INTERNATIONAL | Oo
`JOURNAL |
`OF PHARMACEUTICS
`
`
`
`Editors in Chief
`P.F. D’ARCY(Belfast, N. Ireland) and W.I. HIGUCHI(Salt Lake City, UT, U.S.A.)
`(Associate Editor: J.H. RYTTING, Lawrence, KS, U.S.A.)
`
`Editorial Board
`
`a
`— *
`G. AMIDON (Ann Arbor, MLUSA)
`B.D. ANDERSON(Salt Lake City, UT, U.S.A.)
`G.S. BANKER (Minneapolis, MN, U.S.A.)
`H. BOXENBAUM (Cincinnati, OH, U.S.A.)
`H. BUNDGAARD(Copenhagen, Denmark)
`J.T. CARSTENSEN (Madison, WI, U.S.A.)
`S.S. DAVIS (Nottingham, U.K.)
`A.T. FLORENCE(Glasgow, U.K.)
`JL. FOX(Salt Lake City, UT, U.S.A.)
`H.L. FUNG (Amherst, NY, U.S.A.)
`D. GANDERTON(London, U.K.)
`J. HADGRAFT(Cardiff, U.K.)
`M. HANANO(Tokyo, Japan)
`E.N. HIESTAND (Kalamazoo, MI, U.S.A.)
`T. HIGUCHI (Lawrence, KS, U.S.A.)
`N.F.H. HO (Kalamazoo, MI, U.S.A.)
`W.B. HUGO(Nottingham, U.K.)
`T.M. JONES (Dartford, U.K.)
`K. KNUTSON(Salt Lake City, UT, U.S.A.)
`G. LEVY (Amherst, NY, U.S.A.)
`
`J.A. MOLLICA (Suffern, NY, U.S.A.)
`T. NAGAI (Tokyo, Japan)
`1.H. PITMAN (Parkville, Australia)
`G. POSTE(Philadelphia, PA, U:S.A.)
`B.J. POULSEN (Palo Alto, CA, U.S.A.)
`A.J. REPTA (Lawrence, KS, U.S.A.)
`JR. ROBINSON (Madison, WI, U.S.A.)
`T.J. ROSEMAN (Morton Grove, IL, U.S.A.)
`H. SEZAKI (Kyoto, Japan)
`.
`J.E. SHAW(Palo Alto, CA, U.S.A.)
`E. SHEFTER (Wilmington, DE, U.S.A.)
`D.D. SHEN (Amherst, NY, U.S.A)
`E, SHOTTON(Berkhampstead, U.K.)
`J. SIGGREN (Mélnlycke, Sweden)
`R.S. SUMMERS(Pretoria, South Africa)
`B. TESTA (Lausanne, Switzerland)
`K. THOMA (Munich, F.R.G.)
`R.F. TIMONEY (Dublin, Ireland)
`E. TOMLINSON (Horsham, U.K.)
`G. ZOGRAFI (Madison, WI, U.S.A.)
`
`.
`
`
`
`VOL.32 (1986)
`
`ELSEVIER SCIENCE PUBLISHERSB.V. - AMSTERDAM
`
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`Apotex Exhibit 1010.001
`
`

`

`© 1986, Elsevier Science Publishers B.V. (Biomedical Division)
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`Apotex Exhibit 101 0,002
`
`Apotex Exhibit 1010.002
`
`

