PHARMACEUTICAL
`PREFORMULATION:
`The Physicochemical Properties
`of Drug Substances
`
`JAMES I. WELLS, B.sc.. M.Sc., Ph.D., M.P.S.. MinstPkg.
`Development Group Leader
`Pharmaceutical Research and Development
`Pfizer Central Research, Sandwich, Kent
`
`ELLIS HORWOODLIMITED
`Publishers - Chichester
`
`Halsted Press: a division of
`JOHN WILEY& SONS
`NewYork - Chichester « Brisbane - Toronto
`
`Apotex Exhibit 1011.001
`
`Apotex Exhibit 1011.001
`
`

`

`QV
`
`14Vote
`
`First published in 1988 by
`ELLIS HORWOOD LIMITED
`Market Cross House, CooperStreet,
`Chichester, West Sussex, PO19 1EB, England
`The ublisher’s colophon is reproduced from James Gillison's drawing of the ancient Market Cross,
`rechester,
`
`| AX 3
`
`Distributors:
`Australia and New Zealand:
`JACARANDAWILEY LIMITED
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`JOHN WILEY & SONS CANADA LIMITED
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`Halsted Press: a division of
`JOHN WILEY & SONS
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`JOHN WILEY & SONS (SEA) PTE LIMITED
`37 Jalan Pemimpin # 05-04
`Block B, Union Industrial Building, Singapore 2057
`Indian Subcontinent
`
`
`
`British Library Cataloguing in Publication Data
`Wells, James I. (James Ingram), 7950-
`Pharmaceutical preformulation.
`1. Drugs. Physiochemical aspects -
`I. Title
`615'.19
`
`Library of Congress Card No. 88-9233
`ISBN 0-7458-0276-1 (Ellis Horwood Limited)
`ISBN 0-470-21114-8 (Haisted Press)
`Phototypesct in Times by Ellis Horwood Limited
`Printed in Great Britain by Hartnolls, Bodmin
`
`COPYRIGHT NOTICE
`All Rights Reserved. No part of this publication may be reproduced, stored in a retrieval system, or
`transmitted, in anyform orby any means,electronic, mechanical,photocopying, recording orotherwise,
`without the
`rmission ofEllis Horwood Limited, Market Cross House, Cooper Street, Chichester, West
`
`ussex,
`
`England.
`
`Apotex Exhibit 1011.002
`
`Apotex Exhibit 1011.002
`
`

`

`|
`
`Solubility
`
`Whena preformulation programmebegins, the availability of bulk is always limited
`and the scientist may only have 50 mg. Thus, it is imperative that the best usc of the
`limited bulk is made, to support the continuing efforts of the synthetic chemists and
`the biologists, pursuing activity and toxicity screens. Furthermore, because the
`compoundis new,the quality is invariably poor, so that a numberof impurities may
`be present and often the first seeding comes down as a metastable polymorph
`(Chapter 3). Accordingly if nothing clse is measured, the solubility and pK, must be
`determined since these largely control all future work. The solubility dictates the
`ease with which formulations for gavage and intravenousinjection studies in animals
`are obtained. The pX, allows the informed use of pH to manipulate solubility and
`choose salts, should they be required to achieve good bioavailability from the solid
`State, and to improvestability (Chapter 5) and powder properties (Chapter6).
`Kaplan (1972) suggested that, unless a compound has an aqueoussolubility in
`excess of 1% (10 mg ml~') over the pH range 1-7 at 37°C, then potential adsorption
`problems mayoccur. Healso foundthatif the intrinsic dissolution rate (IDR,section
`2.7) was greater than 1 mg cm~? min“! then adsorption was unimpeded,while less
`than 0.1 mg cm~? min! gave dissolution rate-limited adsorption. This ten-fold
`difference in dissolution rate translates to a lower limit for solubility of 1 mg ml!
`since undersink conditions, dissolution rate and solubility are proportional (Hamlin
`etal., 1965). A solubility of less than 1 mg ml~! indicates the need for a salt,
`particularly if the drug is to be formulated asa tablet or capsule. In the range 1-10
`mg ml7', serious consideration shouldbe given to salt preparation. These guidclines
`are shown graphically in Fig. 2.1. Where the solubility of the drug cannot be
`manipulatedin this way (a neutral molecule: glycoside, steroid, alcoholor where the
`pX,is less than 3 for a base or greater than 10 for an acid), then liquid filling (a
`solution in PEG 400, glyceryl triacetate or fractionated coconutoil) in a soft gelatin
`capsule, or as a paste or semisolid (dissolved in oil or triglyceride) in a hard gelatin
`capsule may be necessary.
`
`INTRINSIC SOLUBILITY(C,)
`2.1
`First examine the chemicalstructure, or determine the solubility in 0.1 N HCI, 0.1 N
`NaOHand waterby UV.An increasein acid over aqueoussolubility suggests a weak
`
`Apotex Exhibit 1011.003
`
`Apotex Exhibit 1011.003
`
`

