Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1027 - Page 1
`Petitioner Amerigen Pharmaceuticals Ltd.
`
`

`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1027 - Page 2
`Petitioner Amerigen Pharmaceuticals Ltd.
`
`

`
`Petitioner Amerigen Pharmaceuticals Ltd.
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1027 - Page 3
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`

`
`204
`
`Evaluation of KC for triamterene (Tr) yields val-
`ues of x=0.5 for chloride, suggesting that one
`proton solubilizes two molecules of the drug, i.e.
`the complex is Tr2H*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 metal containers (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 (i.e.
`freeze-drying). Also,
`their extreme polar nature
`results in excessive hydroscopicity (Boatman and
`Johnson, 1981) eventually leading to deliques—
`cence.
`
`Thus, progression of a hydrochloride salt should
`be a first move, but if the problems with that salt
`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 trends in 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 order of 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 pKa of 8, and therefore gives access to a
`wide variety of salt forms:
`
`CH,
`
`/CH,
`s
`
`N
`‘(J
`
`UK-47880
`melting point. 74° 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 crystal lattice 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
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1027 - Page 4
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1027 — Page 4
`
`

`
`205
`
`
`
`TABLE 2
`
`0.) c: D
`
`MELTING POINT OF SALTS OF EXPERIMENTAL COM-
`POUND (UK47880) AND THE CORRESPONDING CON-
`JUGATE ACID
`
`Melting point (° C) Legend
`
`Salt
`
`Conjugate
`acid
`
`F13 2
`
`UK 47880; free base
`pamoate (embonate)
`4—hydroxynaphthalene-
`1 —sulphonate
`Salicylate
`3—hydroxynaphthalene—
`2-carboxylate
`2—hydroxynaphthalene-1
`—carboxylate
`anthraquinone—3—sulphonate
`dodecylbenzene sulphonate
`mesylate
`citrate
`
`74
`
`235
`
`280
`
`170
`156
`
`1 90
`158
`
`223
`
`220
`
`145
`234
`20
`113
`20
`
`1 20
`225
`—
`20
`153
`
`A
`G
`
`D
`C
`
`E
`
`B
`F
`—
`—
`—
`
`epinephrine
`
`HO—CHCH2NHCH3
`
`i \ OH
`OH
`
`Salt form
`
`Melting
`point ( ° C)
`
`epinephrine
`tartrate
`maleate
`malate
`fumarate
`
`1 57
`149
`182
`1 70
`103
`
`where small highly hydrogen bonding acids such
`as malonic and maleic gave higher melting salts,
`whereas the larger bitartrate and presumably sym-
`metrically unfavoured fumarate gave salts of lower
`melting point.
`
`
`
`/“c 3O
` MELTINGPOINTSALT
`
`so
`
`so
`
`300
`200
`100 *
`MELTING POINT AciDI“c
`
`Fig. 2. Plot of melting point of UK47880 salts vs melting point
`of conjugate acids. Legend given in Table 2.
`
`OH
`
`IC
`
`Q
`O0
`0
`
`C F 3
`
`m.p. acid
`<°C>
`
`17
`53
`
`Salt form
`
`Free base
`HC1
`DL-lactate
`L—lactate
`2—hydroxyethane
`sulphonate
`Mesylate
`Sulphate
`
`m.p. salt
`(°C>
`215
`331
`172
`192
`
`251
`290
`270
`
`solubility
`(mg/ml)
`7.5
`13
`1850
`925
`
`620
`300
`20
`
`The relationship between aqueous solubility
`(SW) and melting point is shown diagrammatically
`in Fig. 3, where log SW 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 DL-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.
`
`Melting point and aqueous solubility
`The trends in melting point (m.p.) and aqueous
`solubility alluded to above are exemplified in the
`salts of a high melting antimalarial drug (Aghar-
`kar et al., 1976).
`
`Melting 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
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1027 - Page 5
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1027 — Page 5
`
`

`
`essentially controls the formation and extent of
`eutectic melts.