`

`——eea—
`
`
`International Journal of Pharmaceutics, 33 (1986) 201-217
`Elsevier
`
`UP 01121
`
`!
`
`201
`
`Salt selection for basic drugs
`
`Philip L. Gould
`Pharmaceutical Research and Development Department, Pfizer Central Research, Sandwich, Kent (U.K.)
`(Received 24 March 1986)
`(Accepted 30 May 1986)
`
`/ ,
`/
`
`Key words: Salt form selection — Pharmaceutical salts
`
`Summary
`
`An attempt has been made using a Kepner=Tregoe decision analysis approach to provide rationale to salt selection for basic drugs.
`The selection objectives are reviewed in terms of the ‘essential’ (MUSTS) and ‘desirable’ (WANTS)issues. The desired characteristics
`of the salt form, given sufficient strength and toxicologicalsuitability of the conjugate acid, are then discussed on the basis of the
`various pivotal physicochemical properties; melting point, aqueous solubility and dissolution rate, stability and hydrophobicity.
`Several trends are established which can then assist the decision of which range of salt forms to evaluate to overcomea particular
`problem with a basic drug.It is concluded that. it is important to view the choice of salt form for development as a compromise, with
`particular focus on the correctly weighted desires to obtain the best balanced choice.
`
`Introduction
`
`Salt formation provides a meansof altering the
`physicochemical and resultant biological char-
`acteristics of a drug without modifying its chem-
`ical structure. The importance of choosing the
`‘correct’ salt form of a drug is well outlined in a
`published review (Bergeet al., 1977) but, although
`salt form can have a dramatic influence on the
`overall properties of a drug, the selection of the
`salt form that exhibits the desired combination
`of properties remains a difficult semi-empirical
`choice.
`In making the selection of a range of potential
`“salts, achemicalprocéssgroup considersissues on
`the basis of yield, rate and quality of the crystalli-
`sation as well as costand availability of the con-
`
`’ Correspondence: P.L. Gould, Pharmaceutical Group, Product
`Research and Development Laboratories, Cyanamid of Great
`Britain Limited, Gosport, Hants, U.K.
`
`jugate acid. The formulation andanalytical groups
`are, on the other hand, concerned with the hygro-
`scopicity, stability, solubility and processability
`profile of the salt form, while the drug metabolism
`group is concerned with the pharmacokinetic
`aspects and the safety evaluation group on the
`toxicological effects of chronic and acute dosing
`of the drug and its conjugate acid. Thus, a clear
`compromise of properties for the salt form is
`required, but the difficulty remains of assessing
`which salt forms are best to screen for a particular
`drug candidate.
`literature has been devoted to
`Little,
`if any,
`discussing the compromise of properties for salt
`form selection. This review addresses the problem
`of salt form selection for basic drugs.
`
`“Approach to the salt selection process
`
`Walking and Appino (1973) have used the
`Kepner-Tregoe (KT)
`techniques
`(Kepner and
`
`0378-5173/86/$03.50 © 1986 Elsevier Science Publishers B.V. (Biomedical Division)
`
`Apotex Exhibit 1010.003
`
`Apotex Exhibit 1010.003
`
`