`

`22
`
`10
`
`
`
`Solubility
`
`[Ch. 2
`
` Codeine X
`
`SALT FORM
`RECOMMENDED
`
`
`
`HIGH SOLUBILITY OR
`
`HIGH BASICITY REGION
`
`
`MAY NOT REQUIRE SALT
`
`
`
`
`.
`.
`
`Digoxin (no px,)
`
`
`X Promazine
`
`Trifluoropromazine
`
`ws-
`
`Prochlorperazine X
`
`+
`
`0.017
`
`0.005
`
`
`Cy = 10/1 + antilog (pK, - 7)
`pk, = 7 4
`log (10/C, - 1)
`
`
`
`0.002
`
`4
`
`5
`
`6
`
`7
`
`8
`
`Xx
`
`9
`
`10
`
`pK,
`
`+f]
`
`Fig. 2.1 — Relationship between drug pX, and solubility. Solubility > 10 mg mI7! at < pH?
`(Kaplan, 1972) is required to ensure good bioavailability.
`
`base,andin alkali, a weak acid. In both cases, a dissociation constant (pK,) will be
`measurable and salts should form. An increase in both acid and alkali solubility
`suggests either amphoteric or zwitterionic behaviour and there will be at least two
`pX,s, one acidic and one basic. No changein solubility suggests a non-ionizable,
`
`Apotex Exhibit 1011.004
`
`eeanentge—pfEPSPS
`
`
`
`X Chlordiazepoxide
`
`0.5
`
`0.2
`
`8601
`
`X Diamorphine
`
`SALT FORM
`REQUIRED
`
`X Morphine
`
`9.054
`
`X Diazepam
`
`0.02
`
`E e=
`
`Oo
`
`= =
`
`a 3=&
`
`é
`~
`
`Apotex Exhibit 1011.004
`
`

`

`Sec. 2.1]
`
`Intrinsic solubility (C,)
`
`23
`
`neutral molecule with no measurable p K,. Here solubility manipulation will require
`either solvents or complexation.
`Whenthe purity of the drug sample can be assured, then the value obtained in
`acid for a weak acid or alkali for a weak base can be assumed to be the intrinsic
`solubility (C,), i.e. the unionized form. However, since absolute purity is often in
`doubt on the first few synthetic batches, it is more accurate to determine this crucial
`solubility from a phase-solubility diagram (Fig. 2.2). The solubility should ideally be
`measured at two temperatures:
`
`(1) 4°C: to ensure good physical stability and extended short-term storage and
`chemicalstability until more definitive data are available. The density ofwateris
`maximum at 4°C andthis imposes the greatest challenge to saturated aqueous
`solubility.
`(2) 37°C: to support biopharmaceutical evaluation, since this is body temperature.
`
`Self association; complexation
`or solubilization by impurities
`
`Solubility
`
`Pure and Nointeraction
`--
`~ ~
`Cy =—_--
`
`Suppression by commonion
`effect of slating out
`
`et
`
` 1
`
`3
`
`2
`
`4
`
`Fig. 2.2 — Effect of drug:solvent ratio on solubility when the drug is impurc.
`
`Drug : solvent phase ratio
`
`Assuming the compoundis a base and the estimate in 0.1 N NaOH gave 1 mg ml7’,
`then four solutions of 3 ml should be set up containing 3, 6, 12 and 24 mg of drug
`respectively. These give the phase ratios shownin Fig. 2.1. Three millilitres is the
`smallest volume which can be manipulated, by either centrifugationorfiltration,
`followed by dilution for UV analysis. The vials containing the samples should be
`agitated continuously for 16 hours (overnight) and then the concentration in solution
`determined. The data should be plotted according to Fig. 2.1 and the line extrapo-
`lated to zero phaseratio, where the ‘solubility’ will be independent of solventlevel
`
`ron
`
`:
`
`Apotex Exhibit 1011.005
`
`Apotex Exhibit 1011.005
`
`