`
`As an additional aspect to the strength of crystal
`forces, the balance of the amorphous to crystalline
`nature in solid salts can dramatically affect their
`stability. This is exemplified by the sodium salts
`of ethacrynic acid (Yarwood et al.. 1983).
`
`m.p. ( ° C)
`% remaining after
`9days@60°C
`
`Sodium ethacrynate
`
`Crystalline
`200
`
`Amorphous
`—
`
`100
`
`92
`
`These results are consistent with the concept of an
`amorphous material being a highly viscous con-
`centrated solution and show that
`the stronger
`crystalline lattice forces result
`in superior solid
`state stability.
`
`Melting point and formulation processing
`Salt formation is frequently employed to raise
`the melting point (and crystallinity) of the drug
`species being processed. However, published work
`concerning this type of manipulation is somewhat
`sparse.
`
`The melting point of drug salts can dramati-
`cally affect their physical storage. Drugs (or salts)
`with low melting points generally exhibit plastic
`deformation (Jones, 1979) and thus during storage
`the stress exerted by the bulk mass on the asperity
`points of interparticulate contact can lead to the
`formation of localized welds leading to bulk ag-
`gregation. Also, if the sublimation temperature is
`low (e.g.
`ibuprofen, m.p. 76°C), intraparticulate
`voids can be bridged by sublimed drug again
`leading to aggregation. Thus on storage, the bulk
`drug salt will begin to cake and aggregate, thereby
`altering significantly its flow, compression and
`long—term dissolution properties.
`Melting point also has a crucial role in drug
`processing, in particular comminution and tablet-
`ing. Since low melting compounds tend to be
`plastic, rather than brittle, they comminute poorly,
`and frictional heating causes melting and deposi-
`tion of the drug on the screens and pins of the mill
`causing it
`to ‘blind’. For production of
`fine
`pharmaceutical powders this aspect is crucial to
`judging the correct level of filler to allow efficient
`
`D X A
`
`Mesylatn
`Erlisylale
`L Lactate
`
`B
`C
`
`206
`
`
`
`SOLUE|L|TY/gnu“ E) i
`
`/
`
`//
`
`D DL'Lactate
`
`n.oi
`
`1
`15
`
`1
`L8
`
`1
`2.0
`
`1
`2 2
`
`(1IMELTiNG POINT} x
`
`103K"
`
`Fig. 3. Plot of aqueous solubility vs inverse of absolute melting
`point for a series of salts of a hydrophobic antimalarial drug.
`Data taken from Agharkar et al. (1976).
`
`required to break chemical bonds, liquefaction of
`the solid (and an increased frequency of molecular
`collisions) occurs before degradation begins. Thus
`the melting point of a compound can be an im-
`portant factor in determining stability.
`Degradation of solid drugs, when it is observed,
`usually occurs in the surface film phase and is
`accompanied by the formation of a liquid phase at
`temperatures below the normal melting point of
`the solid. Using this so-called ‘liquid layer’ ap-
`proach, Guillory and Higuchi (1962) investigated
`the stability of esters of vitamin A employing the
`following equation to determine the relationship
`between degradation rate and melting point.
`
`logK=
`
`AAH[1] _ Ari
`R[Tml
`RTa
`
`where Tm = normal melting point; Td = depressed
`storage temp. = storage temperature; K = degrad-
`ation rate constant; AH = heat of fusion.
`Thus, for a series of related compounds subject
`to a storage temperature T , the logarithm of the
`degradation rate constant is inversely related to
`the absolute melting point of
`the compounds.
`Although this approach may be somewhat simplis-
`tic it may have utility as a method of assessing the
`bulk stability of non-hygroscopic salt forms.