`

`202
`
`Tregoe, 1976) of decision analysis and potential
`problem analysis to aid the selection of a salt
`form. Although their application is more exem-..
`plary of the KT method rather than of the specific
`application, the rational process decision analysis
`approach which defines essential and desirable
`attributes as ‘MUSTS’ and ‘WANTS’,
`respec-
`tively, provides a route to-initially address ‘the
`problem of salt form selection.
`
`“GO”/“NO-GO”issues
`The: major “GO”/“NO-GO” (MUSTS) issue
`for salt selection of an ionizable drug is the con-
`sideration of the relative basicity of the drug and
`the relative strength of the conjugate acid. Clearly
`to form a salt the pK, of the conjugate acid hasto
`be less than or equal to the pK, of the basic centre
`of the drug.
`Thus the potential range of salts of drugs con-
`taining for example triazoyl bases (I; pK, ~ 2) is
`restricted to strong acids (mineral and sulphonic,
`but excluding the carboxylic), whereas imidazole
`bases (II; pK, 6-7) arefar less restricted and the
`greatest scope for salt formation occurs for the
`aliphatic tertiary aminés (III; pK, 9-10).
`
`x
`
`aN
`
`» eK. oe6]CHs-N pK, 9)
`CH,
`ay ot
`(in).
`
`CH,
`|
`
`N
`)
`
`The relative acid/base strength of the resultant
`salts also dictates their stability to disproportiona-
`tion, since all salts will be acid and therefore
`potentially reactive towards basic formulation ad-
`ditives.The other essential selection issue for a salt
`form is the relative toxicity of the conjugate an-
`ion; some salts clearly fall into a desirable cate-
`gory, some acceptable but
`less desirable (both
`“GO”) and some undesirable (“NO GO”). A ta-
`ble of salts used in pharmaceutical products
`marketed in the U.S. up to-1974 is given in Table
`1. It would seem sensible that any acid relating to
`normal metabolism, or present in food and drink
`can be regarded as a suitable candidate for prepar-
`ing salts. Clearly anions that cause irritancy to the
`
`TABLE 1
`
`FDA-APPROVED COMMERCIALLY MARKETED SALTS
`
`
`Anion
`Percent *
`Anion
`
`Percent *
`
`/
`
`_
`
`.
`
`0.13
`0.25
`
`©
`
`0.25
`3.16
`
`Acetate
`1.26
`Todide
`/
`2.02
`
`‘Benzenesulfonate
`0.25
`Tsothionate *
`0.88
`- Benzoate
`70ST
`"Lactate
`0:76
`Bicarbonate
`~
`0.13
`Lactobionate
`0.13
`Bitartrate
`0.63
`Malate
`0.13
`Bromide
`4,68
`Maleate
`3.03
`Calcium edetate
`0.25
`Mandelate
`0.38
`Camsylate?.
`.
`0.25
`Mesylate
`2,02
`Carbonate
`0.38
`Methylbromide
`0.76
`Chloride
`4.17
`Methylnitrate
`0.38
`Citrate
`. 3.03
`Methylsulfate
`0.88
`Dihydrochloride
`0.51
`Mucate
`0.13
`Edetate
`0.25
`Napsylate
`0.25
`Edisylate °
`0.38
`Nitrate |
`0.64
`Estolate 4
`0.13 ~
`Pamoate "1.01
`a
`(Embonate)
`Esylate °
`Pantothenate
`' Fumarate _
`Phosphate/
`’ diphosphate
`_ Polygalacturonate 0.13
`‘’ Salicylate
`“0.88
`“Stearates ~~ 0725-
`Subacetate
`.
`0.38
`Succinate
`0:38
`Sulfate
`. 746
`Tannate
`0.88
`Tartrate
`3.54
`
`|
`
`0.18
`Gluceptate !
`0.51
`Gluconate
`~~ -—-Giotamate 20.25
`Glycollylarsnilate ® 0.13
`Hexylresorcinate
`0.13
`Hydrabamine ®
`0.25
`Hydrobromide
`1.90
`Hydrochloride
`42.98
`Hydroxynaph-
`thoate
`
`.
`
`0.25
`
`—
`
`j
`Teoclate /
`Triethiodide
`
`0.13
`0.13
`
`Cation
`~ Percent *
`Cation
`Percent,*
`
`
`”
`~
`“Metallic:
`oe
`Organic:
`0.66
`Aluminium
`0.66
`Benzathine *
`Calcium 10.49
`0.33 |
`Chloroprocaine
`Lithium 1.64
`0.33
`Choline
`Magnesium
`131,
`0.98
`Diethanolamine
`~ Potassium
`10.82
`0.66
`Ethylenediamine
`Sodium
`61,97
`2.29
`Meglumine’
`
`
`
`0.66 Zinc .Procaine 2.95
`
`
`
`* Percent is based on total number of anionic or cationic salts
`in use through 1974. © Camphorsulfonate. *1,2-Ethanedisul-
`fonate. 4 Laurylsulfate.
`* Ethanesulfonate.
`‘ Glucoheptonate.
`® p-Glycollamidophenylarsonate.
`1 NWN ’-Di(dehydroabietyl)
`ethylenediamine.
`1 2.Hydroxyethanesulfonate.
`4 8-Chlorotheo-
`N,N’-Dibenzylethylenediamine. ' N-Methylgluca-
`/ phyllinate. *
`mine.
`
`Reproduced from Berge et al. (1977) with permission of the
`copyright owner (J. Pharm. Set.).
`
`Apotex Exhibit 1010.004
`
`Apotex Exhibit 1010.004
`
`€
`

