIygrosc<.rpiril.).-'
`Reclucetl pain on injection
`'l‘oxicit.y, faster onset of action
`Reduced pain on in_ie<:tion
`Organnleptlc properties
`Prolonged action
`Urganolcptic propert it-s
`Prolongctl action
`Activity
`Urganolcptic properties
`Prolonged action
`Aim n'}'.lt.lI_1r't (oral!
`l‘l1ys'n-al state
`
`:31
`.31!
`as
`.-'1-I
`-3:71
`Fsfi
`.1‘.
`.3.‘-t
`.39. Fill
`fit
`H2
`GI?
`ii-I
`ti?»
`iitt
`ii?
`HR
`69
`Ti]. 71
`T.-‘
`Til
`T4
`T5
`TR
`T‘.
`
`:7
`
`5'.’
`To
`TE)
`htl
`h'1
`H15
`til
`‘'3
`Iii
`73
`Hit
`7‘-J
`H-1
`(:18
`R5
`tilt. is?
`83
`H9
`58
`Ettt
`9!
`
`tion, the relative toxicity, and the possible routes of ad-
`ministration (2).
`In a review in 1960, Miller and Holland (92) stated that.
`“rlifferent salts of the same drug rarely differ pharmaco-
`logically; the differences are usually based on the physical
`properties." In a subsequent review (93), Wagner ex-
`panded upon this statement, asserting that, although the
`nature of the biological responses elicited by a series of
`salts of the same parent compound may not differ appre-
`ciably, the intensities of response may differ markedly.
`The salt form is known to influence a number of physi-
`cochemical properties ofthe parent compound including
`dissolution rate, solubility, stability, and hygroscopicity.
`These properties, in turn, affect the availability and for-
`mulation characteristics of the drug. Consequently, the
`pharmaceutical industry has systematically engaged in
`extensive preformulation studies of the physicochemical
`properties of each new drug entity to determine the most
`suitable form for drug formulation. Published information
`concerning such studies, however, is sparse. Preforrnula-
`tion studies have been outlined, and the influence of the
`salt form on the volatility and hygroscopieity of an agent-
`under investigation was discussed (94).
`
`In one such study, methylpyridinium-2-aldoxime
`ipralidoxime} salts were investigated (95). This study set
`out to prepare a salt with water solubility adequate to allow
`intramuscular injection of a low volume (2-3 ml) thera-
`peutic dose. The original compound, the 111El;—l1lUCllCl9, had
`the disadvantages of limited aqueous solubility and ltigh
`potential toxicity, since its high iodide content. could result
`in iodisrn. On the basis of physiological compat.ibility,
`better water solubility, favorable stability. and relat.ively
`high percentage of oxirne, the chloride salt of pr-alirloxime
`was selected for therapeutic administration; it was claimed
`that “the anion usecl to form the salt can confer physical
`properties of importance and significance for the forum-
`lation and administration of the compound" {Q5}.
`Some physicochemical properties ofa series of mineral
`acid salts of lidocaine also were determined (96). While the
`hyd rochloride and hyclrobromiole were more hygroscopic.
`they were more soluble in a number of solvents than the
`nitrate, perchlorate, phosphate, or sulfate salts.
`Dissolution Rate——The dissolution rate of a pharma-
`ceutical agent is of major importance to the Formulator‘. In
`many cases, particularly with poorly soluble drtigs, this
`characteristic best reflects the bioavailability of the com-
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1013 - Page 6
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1013 - Page 6
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`Vol. titi. Nrt l. :l'm1or::'_\-' I97? 3' 5
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`
`administration of three different salts and the free acid,
`was the same as the rank order of their rates of dissolution
`in oitro. While the investigators ascribed these differences
`to the solubility properties of the salts, their experiments
`actually compared dissolution rates, not solubilities. The
`relative order of dissolution rates and mean mardi-rial blood
`levels was: potassium salt > calcium salt > free acid >
`benzathine salt.
`Nelson (100) determined dissolution rates for several
`weak acids and their sodium salts in media whose pl-{'3
`represented GI fluids. In all cases, the sodium salt. dis-
`solved more rapidly than the free acid. This finding re-
`solved the misconception that absorption of drugs is re-
`lated only to solubility in the appropriate medium; rather.
`solubility affects absorption only to the extent that it ef-
`fects dissolution rate. Absorption of drugs is a dynamit-
`process. and the ultimate solubility of a drug in fluid al
`absorption sites is of limited consequence since absorption
`prevents the attainment of saturated solutions. Therefore.