`The melting point of a salt form also has some
`influence on its relative compatibility with drug
`combinations (Hirsch et al., 1978) or formulation
`excipients (Li Wan Po and Mroso, 1984) since it
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1027 - Page 6
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1027 — Page 6
`
`

`
`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 (Tm) with the pressure on the
`solid (PS)
`
`dTm
`dp,
`
`— v,T
`AH,
`
`where AHf = heat of fusion; VS = volume of solid;
`T: temperature, and therefore as well as those
`salts which are intrinsically low melting, salts of
`different values of AHf would be expected to have
`different abilities to cold weld in the compression
`process. If we compare, for example, the melting
`points and heats of fusion of
`the salts of an
`experimental drug candidate:
`
`Salt
`
`Hydrochloride
`Mesylate
`Tartrate
`Citrate
`Phosphate
`Acetate
`
`T,,,(°C)
`
`AH, (kl-moi”)
`
`280
`13 5
`213
`180
`250
`180
`
`56.5
`20.5
`63.6
`27.2
`136.5
`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 on drug bonding (Parrot, 1982) or
`cause the drug to adhere to the punches on com-
`pression (Wells and Davison, 1985).
`
`Conclusion
`
`The consideration of melting point
`
`is a key
`
`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 made in situ is likely to be
`preferable.
`
`The pivot of drug solubility
`
`There are various solubility issues that can de-
`cide the viability of a particular salt form and it is
`perhaps worth addressing these separately to iden-
`tify trends that may aid salt selection.
`
`Aqueous solubility per se
`As indicated earlier, the solubility of a drug can
`enhanced dramatically by salt
`formation
`be
`(Agharkar et al., 1976). This enhancement may
`arise from a reduction in melting point, or from
`improved water-drug interactions. A good exam-
`ple of this is with the salts of chlorhexidine (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.
`Chlorhexidine
`
`C1 H— CNHCNH(CH2)6NHCNHCNH@Cl
`
`H
`II
`NH NH
`
`ll
`II
`NH NH
`
`Salt
`
`Structure
`
`above
`base
`dihydrochloride HCl
`
`Melting Solubility
`point
`% w/v
`(° C)
`@ 20° C
`134
`0.008
`261
`. 0.06
`
`di—2hydroxy—
`
`COZH
`
`—
`
`0.014
`
`naphthoate
`
`I
`
`I
`
`OH
`
`diacetate
`dilactate
`digluconate
`
`154
`CH3CO2H
`—
`CH3CHOHCO2H
`HOZC(CH0H),,CO2H low
`
`1.8
`1.0
`70
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1027 - Page 7
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1027 - Page 7
`
`

`
`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 pK,_‘ of the conjugate
`anion.
`
`B = free base of
`BH‘ X (S, :BH‘*aq) +X;q
`experimental drug
`salt
`llK,, K, ll + H‘
`BM r—’ Bmq)
`Hxmq) # HXN
`H +
`
`1115 aoove ionic equilibria Show that even sparing
`solubility of the salt means that the level of the
`conjugate anion in solution will depend markedly
`on the pH of the fluid. Consideration of the above
`for a pamoate salt, which has pKa’s of the parent
`acid of 2.5 and 3.1 and virtually insoluble un-
`ionized form, indicates that solutions of pH 5-6
`will drive the equilibria to the right, with full
`precipitation of the free acid HX(S) and liberation
`of a full component in solution of the ionized base
`(BH+). However, if we consider the hydroxynaph-
`thalene sulphonic acid (pKa = 0.11) then this sys-
`tem provides ‘insolubility’ over a much wider pH
`range and is therefore far more tolerant to fluctua-
`tions in the fluid pH.
`The above aspect is important when consider-
`ing the potential use of
`‘insoluble’
`salts (e.g.
`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-
`
`fluid, with rapid
`in the former
`tially identical
`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
`
`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
`and 39% for the maleate.
`
`is the dissolution rate of a drug
`Usually it
`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-liniiting factor in their absorp-
`tion. It is also possible that increased drug absorp-
`tion may occur with salts due to their effect on the
`surface tension of the gastrointestinal fluids (Berge
`et al., 1977).
`
`Salt solubility and pH of salt solutions
`Enhancement of the aqueous solubility of a
`drug by salt
`formation can occur due to dif-
`ferences in the pH of the saturated salt solutions.