`

`
`
`*
`
`203
`
`1.20
`
`1.6
`
`GI tract should be avoided for some types of drug,
`e.g. anti-inflammatories, laxative surfactant anions
`for anti--secretory drugs: and conjugate <anions5 with
`intrinsic tonicity,€.2. oxalate.
`Properties desired of the salt form (WANTS)
`The desires or ‘WANTS’ of a salt form are
`dictated by the nature of the required dosage
`forms, their process and desired biological perfor-
`mance. Thus, it is somewhat difficult to provide a
`complete overall specification of ‘WANTS’ for a
`series of salt forms, but ideally the bulk salt
`should be completely chemically stable, non-hy-
`sroscopic, not cause processing problems,and dis-
`solve quickly from solid dosage forms.
`Because of simple availability.and physiological
`reasons, the monoprotic hydrochlorides have been
`by far the most frequent (~40%) choice of the
`that a precipitous drop in drug solubility occurs as.
`available anionic salt-forming species. Thus, there ©
`the free Cl~ level is increased.
`is clear precedent, and an ‘overwhelming argument
`An example of a basic drug showing a strong
`on many grounds to immediately progress to the
`chloride-iondependence4is prazosin.
`hydrochloride salt and evaluate other forms only
`if problems with the hydrochloride emerge.
`
`0.4
`
`#408
`
`$12
`
`0.4 08
`1.6
`LOGS, mg/ml
`Fig. 1. Relationship between solubility in water and salting-out
`constant at 25°C (left) and 37°C (right), Key: A=
`phenazopyridine; B = cyproheptadine; C = bromhexine; D =
`trihexyphenidyl; E = isoxsuprine; F=chlortetracycline; G =
`methacycline; H = papaverine; and I = demeclocyline.
`
`Adapted from Miyazaki etal. (1981). Reproduced withpermis-
`sion of the copyright owner (J..Pharm. Sci.).
`
`CH,O0.
`
`ae
`
`eeoustveseo
`
`Prepare the hydrochloride; pros and cons
`Kramer and Flynn(1972) suggest that the solu-
`bility of an amine hydrochloride generallysets the
`maximum -obtainable concentration for a given
`amine.
`Many reports (Miyazaki et al., 1980, 1981) have
`shown that hydrochloridésalt formation does not
`necessarily enhance thesolubilityof poorly solu-
`ble basic drugs and result in improved bioavaila-
`bility. This finding is based onthe common ion
`effect of chloride on the solubility product equi-
`
`librium:
`
`| Ky, =2.2x107§ M@ 30°C
`
`Solubility/mg.ml~? @ 30°C
`
`Base
`Hydrochloride .
`0.1M:HCl water water
`0.037
`1.40
`0.0083
`
`BHtcz ==BH2, + Clay
`Chloride, as well as other inorganic anions have
`Hydrochloride salts therefore, have the potential
`the potential to forminsoluble complex salts with
`weak bases (Dittert at al., 1964), which are then
`
`to exhibit a réduced dissolution rate in gastric
`potentially less bioavailable than the free base
`“fluidbecause oftheabundance of chloride ion
`form. The formation of these complex salts is
`(0.1-0.15 M). Indeed, the Setschenow salting-out
`controlled by their stability constantK..
`constants (k) for chloride are greatest for drugs of
`.
`very low solubility (Fig. 1), and can decrease the
`dissolution rate of the salt to below that of the
`- free base form(Migazaki et al., 1980), which shows
`
`Drug, = Drug(4) + xH* = Dmg: H; (aq)
`
`Apotex Exhibit 1010.005
`
`Apotex Exhibit 1010.005
`
`

`

`204
`
`.
`
`Evaluation of K, for triamterene (Tr) yields val-
`ues of x=0.5 for chloride, suggesting that one
`proton solubilizes two molecules of the drug,Le.
`the complex is Tr, H~ Cl.
`With hydrochloride salts there is frequently an
`‘overkill’ on acid strength, which leads to a very
`low pH for.an aqueous solution (Nudelman et al.,
`1974) of the salt. This can then limit the utility of
`hydrochloride salts in certain parenteral dosage
`forms, or lead to packaging incompatibilities with
`pharmaceutical metalcontainers (aerosols).
`Other problems frequently arise as the result of
`the polar nature of hydrochloride salts. Their high
`hydrophilic nature, favouring wettability probably
`as a result of the polar ionized groups being
`exposed on the crystal surfaces,
`leads to water
`vapour sorption (hygroscopicity) which on occa-
`sions, may be excessive. This can result
`in
`processing. difficulties (e.g. powder flow) and re-
`_ duce the stability of a hydrolytically unstable drug.
`-, This latter effect is exacerbated by the resulting
`very low pH of the loosely bound moisture.
`“~ These-problems can be particularly acute with
`dihydrochlorides (or disulphates).. Also,
`the dif-
`ference in the strength of the basic centres in
`dihydrochloride salts can lead to a gradual loss of
`one of the hydrochloride moieties by release.of
`hydrogen chloride gas (Lin et al., 1972) at elevated
`temperatures or under
`reduced pressure (ie.
`freeze-drying). Also,
`their extreme polar nature
`“results in excessive hydroscopicity (Boatmanand
`--r-Johnson, 1981) eventuallyleading to deliques-
`cence.
`Thus, progression of a hydrochloride salt should
`be a first move, but if the problems with thatsalt
`form arises due to some of the reasons outlined,
`then the real selection issue for a salt
`form
`emerges—what trends are available for guidance?
`
`' The pivotal issues for salt selection
`
`Each drug and its associated range of dosage
`forms will present different salt form require-
`ments, and it is perhaps best to discuss salt -selec-
`tion further ‘by outlining some of the trendsin salt
`properties that may facilitate selection.
`
`The pivot of melting point —
`
`- A change in the development of a compound
`from the free base to a salt may be promoted by a
`need to moderate the kinetics and extent of drug
`absorption, or to modify drug processing. Unfor-
`~ tunately these desires may be mutually exclusive,
`as the balance between these properties is fre- |
`quently pivoted around the melting point of the
`salt form. For example, an increase in melting
`point is usually accompanied by a reduction in
`salt solubility (the ideal solubility of a drug in all
`solvents decreases by an orderof magnitude on an
`increase of 100°C in its melting point), whereas
`high melting crystalline salts are potentially easier
`to process.
`The increase or decrease in melting point of a
`series of salts is usually dependent on the control-
`ling effect of crystallinity from the conjugate an-
`ion. This is exemplified by considering an experi-
`mental drug candidate (UK47880) which has a
`basic pK, of8, and therefore gives access to a
`wide varietyof salt forms:
`
`CH,
`
`
`Js
`5
`UK-47880
`
`Pyavon4°-C
`
`
`_.
`
`Salts prepared from planar, high melting aromatic
`sulphonic or hydroxycarboxylic acids yielded
`crystalline salts of correspondingly high melting
`point
`(see Table 2), whereas flexible aliphatic
`Strong acids such as citric and dodecyl benzene
`sulphonic yielded oils. Thus,
`the comparative
`planar symmetry of the conjugate acid appears
`important for the maintenance of high crystal
`lattice forces. This is shown by the melting point
`of the conjugate acid being highly correlated with
`the melting point of the resultant salt form (Fig.
`2). Therefore the highly crystalline salts are in this
`case best suited to reducing drug solubility.
`Alternatively it should also be feasible to build
`up crystallattice forces of drugs with good hydro-
`gen bonding potential, by considering symmetry
`and hydrogen bonding potential of the conjugate
`acid. One salt
`series of
`interest
`is
`that
`for
`
`Apotex Exhibit 1010.006
`
`Apotex Exhibit 1010.006
`
`