`dissolution rate, more than solubility, influences absorp-
`tion since it is a preceding process.
`In two subsequent studies, Nelson and coworkers fur-
`ther illustrated the effects of changing nonionized drugs
`into salts. A report concerning tolbut-amide {I01}, a weal
`acid, showed that the initial dissolution rate of tolbu tamide
`sodium was approximately 5000 times more rapid than the
`free acid in acidic media and 300 times more rapid in
`neutral media. This difference, measured in oitro. reflecterl
`the differences observed between the free acid and the salt
`when administered to htunan-subjects. Oral administration
`of tolbutamide sodium produced an immediate drop in
`blood sugar comparable to that produced by intravenous
`injection of the salt, while the slowly dissolving tolbuta
`inide produced a smooth, sustained fall in blood sugar
`(102).
`Correlation of urinary excretion rates and dissolution
`rates of tetracycline and some of its acid salts also was
`demonstrated by Nelson (103). The salts that exhibited
`greater in tiitro dissolution rates showed greater urinary
`excretion rates, indicating more rapid absorption.
`Benet {I04}, in a discussion of the biopharmaceutical
`basis for drug design, referred to the influence of the salt
`form on dissolution. He compared the dissolution rates ol
`tetracycline and tolbutarnide and their salts, as reporteil
`in the studies previously cited, and explained why the rates
`differ at the pl-l's exhibited by physiological fluids.
`Although salt formation usually increases the dissolution
`rat.e of a drug, studies with aluminum acetylsalicyla te l 105.
`106), warfarin sodium {107l. and benzphetamine panioalt
`(108) showed that. administration of the salt .~_.'i’oii'ed dis-
`solution of the drug and subsequent absorption compared
`to the nonionized form. This decrease appeared t.ii resuli
`from precipitation of an insoluble particle or film on the
`surface of the tablet. Such a phenomenon decreases the
`effective surface area and prevents deaggregation of the
`particles. Theoretical considerations of the processes
`controlling dissolution of an acid salt ofa base (108) and
`the sodium salt of a weak acid (109, 110) in reactive media
`have been discussed.
`
`Tablet processing and various formulation factors can
`decrease the dissolution rate of a salt. in human gastric juice
`over its nonioriized form (111). Granulation and tableting
`caused the dissolution rate of phenobarbital sodium tii
`
`decrease bu
`Therefore, 5
`the sodium:
`results were
`properties c
`]Lition may i
`Others he
`the dissolut
`form. Lin et
`
`and biologic.
`base of an e
`
`HCl, and pi‘
`the monoby
`base in 0.1 1
`water and p
`variation to
`experiment.
`monohydroi
`the implicai
`the activity
`must be con
`hydrocblori
`Some con
`formation o
`
`tionship lilel
`pearance of
`et oil. (114)
`of salts of a
`the Eu'ill.—ft'!l‘I2
`They state:
`dissolution
`be the case i.
`dissolving s
`more rapid
`forrnation o
`
`higicol ("oni
`Several re
`tion rate on
`
`(us, 117). C
`and salt. for"
`Solubilit;
`of a pharrns
`is usually a
`profile, the
`mulation of
`a primary fr
`uhility ofar
`and chemicr
`
`point. for a r
`lattice ener
`
`Solubility c
`perature. pi
`pH), and, tr:
`solute.
`
`Ari impor
`involves the
`ride salts of
`
`hility in gas‘
`ions. The er
`
`Salt forrn
`
`pound. As a rule. a pharmaceutical salt exhibits a higher
`dissoliition rate than l.he corresponding conjugate acid or
`base at no equal pl-I, even though they may have the same
`equilihriiiin soh.ilJilil._v. The explanation for this result lies
`in the processes that control dissolution.
`Dissolution can be described by a di ffusion layer model‘
`in terms of an equation developed by Nernst and Brunner
`1971:
`
`lEq. ii
`
`,
`..
`l)‘S
`dill’
`till = T H G — r I
`where W is the mass of the solute dissolved at time t,
`(ll/Wdt is the rate of mass transfer per unit time, D is the
`solute inoleculc diffusion coefficient, 5‘ is the surface area
`of the rlissoiving solid. ii. is t.he diffusion layer thiCli11€SS.
`t_' is the concent.ral'.ioi'i of the drug in t.he bulk solution at
`time if, and C,
`is the saturation solubility of the solute in
`the diffusion layer.