`A soluble acid salt of a weakly basic drug will
`cause the pH to drop as the salt is added to the
`solution. This pH drop will,
`in turn cause more
`drug to dissolve, and this process will continue
`until the pH of maximum solubility is reached (see
`Fig. 4). The equilibrium solubility(ies) are then
`given by:
`
`s=s+(i +iovH-PK-)
`
`i.e. when the ionized form is
`for pH=pHmax,
`solubility limiting and
`
`s = Si(1 + 10?“-W“)
`
`for pH=pHmaX, where the unionized form is
`solubility limiting and pHmax is given by the solu-
`tion of the equality of pH for
`the above two
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1027 - Page 8
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1027 — Page 8
`
`

`
`I
`
`°>
`
`~10
`
`SOLUBILITYmglml
`
`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
`terms of free base equivalent. The lines drawn 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 8.85 as the pK,,. Data by both gravimetrie (I) and GLC
`(O) procedures were in good agreement.
`
`Adapted from Kramer and Flynn (1972), with permission of
`the copyright owner (J. Pharm. Sci.).
`
`equations where
`
`3?
`pHmax = pKa + log ?
`
`and implies that both free base and salt form can
`exist
`simultaneously in equilibrium with the
`saturated solution.
`
`large pH shifts on dissolution of salts
`Thus,
`suggests that a large amount of conjugate acid is
`dissociating and therefore, a relatively high solu-
`bility is then obtained. If we consider physiologi-
`cal pH, a low pKa for a conjugate acid of high
`aqueous solubility, would appear to give the best
`change of obtaining the lowest pHmax and the
`highest aqueous salt solubility. For example,
`the
`solubilities of a series of salts of a drug candidate
`and the pH of the saturated solutions were as
`follows:
`
`209
`
`Conjugate acid
`
`Solu-
`bility
`(mg/
`ml)
`
`1470
`2400
`
`Solu—
`bility
`(mg/
`ml)
`
`35.9
`51.2
`0.49
`2.16
`
`10.31
`8.04
`
`pKa
`
`— 6.1
`— 1.2
`3.03
`3.13
`
`2.15
`4.76
`
`Type
`
`Salt
`
`pH max
`
`Hydro-
`chloride
`Mesylate
`Tartrate
`Citrate
`Phos-
`
`phate
`Acetate
`
`2.71
`2.57
`4.21
`3.30
`
`5.31
`5.29
`
`indicating that the salts of stronger acids (HCI,
`methane sulphonic) produce the lowest slurry pH
`and the highest salt solubility. In this case the
`solubility and resultant low pH of the hydrochlo-
`ride is suppressed by the common ion effect. The
`solubility of salts such as the lactate (pKa of
`conjugate acid is 3.85, with infinite solubility) may
`offer significant advantage over for example the
`acetate, tartrate and citrate.
`
`The pH of a salt solution can be a deciding
`factor in the selection of a salt for a parenteral
`dosage form. Ideally to avoid pain on injection the
`pH of i.v. parenterals should be between pH 3 and
`9, and so highly acidic salts such as the hydrochlo-
`ride and mesylate are probably best replaced by
`an acetate salt.
`
`Kramer and Flynn (1972) have shown that for
`a series of hydrochloride salts, by making analysis
`of the differential heat of solutions of the ionized
`
`the temperature de-
`that
`and unionized species,
`pendencies of the solubilities of the hydrochloride
`salts were considerably lower than those of the
`corresponding free base form. This may have im-
`portant implications for solution dosage form des-
`ign and storage conditions.
`
`Salt solubility and salt stability
`As well as the relationships between salt melt-
`ing point and stability raised earlier, it is also clear
`that
`low solubility and low hygroscopicity can
`contribute significantly to the stability of a salt
`form. The former aspect is obviously important in
`developing a stable aqueous suspension formula-
`tion of a hydrolytically unstable water soluble
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1027 - Page 9
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1027 — Page 9
`
`

`
`210
`
`drug; e.g. penicillin-benzithine.