`

`
`
`
`o
`~ 500
`2wo
`5
`2
`t 100
`Zz
`90
`E 80
`> 70
`
`5080
`
`300
`700
`MELTING POINT ACIDIC
`Fig. 2. Plot of melting point of UK47880 salts vs melting point
`of conjugate acids. Legend given in Table 2.
`
`_
`
`a
`
`205
`
`ce
`
`~~
`
`TABLE 2
`
`300
`
`MELTING POINT OF SALTS OF EXPERIMENTAL COM-
`POUND (UK47880) AND THE CORRESPONDING CON-
`JUGATE ACID
`
`-
`
`..
`
`Melting point (° C) Legend
`Salt
`Conjugate
`Fig. 2
`acid
`
`74
`
`235
`170
`156
`223
`
`LA
`G
`D.
`Cc
`E
`
`:
`UK 47880; free base.
`280
`pamoate (embonate)
`4-hydroxynaphthalene-
`190
`1-sulphonate
`158
`Salicylate
`3-hydroxynaphthalene-
`220
`2-carboxylate
`;
`_
`2-hydroxynaphthalene-1
`“8B
`120
`-carboxylate © - 145
`F
`225
`anthraquinone-3-sulphonate
`234
`cos
`=
`0.
`dodecylbenzene sulphonate
`20
`- 20 7
`mesylate
`toy
`113.
`citrate
`30 «1530
`-
`
`—epmephrine
`
`
`
`HO-CHCH,NHCH;
`
`\(
`OH
`
`‘OH
`
`m.p. salt
`Salt form
`(°C)
`7
`215
`Free base
`331
`HCl
`Di-lactae § 172.
`L-lactate .-
`192
`2-hydroxyethane
`
`mp. acid
`(°C)
`
`~~
`
`£17
`53
`
`‘
`
`solubility
`(mg/m)
`7.5
`13:
`. 1850
`925
`o
`
`620
`. 251
`sulphonate
`Melting
`Salt form
`
`-Mesylate ~.300290
`
`_ Sulphate
`270 -
`20-
`
`point(°C).
`
`157 °
`- 149 v.
`182.
`170°
`103
`
`epinephrine
`tartrate
`maleate
`malate
`fumarate
`
`~
`
`where small highly hydrogen bonding acids. such
`as malonic and.maleic gave higher melting salts, .
`whereasthe larger bitartrate and presumably sym-
`metrically unfavoured fumarategavesalts.of lower
`meltingpoint.
`Meltingpoint and aqueous.solubility
`The trends in melting point(m.p.) and.aquecus
`solubility alluded to above are exemplified in the’
`salts of a high melting antimalarial drug (ghar
`
`kar et al., 1976).
`
`.,
`
`The relationship between aqueous’. solubility
`-.(S,,) and melting point is shown diagrammatically -.
`in Fig. 3, where log-S, is correlated over a range
`_ of salts with the inverse of the melting point.
`Interestingly with this compound, the solubility of
`the hydrochloride salt in water is only approxi-
`mately twice that of the free base, whereas the low
`‘~melting Di-lactate provides a 200-fold advantage
`over, the free base in terms of solubility, which is a
`_ result in part of the reduced lattice energy.
`Meelting point and chemical stability *
`The stability of.organic compounds in the solid
`“State ‘is intimately related to the strength of the
`‘crystal lattice. Since the forces between molecules
`: in a crystal. are small compared with the energy |
`
`Apotex Exhibit 1010.007
`
`Apotex Exhibit 1010.007
`
`