`The driving force for dissolul ion in Eq. 1 is the difference
`between the saturation solubility of the drug and the
`I.".t‘)l'1t'E‘]1ll'al'll)l'1 of the drug in the bulk fluid. If the drug is
`iioi rapidly absorbed after it dissolves, then C, the con-
`centration in the bulk solution. approaches C’, and the
`i..lissolin.ion rate is retarded. When this occurs. absorption
`is “absorption i'at.i3" limited (or "membrane transport"
`limited). if the absorption rate is rapid (or if the absorption
`rnai-is transfer coefficient is much larger than .DS/h. ofEq.
`it. however. ll‘ becornes negligible compared to C, and
`dissolui ion i'_:c.c.urs under "sink” conditions. Absorption is
`then S::IlCl to be dissolution rate |imit.ed, which is what oc-
`curs with most" poorly soluble drugs. In either case. an in-
`t-.reasc in
`as in salt. formation, increases dissolut.ion.
`!~i:-ilts olten speed dissolution by effectively acting as
`their own ln_ii’fers to alter the pH of the diffusion layer, thus
`increasing the solubility of the parent cofhpound, C,. in
`that la_\’€!r over its inherent solubility at the pH of the
`dis.»:olI_itioi'i medium. Hence, dissolution is controlled by
`solubility in the diffusion layer which, in turn, is deter-
`mined by the pH of that layer. The influence i'ifK_,.,, on the
`solubility term, (_‘,, and dissolutioii rate. should an accu-
`il'l1llli‘tl'.lt}l‘I of ions be allowed to oc.cur. will be treat-ed
`ater.
`Nclsoii {BS}. in a study of theophylline salts. was the first
`to show the coi‘relat.ion between diffusion l.ayei' pH and
`dissolution rate. The major impact. that. this study had on
`the pliarniaceiitii~al sciences was its conclusion that, if
`other factors remained constant._ the dissolutioii rate ofa
`compound determined the rate of buildup of blood levels
`vvitli time and the maxiinum levels obtained. Those salts
`of the acidic llieophylline with high diffiision layer pH's
`had grc.at.ei' in i_v'i.ro dissolution rates than those exhibiting
`a lower di1'i'usioii layer pl-l. And, indeed, the rank order of
`dissoliition rates correlated well with cliiiii:-ally determined
`blood levels. l-’resumal:il_v. the higher pH in the diffusion
`layer i'etai'ils l't_\'ClI‘(ll_\:"S‘«lS oftlie salt, thereby inaintaining
`the ‘c1Illt_Il‘tll‘ charge of the tlieiiphylliiiale ion. This report
`led to nisiiy additional studies which illustrate the influ-
`ence of the sail. form on dissolution and the beneficial ef-
`fects of cliai'i,v,'i1ip' [‘lUI]lDl1li.ECl drugs into salts.
`-luncher and Raaschou (99) dernoiisi'.rat.edthat. the rank
`order of peak blood levels of penicillin V. obtained upon
`
` '
`
`'l'.‘ii :iiil llnl" r'i_-i'iI-_'rii:v_i_- Iln: (-\ri.-a1t-ii:-i- l,‘l
`I-ii‘ Illll-'ll':'ill‘—'E ]|||!'|lII'.-'~|.'-1
`
`i-1 l'It’|' Iniiile-l-'_ ll1l,€.n-J11) Wu-.-'. l']'IlI1-'I‘ll .~:iiIi1:l_\'
`
`ll
`
`,4 Jiiirriiirl of l’.litir.ii1ur'i_'ti.ltf'nt' .‘i'r'ii'rii'i=.<
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1013 - Page 7
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1013 — Page 7
`
`
`
`

`
`
`
`is free acid,
`Tdissolution
`2 differences
`
`.-xperirnents
`hilities. The
`iximal blood
`free acid >
`
`a for several
`whose pl-i's
`um salt dis-
`:-. finding re-
`drugs is re-
`liumzrather,
`nt that it of-
`s a dynamic
`g in tluid at
`e absorption
`s. Therefore.
`aces absorp—
`
`
`
`--,_—.-_.<_
`
`worl<ers fur-
`llll.7.(-‘fl drugs ‘
`llll l, a weak
`tolbutamide
`spid than l.he
`ore rapid in .
`trn_ rellected
`l and the salt
`lrninistration -
`liate drop in
`intravenous
`
`sing t.olbuta-
`l‘;luur.|
`.-iugar
`
`d rlissnlution
`alts also was
`rat exhiliited
`Eater urinary
`prion.