`For salts of weak bases, the moisture associated
`
`with the bulk can be very acidic (the salt will
`buffer the available moisture), and can potentially
`cause severe hydrolytic degradation of the parent
`drug. Classic examples of this phenomenon are
`thiamine salts (Yamamoto et al., 1956, 1957) where
`the stability is
`related to their hygroscopicity,
`aqueous solubility and the resulting pH.
`Thus, to improve drug stability by salt forma-
`tion,
`it
`is clearly not only important
`to control
`hygroscopicity, but also to consider carefully the
`strength of the conjugate acid used to form the
`salt. This is particularly important for compacted
`dosage forms where salt and excipient share the
`available moisture, particularly when the majority
`of the available moisture comes from the excipient
`rather than the drug. Thus, assessment of salt
`stability in compressed and non-compressed sys-
`tems is an important activity in preformulation
`studies. However,
`in selection terms
`salts of
`
`mineral acids will produce a lower pH, and higher
`solubility in the available moisture and therefore
`produce a more hostile stability environment than
`that from a sulphonate or carboxylate type salt. It
`is also apparent that another consideration in the
`relationship of salt stability is the hydrophobic
`portion of the conjugate acid. This is exemplified
`with xilobam (Walking et al., 1983), where aryl
`sulphonic acids salts were prepared to protect this
`easily hydrolyzed base.
`
`CH3
`
`SO_,H
`
`£3 ON
`
`CH]
`
`xilobam
`
`S 03H
`tosylate
`168°C
`
`1 .2-napsylate
`177°C.l77°C
`
`saccharinate
`150°C
`
`The rationale behind the choice of these salt forms
`
`they comprise fully ionized acids and
`was that
`therefore present pH-independent aqueous solu-
`
`bility in biological fluids. However, as opposed to
`the poorly stable hydrochloride and sulphate salts,
`the aryl groups present a hydrophobic barrier to
`minimize hygroscopicity and dissolution in the
`surface moisture. The highest melting (least solu-
`ble?) salt, 1-napsylate, proved to be the most
`stable, with full retention of potency following 7
`days storage at 70°C/74% RH, whereas only 18%
`of the base remained after this challenge. The
`1-napsylate salt also provided full and rapid dis-
`solution in vitro (t90%, 15 min).
`
`The pivot of salt hydrophobicity
`
`Although the xilobam example above serves to
`demonstrate that one has to consider
`the hy-
`drophobicity of the conjugate anion to control salt
`stability, it is clear that this property is pivotal on
`two others; salt hygroscopicity and wettability.
`Thus, once again, a balance of salt properties is
`required so that hygroscopicity is not reduced at
`the gross expense of salt wettability leading ulti-
`mately to dissolution rate and bioavailability
`problems.
`
`Hydrophohicity and hygroscopicity
`Soluble ‘polar’ salts have a propensity to be
`hygroscopic, presumably through favourable hy-
`drogen bonding interactions with the available
`atmospheric moisture; i.e. by a similar mechai ism
`that contributes to their high aqueous solubility.
`Thus,
`the more polar or less hydrophobic the
`conjugate acid and salt form, the greater will be
`the propensity to adsorb moisture at a set humid-
`ity and this accounts for the frequent acute hygro-
`scopicity of dihydrochloride over monohydrochlo-
`ride salts (Boatman and Johnson, 1981).
`The high solubility and associated hygroscopic-
`ity of hydrophilic salts can preclude their isolation
`and exploitation in certain dosage forms. For
`parenterals or topical solutions they are usually
`made in situ. A good example is that provided
`with the gluconate salt of chlorhexidine (Senior.
`1973).
`It is also apparent that the hygroscopic char-
`acter of polar salt forms will also depend on the
`nature of the solid. For crystalline materials hy-
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1027 - Page 10
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1027 — Page 10
`
`

`
`211
`
`groscopicity will depend on the nature of the
`exposed surfaces which will vary with crystal habit
`(i.e.