`

`206
`
`SOLUBILITYfgmt!
`
`
`
` Mesylate
`
`Edisylate
`
`L- Lactate
`
`DL-Lactate
`
`
`16
`
`18
`
`20
`
`2.2
`
`essentially controls the formation and- extent of
`eutectic melts.
`_ As an additional aspect to the strength of crystal
`forces, the balance of the amorphousto crystalline
`nature in solid salts can dramatically affect their
`' stability. This is exemplified by the sodium salts
`ofethacrynic acid (Yarwoodet al., 1983):
`
`Sodium ethacrynate
`
`Crystalline
`200
`
`Amorphous
`-
`
`mp. (°C) -
`% remaining after
`9 days @ 60°C
`
`-
`(Q7MELTING POINT) x
`102K"!
`- Fig. 3-Plot of aqueous solubility vs inverse of absolute melting
`These results are consistent with the concept of an
`point for a series of salts of a hydrophobic antimalarial drug.
`amorphous material being a highly viscous con-
`Data taken from Agharkaret al. (1976).
`centrated solution and- show. that the stronger
`crystalline lattice forces result
`in superior solid
`required to break chemical bonds, liquefaction of.
`state stability.
`.
`the solid (and an increased frequency of molecular
`Melting point and formulation processing
`collisions) occurs before degradation begins. Thus
`the melting point of a compound canbe an im-
`Salt formation is frequently employed to raise
`_portant factor in determining stability. °
`the melting point (and crystallinity) of the drug
`“Degradation of solid drugs, whenit is observed,
`species being processed. However, published work
`usually occurs in’ the surface film phase and.is
`concerning this type of manipulation is somewhat
`accompanied bythe formationof a liquid phase at
`sparse.
`,
`temperatures below the normal melting point of
`The melting point of drug salts can dramati-
`cally:affect_their_physicalstorage.Drugs((orsalts)_
`the solid. Using this so-called. ‘liquid layer’ap-
`proach, Guillory and Higuchi (1962) investigated
`with low melting points generally exhibit plastic
`the stability of esters of vitamin A employing the
`deformation (Jones, 1979) and thus during storage
`following equation to determine the relationship
`the stress exerted by the bulk mass ontheasperity
`between degradation rate andmelting point.
`points of interparticulate contact can lead to the
`formation of localized welds leading to bulk’ag-
`AAH[1]_ 4H |
`gregation. Also, if the sublimation temperature is
`. R[T,,]
`.“RT,
`108
`Ka-oot
`low (e:g. ibuprofen, m.p. 76°C), intraparticulate
`where T_,= normal melting point; T, = depressed —
`voids can be bridged by sublimed drug again
`leading to aggregation. Thus on storage, the bulk
`storage temp. = storage temperature; K = degrad-
`drug salt will begin to cake and aggregate,thereby
`ation rate constant; AH = heat of fusion.
`Thus, for a series of related compoundssubject
`altering significantly its flow, compression and
`to a storage temperature T,, the logarithm of the
`long-term dissolution properties.
`Melting point also has a crucial role in drug
`degradation rate constant is inversely related to
`processing, in particular comminution and tablet-
`the absolute melting point of
`the compounds.
`ing. Since low melting compounds tend to be
`Although this approach may be somewhat simplis-
`tic it may have utility as a method of assessing the
`plastic, rather than brittle, they comminute poorly,
`and ‘frictional heating causes melting and deposi-
`bulk stability of non-hygroscopic salt forms.
`tion of the drug onthe screens and pins of the mill
`The melting point of a salt form also has some
`causing it
`to ‘blind’. For production of
`fine
`influence on its relative compatibility with drug
`pharmaceutical powders this aspect is crucial to
`combinations (Hirsch et al., 1978) or formulation
`judging the correctlevel offiller to allow efficient
`_ excipients (Li Wan Po and Mroso, 1984) since it
`
`100
`
`92.
`
`Apotex Exhibit 1010.008
`
`Apotex Exhibit 1010.008
`
`