`Eirmaceutical
`ICE‘ oi" the salt
`uiion rates of
`I. as reported .
`wl1_\‘thr:1'aI'.es
`l fluids.
`he dissolution
`alicx-'lat.e 1.105,
`nine pamoate
`ll .-:lo1red dis-
`ion (J! srnpared
`ared to result
`If film on the
`iecreases the
`
`agation of the
`he processes
`ase {_lt’l:':l) and
`ear-l.ive media
`
`in factors can
`
`.11 gastric juice
`and tableting
`tal sodium to
`
`decrease but had the opposite effect on phenobarbital.
`Therefore, as a tablet dosage form, the dissolution rate of
`the sodium salt was slower t.han that of the free acid. These
`results were attributed to differences in the disintegrating
`properties of the tablets; in some instances, rapid disso-
`lution may in fact, be a problem for very soluble drugs.
`Others have illustrated a phenomenon that decreases
`the dissolution rate of a salt below that of its nonionized
`form. Lin et at. {J 12) studied the relationship between salts
`and biological activity by dissolving three salts and the free
`base of an experimental antihypertensive in water, 0.1 N
`HCl, and pH T2 phosphate buffer. The dissolution rate of
`the monohydrochloride salt was lower than that of the free
`base in 0.1 N HCl and higher than the free base in both
`water and phosphate buffer. These authors ascribed this
`variation t.o the common ion effect and substantiated it
`experimen tally. Although the biological activity of the
`monohyd rochloride was greater than that of the free base,
`the implications of altered absorption characteristics on
`the activity of any other hydrochloride salt in GI fluids
`must be considered. Similar results also were reported for
`hydrochloride salts of some tetracyclines (113).
`Some consideration must be given to the influence of salt
`formation on oral toxicity, which often reflects the rela-
`liunship bet.ween the in vino dissolution rate and the ap-
`pearance of drug in the circulation (114, 115}. Morozowich
`:21 at. (114) showed that the relative toxicities of a series
`of salts of a drug reflect the rate of absorption, providing
`the salt.-forming agents themselves are relatively nontoxic.
`They stated that “when absorption is rate-limited by
`dissolution of the salt in the gastrointestinal tract, as will
`be the case with slowly soluble salts, the toxicity of a slowly
`dissolving salt will most probably be lower than that of a
`more rapidly dissolving salt." The implications of salt
`lllI‘]'l'lal.lt}fl on toxicology will be discussed under Toxico-
`logical Corisiclerrrtiorts.
`Several reviews dealt with the influence of the dissolu-
`tion rate on drug availability and, in particular, salt effects
`l l 16.
`I 17}. Other reports illustrating the influence of salts
`and salt form on dissolution rate are listed in Table IV.
`Solubility—~Knowledge of the solubility characteristics
`of :2 pharmaceutical agent. is essential, because solubility
`is usually an important factor in the pharmacokinetic
`profile, the chemical stability, and, ultimately, the for-
`mulation of the drug. As discussed previously, it is certainly
`a primary l'actor\in controlling dissolution rates. The sol-
`ubility of a compound depends basically upon the physical
`and chemical properties of the solute; e.g., a lower melting
`point for a compound within a series reflects a decreased
`lattice energy, which would suggest a higher solubility.
`Solubility depends as well upon such elements as tem-
`perature, pressure, solvent properties [such as resulting
`pH l. and, to a lesser extent, the state of subdivision of the
`solute.
`An important solvent property which is often overlooked
`involves the common ion effect; in particular, hydrochlo-
`ride salts of drugs often exhibit less than desirable soluv
`hility in gastric juice because of the abundance of chloride
`ions. The equilibrium involved is shown in Scheme 1.
`
`ou+c1-._..,.,,, 7% tDH*l,... + tc1—i..,
`Scheme l'
`
`Salt. formation is perhaps one of the first approaches
`
`Table IV—Addil:ional References on Salt Form and
`Dissolution Rate
`
`Topic
`
`lilelereiice
`
`Dissolution rate of mixtures of weak acids and tribasic
`sodium phosphate
`Physiological availability and in uitro dissolution
`characteristics of some solid dosage formulations of
`aminosalicylic acid and its salts
`Biopharmceutics, rate of rlissolution: chronological
`bibliography
`Biopharmaceutics: rate ofdissolution in crtrn and in cioo
`Dissolution tests and interpretation ofanomalies observed
`in the dissolution process ot' sulfaquinoxaline based on
`salt formation
`ln|'|ur_-nce. of the dissolution rate of lithium tablets on side
`elllecis
`Dissolution kinetics of drugs in human gastric juice
`Comparison of dissolution and absorption rate:-'. of
`different cornrnercial aspirin tablets
`In uitro dissolution rates ofarninorex dosage forms and
`their correlation with in Lritro availability
`
`118
`llll
`
`L-.'.'‘S
`
`l
`
`»-0-A r-.'.-N.{O>—-
`
`..n..