`the balance of hydrophobic to hydrophilic
`faces) as well as the more obvious physical proper-
`ties like particle size distribution. Furthermore,
`the degree of crystallinity in the solid may be
`important, as an increase in amorphous nature
`may prevent
`the dominant exposure of hydro-
`phobic faces, and lead to a consequent increase in
`hygroscopicity. It should also perhaps be noted
`that different polymorphs have the potential for
`yielding salts of varying hygroscopicity due to
`different arrangements of the hydrophobic and
`hydrophilic crystal faces.
`
`Hydrophobicity and wettability
`The ability of a dissolution fluid to wet a solid
`is intimately related to the polarity of that solid.
`Usually the wettability of a solid, as indicated by
`the magnitude of the contact angle, 0, is linearly
`
`related to the surface tension of the fluid, and
`
`interpolation of surface tension for cos 6 = 1 (0 =
`0) yields values for the critical surface tension for
`wetting yc. Polar solid surfaces (e.g. polydroxy
`acids) would have high yc values (i.e. near water)
`and are consequently wetted more easily than
`hydrophobic surfaces with low yc values. Thus
`salt stability exerted using hydrophobic conjugate
`strong acids may be difficult to wet and therefore
`ultimately lead to prolonged dissolution.
`
`Selection of the most suitable salt forms to evaluate
`
`The ‘pivots’ on the properties of salt forms
`outlined above need to be considered before de-
`
`ciding on the most suitable range of salt forms to
`prepare. Clearly one can use the broad generaliza-
`tions already outlined, but there remains a need to
`consider ‘balance’. With a specific problem (e.g.
`
`ACTION
`
`DECREASE
`CHANGE AND REASON
`
`PROPERTY
`
`INCREASE
`CHANGE AND REASON
`
`ACTION
`
`use more flexible aliphatic
`acids with aromatic bases
`move to more highly
`substituted acids that
`destroy crystal symmetry
`
`DECREASE %——-T HELTING POINT-—9INCREASE
`lncrease solubility
`process problems
`form oil
`reduce solubility
`
`increase melting point
`increase hydrophobicity
`of conjugate annion
`
`DECREASE (T-——— SOLUBILITY———)INCREASE
`suspensions
`. Eioavailability
`controlled release
`(DISSOLUTION)
`liquid formulation
`RATE
`
`DECREASE
`
`S'I'ABILITY———% INCREASE
`
`increase hydrophobicity
`of conjugate annion
`
`DECREASE “—*":* VETIABILITY-2) INCREASE
`to control to some
`. dissolutionl
`degree
`bioavailability
`hygroscopicity
`
`use small counter ions
`e.g. C1
`, Br
`use aromatic conjugate
`annions if aromatic base
`use small hydroxy acids
`if drug has good hydrogen
`bonding potential
`
`decrease pKa and increase
`solubility of conjugate
`acid
`decrease melting point
`increase hydroxylation of
`conjugate acid
`if common ion dependence
`move to small organic
`acid
`
`reduce hygroscopicity by
`increasing hydrophobicity
`of acid. Also move to
`carboxylic rather than
`sulphonic or mineral acid
`use acid of higher pKa to
`raise pH of sorted water
`decrease solubility and
`increase crystallinity by
`increase of melting point
`
`increase polarity of
`conjugate annion
`lover pKa of conjugate
`acid
`attempt recrystallisation
`from different solvents to
`alter crystal habit
`move to acid with high
`degree of hydroxylation
`
`Fig. 5. Flow chart for manipulation of drug characteristics by change of salt form.
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1027 - Page 11
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1027 — Page 11
`
`

`
`212
`
`TABLE 3
`
`SERIES OF SALTS WHICH MAY PROVIDE SET PROPERTIES AS REFERRED TO IN “SELECTION OF THE MOST
`SUITABLE SALT FORMS TO EVALUATE".
`
`SERIES 1
`
`Hci
`
`CH3SO3H ——7 ,
`
`-——>
`
`503M
`
`503“
`
`COZH
`
`[;;:;1;§OH
`
`O
`
`NH
`
`I5
`
`02
`
`OH
`I
`
`CH3-CH-COZH
`
`[COZH
`
`cozn
`
`CH
`
`3
`
`SERIES 2
`
`/5031»!