`

`manufacture using a cost-effective feed rate.
`Salt melting point can also have important
`implications for particle bonding on compression
`for tableting! Since bonding on compression oc-
`curs by point welding at the deformed or frag-
`mented particle surfaces, then at a fixed tempera-
`ture and pressure, a lower melting species would
`be expected to improve bonding. However,
`the
`pressure on the powder (and the eutectics formed
`with the other excipients) suppress the melting
`point further. The Skotnicky equation defines the
`‘fall in melting point (T,,) with the pressure on the
`solid (P.)
`
`dT, i —V.T
`‘dP,’ AH,
`se
`
`"207
`
`parameter in assessing the ‘viability’ of certain
`salt forms. In general, an increase in melting point,
`usually by maximizing or encouraging crystal sym-
`metry, leads to reduced solubility in all solvents,
`but generally improved stability, particularly if
`salt formation results in-a crystalline solid, and
`easier formulation processing. For a specific salt
`form for parenteral use, i.e. where solubility and
`resultant pH is a major issue, a low melting point
`salt produced using a soluble fairly weak acid (see
`next section) probably miadein situ is likely to be
`preferable.
`
`The pivot of drug solubility
`
`- There are varioussolubility issues that can de-
`cide the viability of a particular salt form anditis __
`where AHf = heat of fusion; V,= volumeofsolid;
`perhaps worth addressingthese separately to iden- _
`JT =temperature, and therefore as well as those
`tify trends that may aid salt selection.
`salts which are intrinsically low melting, salts of
`different values of AHf would be expééted to have
`Aqueous solubility per se
`|
`different abilities to cold weld-in the compression
`Asindicated earlier, the solubility of a drug can
`—process:-If-we-compare;-for-example;the-melting-—~~he~enhanced dramatically by salt
`formation
`points and heats of fusion of the salts of an
`(Agharkar et al. 1976). This enhancement may
`experimental drug candidate:
`arise from’ a reduction in melting point, or from
`improved water-drug interactions. A good exam-
`ple of this is with the salts-ofchlorhexidine (Senior,-
`1973), where increased water solubility was not
`‘only produced by a lowering of melting point, but
`by increasing the hydroxylation of the conjugate
`acid.
`a
`|
`
`.
`
`.
`
`AH; (kJ-mol7})
`Te (PS)
`Salt
`=“ Hydrochloride 280-0 56Str
`Mesylate -----
` ~-----135~--0
` --
`--- -20:5
`Tartrate
`2130
`63.6
`Citrate.
`180.
`27.2...
`Phosphate’
`250.
`136.5
`Acetate
`180
`167.9
`
`.
`
`the data suggest that the low melting point and
`low AH, for the mesylate salt would make it the
`most suitable. candidate, on bonding grounds, for
`a direct compression tablet. Since the melting
`points of compounds are reduced under pressure,
`the solubility of salt forms would be expected to
`increase with increasing pressure. This can poten-
`tially cause the formation of solutions of the salts
`in the film of absorbed moisture on the surface of
`the drug (and excipient) particles which then may
`have an effect ondrug bonding (Parrot, 1982) or ~
`causethe drug to adhere to the punches on com-
`pression (Wells and Davison, 1985).
`-
`
`~~"
`
`Chlorhexidine
`
`cKxn CNHIENH(CH,NHENHENEea
`her NH
`NH ee
`.
`|
`|
`
`;
`
`- Salt
`
`___, Structure
`
`above
`base /
`dihydrochloride HC]
`di-2hydroxy-
`
`naphthoate
`
`|
`
`—
`
`~ 2.
`
`7
`CO.H
`
`:
`
`OH
`
`' Meiting Solubility
`point %w/v
`(°C) @ 20°C
`134
`0.008
`261
`«0.06
`- 0.014
`
`15418
`CH,CO,H
`“diacetate -
`-
`1.0
`‘CH;CHOHRCO,H
`dilactate
`Conclusion:
`HO,C(CHOH),CO,H low—70
`digluconate
`The consideration of melting point is a key
`
`Apotex Exhibit 1010.009
`
`Apotex Exhibit 1010.009
`
`