`
`131
`[94
`135
`
`125
`
`considered as a means of increasing a cornpound’s water
`solubility. As with dissolution rates, however, salt forma-
`tion does not always confer greater solubility. Liberally
`dispersed throughout. the pharmaceutical literature are
`studies that compare the solubilities of different. salt forms
`of the same compound with those of its free acid or base
`(Table IV). Selection of the salt form exhibiting the desired
`solubility properties is critical, since these properties often
`dictate the formuiation characteristics of the drug.
`Phase solubility techniques were used to study the for-
`rnation of complex salts oftriamt.erene (127). The results
`indicated that the organic acid salts of basic drugs, such
`as amines, were more soluble in water than the corre-
`sponding inorganic (halide) saits. This consideration is
`important in the synthesis and selection of a salt form that.
`will exhibit enhanced bioavailability and desirable for-
`mulation characteristics.
`The hydrogen-ion concentration can significantly affect
`the solubility of a salt. Anderson (128) discussed the in-
`fluence of pH on the solubility of pharmaceuticals.
`Mathematical relationships between pH and solubility of
`therapeutically useful weak acids and bases and their salts
`were given along with some considerations in the formu-
`lation of solutions of these particular agents.
`An extensive study on the solubility interrelationships
`of the hydrochloride and free base of two pharmaceutically
`useful amines was reported (129). Mathematical equations
`describing the t.ot.al solubility at an arbitrary pH in terms
`of the independent. solubilities of the hydrochloride and
`free base species and the dissociation constant of the salt.
`were derived and fitted to eirperimental data with good
`results. This report elucidated the point that. while the
`solubility of the amine hydrochloride generally sets the
`maximum obtainable concentration for a given amine, the
`solubility of the free base and the pKa determine the
`maximum pH at which formulation as a solution is possible
`(assuming that. the desired concentration exceeds the free
`base solubility}. Shifting the pl-Lsolubility profile 1.o higher
`pH values for formulation purposes may require increasing
`the solubility of the free base. This increase might be ac-
`complished by using an appropriate cosolvent. Since the
`dissociation characteristics of carboxylic acids and other
`acidic organic species are similar to those of organic hy—
`drochlorides, it is expected that the pl-l—soluhiiity profiles
`
`
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1013 - Page 8
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1013 — Page 8
`
`Vol. 56, No. .T,Jonnor_i- ff???"/‘ 7
`
`

`
`
`
`of these organic acids, although reversed, can be charac-
`terized theoretically using the same treatment.
`Several reports showed that the structure of-an organic
`salt-forming radical influences the solubility of t.he re-
`sulting salt. The water solubilities of 18 salts tcarboxylates.
`sulfates. sulfamates, and phosphates} of the weak base
`erythromyci n were dependent on the size. of the alley] group
`of the. acid (1301. In a study wi1;h N-alkylsulfamates of
`lincomycin (66), a similar phenomenon was observed:
`solubility of these salts decreased as the size of the alkyl
`group attached to the acidic function increased.
`Senior £131}, in a study on t.he formulation and prop-
`erties of the antibacterial chlorhesidine, determined the
`water soiubilities of 35 salts and the free base. He found
`that inorganic salts had remarkably low solubilities while
`those of the lower aliphatic acids proved to be somewhat
`more soluble. Hydroxylation of the acid increased solu-
`bility, since salt formation with polyhydroxy acids, par-
`ticularly the sugar acids, conferred extensive water solu-
`hiiity to the molecule.
`Several investigators reported the influence of the sol-
`ubility ofa drug on its formulation and subsequent avail-
`ability from the dosage form. In a discussion of the prep-
`aration and lorrntilation of epinephrine salts in an aerosol
`system using liquefied gas propellants, Sciarra cc of. (1232)
`pointed out that the. solubility characteristics ofthe agent
`are important. in two respects. First, the solubilit.y of the
`therapeutically active ingredient in the various propellalits
`is an important consideration if the product is to be used
`for either local action in the lungs or systemic therapy.
`