`CH2
`I
`CH2\
`
`SO3H
`
`CH3CO2H
`
`CH2-COZH
`I
`CH2-COZH
`
`CH2C02H
`
`Ho—cH—co2H
`H0—CH—CO H
`2
`
`HO
`
`CO2}!
`
`CHZCOZH
`
`SERIES 3
`
`CH3(CH2)AC02H
`
`CH3(CH2)5CO2H
`
`C12H25S03H
`
`CH2=CH~(CH2)8 COZH
`
`CH3(CH2)7CH=CH*(CH2)7CO2H
`
`stability) there is probably a need to consider a
`specific range of salts, whereas at other times, e.g.
`to control
`in vivo absorption it may be more
`fitting to consider a wider spectrum of salts in
`order to assess the most suitable salt forms for
`
`progression.
`Conjugate acids can be ‘clustered’ into groups
`for addressing specific issues. The following, which
`is summarized in Fig. 5, may provide some first
`line generalization.
`
`(i) Manipulation of melting point
`For aromatic type bases, melting point could
`conceivably be increased by considering the range
`of acids given in series (1) of Table 3. For more
`flexible low melting basic drugs of a hydrophilic
`nature, acids with good hydrogen bonding poten-
`tial may provide a route to increasing melting
`
`point, e.g. by exploiting hydroxy acids within series
`(2)-
`Alternatively, series (2) can be used on occa-
`sions to reduce melting point (probably with a
`desire to increase aqueous solubility) in planar
`symmetrical aromatic drugs.
`to
`Alternatively to reduce melting point, e.g.
`in-
`give hydrophobic oils (ion pairs?), e.g.
`for
`tramuscular injection or vaginal ovules, it may be
`more feasible to use long chain, flexible saturated
`or unsaturated acids
`such as decanoic
`(e.g.
`heptarninol), octanoate (e.g. heptaminol), or unde-
`cylenic.
`
`(ii) Solubility
`The above rationale for the latter portion of
`series (1) would also serve for movement to poten-
`tially more insoluble salt forms; for example, for
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1027 - Page 12
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1027 — Page 12
`
`cozn
`
`OH8
`8COZH
`
`CH2
`
`on
`
`

`
`to control taste, or con-
`
`suspension formulation,
`trol of drug absorption.
`An often overlooked series of conjugate acids is
`the ion-exchange resins. These have virtues that
`the systems are essentially insoluble in water, but
`release drug rapidly by proton exchange in the
`gut. They also have potential for taste masking
`organoleptically unpleasant drugs, since the pH of
`saliva is considerably higher than the gut and so
`minimal exchange occurs in the mouth. In this
`latter respect there seems some rationale also to
`consider
`the preparation of a saccharinate or
`aspartamate salt to mask the taste of a bitter drug.
`To increase aqueous solubility for basic drugs it
`would seem appropriate to proceed half way up
`series (1) (i.e. before crystal forces dominate the
`solubility) or to extend into the hydroxy acids
`series (2). For pH-independent solubility it would
`seem sensible to progress with fully ionized acids,
`e.g. sulphonic, using a moderately hydrophobic
`organic portion to control hygroscopicity. If sta-
`bility is a problem, and the salt is hygroscopic it
`would seem more sensible to select a less polar
`acid, e.g. carboxylic.
`
`(iii) Stability
`If a salt form proves unstable, then a salt form
`with an increase in melting point should help to
`increase crystallinity, decrease the effects of any
`surface liquid amorphous film and also decrease
`solubility in the available moisture. A balance of
`these effects, together with considerations of over-
`all salt hydrophobicity, and the strength of the
`acid moiety are also required. Investigating around
`the lower to middle of series (1) would seem a
`
`213
`
`sensible place to start for attempting to identify a
`stable salt form.
`
`Other salt opportunities
`
`Amino acids such as choline, and acid vitamins
`such as ascorbic and pantothenic,
`together with
`the ion-ex