`

`208
`
`The above data exemplify the importance of
`considering the hydrophilic nature of the con-
`jugate anion, as well as its role in controlling
`crystallinity, when considering the potential ‘solu-
`bility of salts.
`:
`Reduced aqueous solubility may occasionally
`be a crucial development factor for a drug, e.g. for
`an organoleptically acceptable or chemically sta-
`ble suspension. Such systems demand salts of low
`solubility, but recent experience with a series of
`purposely designed insoluble salts of an experi-
`mental drug candidate also highlighted the need to
`consider the solubility and PR, of the conjugate
`
`-
`
`fasted state are also important. In fact in this case,
`the bioavailability in the dog of the two salt forms
`when dosed orally from a standard capsule formu-
`lation were of the same order; 24% for the pamoate
`and39% for the maleate.
`Usually it is the dissolution rate of a drug
`which is of major importance to the formulation
`and as a rule a salt exhibits a higher dissolution
`rate than the base at an equal pH, even though
`they have the same equilibrium solubility. This
`latter effect, which is exemplified by theophylline
`salts (Nelson, 1957), is due to the salt effectively
`acting as its own buffer to alter the pH of the
`diffusion boundary layer, thereby increasing the
`apparent solubility of the parent drug in that
`layer. Thus, administration of basic drugs as their
`salt forms(e.g. tetracycline hydrochloride) ensures
`that stomach emptying rather than in vivo dissolu-
`tion will be the rate-limiting factor in their absorp-
`tion. Itis alsopossible that increased drug absorp-
`tion may occur with salts due to their effect on the
`surface tensionof the gastrointestinal fluids (Berge
`ét al; 1977).
`°
`
`-
`
`anion.
`=free base of
`BHt X™ sy = BHGg) + Xaq
`salt
`.
`kK, K,t+H*...... .experimental drug
`Bi =Boagy
`HX (aq) @# AX oy
`Ht
`1us apove lonic equilibria show that even sparing
`solubility of the salt means that the level of the
`conjugate anion in solution will depend markedly
`onthe pH ofthe fluid. Consideration of the above
`for a pamoate salt, which has pK.,’s of the parent
`acid of 2.5 and 3.1 and virtually insoluble un-
`ionized form, indicates that solutions of pH 5-6
`Salt solubility and pH of salt solutions
`will drive the equilibria to the right, with full
`Enhancement of the aqueoussolubility of .a
`precipitation of the free acid HX... andliberation___
`.drugbysaltformation can occur dué to” dif-
`of a full component in solution of the ionized base
`ferences in the pH of the saturated salt solutions.
`(BH*). However, if we consider the hydroxynaph-
`.
`A soluble a¢id salt of a weakly basic drug will
`thalene sulphonic acid (pK, = 0.11) then this sys-
`cause:the pH to drop as the salt is added to the
`tem provides ‘insolubility’ over a much wider pH
`solution. This pH drop will, in turn cause more
`“range and is‘therefore farmore tolerant to fluctua-
`drug to dissolve, and this process will continue
`tions in the fluid pH.
`until the pH of maximumsolubility is reached (see
`The above aspect is important when consider- .
`Fig. 4). The equilibrium solubility(ies) are then
`ing the potential use of
`‘insoluble’
`salts (e.g.
`‘given by:
`/
`pamoate) to control
`the absorption of a drug
`candidate.. For example,
`the in vitro dissolution
`rates of the dimaleate and pamoate salts of a drug
`candidate were compared in simulated gastric and
`“intestinal fluid. The dissolution rates were essen-
`tially identical
`in the former fluid, with rapid
`deposition of the pamoic acid and liberation of
`the free base, whereas in the latter the pamoate
`salt exhibited a much slower dissolution rate than
`the maleate. Therefore ‘control’ on the drug ab-
`sorption (and toxicity) may then. depend on the
`duration of gastric residence and the pH of the
`gastric contents. Thus aspects such as food vs the
`
`S=S,(1+10°Ks-PH) |
`for pH= pH... where the unionized form is
`solubility limiting and pH.,,,,. is given by the solu-
`tion of the equality of pH for the above two
`
`S=S*(1+ 10PH-PK:)
`
`|‘
`
`for pH = pH,,,,, Le. when the ionized form is
`solubility limiting and
`
`Apotex Exhibit 1010.010
`
`Apotex Exhibit 1010.010
`
`

`

`-pK
`.
`S-s't1-19PTPM
`
`J mar
`
`pKa + logSi_
`Si
`
`SOLUBILITY
`
`mgim
`
`Fig. 4. Solubility of A in water at ambient temperature ( ~
`23°C) as a function of pH. All data are in mg/ml calculated in
`termsoffree base equivalent. The linesdrawn through the data
`are theoretical and were calculated using 0.067 mg/ml as the
`free base solubility, 11.5 mg/ml as the hydrochloride solubility
`and 8.85as the pK,. Data by both gravimetric (@) and GLC
`(@). procedures were in good agreement.
`
`Adapted trom Kramer and Flynn (1972), withpemisspermissionof
`
`
`the copyright owner-(J. Pharm. Sci.)..
`
`equations where
`
`+
`S:
`pH,= PK, + log =
`
`and implies that both free base and salt form can
`exist
`simultaneously in equilibrium with the:
`saturated solution.
`Thus,
`large pH shifts on1 dissolution of salts
`suggests that a large amount of conjugate acidis
`dissociating and therefore, a relatively high solu- |
`bili