`

`24
`
`Solubility
`
`[Ch. 2
`
`and a true estimateoftheintrinsic solubility. Since any deviation fromthe horizontal
`(at saturation)is indicative of impurities, as higher drug loading cither promotes or
`suppresses solubility, the USP uses this method to estimate the purityof mecamyia-
`mine hydrochloride.
`In the case of a pure sample then the phase-solubility diagramwill approximate
`to Fig. 2.3. Up to point C alongthe solubility linc OC all the solute dissolves in the
`
`Saturated solubilities
`
`
`C, True solubility
`.
`Cc > C’
`
`
`
`
`
`Saturation
`point
`
` Pure substance Solubility
`ll solute dissolves
`
`
`
`‘ A
`
`0
`
`Weight of solute per volume of solvent
`
`Fig. 2.3 — Phase-solubility diagram for a pure substance,
`
`available solvent. At C saturation occurs and thenthereis nofurther dissolution, and
`the slope ofline CC’ is zero. Extrapolation back to the ordinate yiclds the true
`solubility as in Fig. 2.2. Where a sample contains a mixture of components, their
`solubility and proportions within the mixture can be determined applying the same
`technique. The form of the phase-solubility diagram is shownin Fig. 2.4. From O to
`A all solutes dissolve, whenat A, the solute that is most soluble and/or presentin the
`highest proportion reaches saturation. Along AB, the other twosolutes dissolve, at
`B the secondsolute reaches saturation, and along BCthe third componentdissolves
`to reach saturation at C. CD has zero slope becauseall components have reached
`saturation. Since the tie lines OA, AB and BCreficctthefraction dissolving, their
`slopes give the proportion in the mixture and the intercepts yield the arithmetic sums
`of their solubilities. Isolation of pure componentsis also possible since beyond A,
`dissolution proceeds leaving excess pure solid (component 1) which has reached
`saturation and so on.
`An example for chlordiazepoxide and the hydrochloride salt is shown in Fig 2.5.
`Apotex Exhibit 1011.006 |
`
`Apotex Exhibit 1011.006
`
`

`

`Sec. 2.2
`
`pA, from solubility data
`
`~~ ta
`
`C,4+C,+¢|— ——Ss——S=_s ———-_
`
`(2.1)
`
` ——- —_— —_
`
`
`
`mixture
`
`Solubility
`
`Slopes = proportion in mixture
`
`Weightof solute per volumeof solvent
`
`Fig. 2.4 — Phase-solubility diagram for a multicomponent mixture.
`
`Theselection of solvent is governed by solubility and usually the range 1-10 mg ml~!
`is most convenient. Chemicalstability is also important since hydrolysis will change
`the measured solubility. Although chlordiazepoxide andthe hydrochloride are pure,
`the positive slope for the hydrochloride indicates the acid-catalysed hydrolytic
`instability of chlordiazepoxide even in a non-aqueoussolvent. This analysis finds
`most use in the study of complexation. Here phase diagramsallow the stoichiometry
`of the complexing agent(ligand)-drug (substrate) complex to be determined (see the
`review by Higuchi and Connors, 1965).
`
`2.2 pK, FROM SOLUBILITY DATA
`Seventy-five per centofall drugs are weakbases (of the rest 20% are weak acids and
`the remaining 5% made up of non-ionics, amphoterics or alcohols). It is therefore
`more appropriate to consider the ionic equilibria of a weak base (B):
`
`B+H.,O = BH*+OH-
`
`and
`
`K, = [BH*][OH7}
`°
`[B]
`
`taking logarithms:
`
`_
`
`pk, = pOH+ og(el
`
`[B}
`
`Apotex Exhibit 1011.007
`
`ereee—__
`
`|
`
`Apotex Exhibit 1011.007
`
`

`

`Sec. 2.2]
`
`pK,from solubility data
`
`pH = pK,+ os(41)
`
`These cquations (2.2) and (2.3) are used:
`
`the drugwill be either completely ionized (BH*, A”) or unionized (B, HA):
`
`(1) to determine the pK, by following changesin solubility,
`(2) to allow the prediction of solubility at any pH provided the intrinsic solubility
`(C,) and pK, are known,
`(3) to facilitate the selection of suitable salt-forming compounds,
`(4) to predict the solubility and pHpropertiesofsalts.
`
`Albert and Serjeant (1984) give a detailed accountof how to obtain precise pK,
`values. The following method gives an acceptable estimate.
`From equations(2.2) and (2.3), when the pH is 2 units citherside of the p K,, then
`
`pH = pK,-—2 — BH* orHA
`
`pH=pK,+2—-B or A
`
`To haveany chance ofsignificant pHsolubility manipulation, the pX,for a base must
`be greater than 3 andforan acid less than 11. Consequently,if the solubility of the
`drug is measuredin either 0.1 N HCI(HA) or 0.1 N NaOH(B)then the solubility will
`be intrinsic (Cg), solely due to the unionized free acid or base. If the solubility is then
`measured at pH 4 and 6 for bases (pH 6 and8 for acids), the resultant saturated
`solubilities (C,) can be used in equations (2.2) and (2.3) to calculate the p&,;
`
`since}
`and
`
`then
`
`=C, = [B]
`C, = [B]+[(BH*]
`
`[BH*] = (C,-C,,)
`
`Substituting in equation (2.2)
`
`pKa = pH+log(= “:)
`
`
`
`or antilog (2.4)
`
`C, = C,(1 +antilog (pK, — pH))
`
`(2.4)
`
`(2.5)
`
`For example:
`
`the intrinsic solubility of chlordiazepoxide (a weak base) is
`
`Apotex Exhibit 1011.008
`
`adSS
`
`Apotex Exhibit 1011.008
`
`

`

`26
`
`Solubility
`
`[Ch. 2
`
`
`15
`Chlordiazepoxide
`
`
`Slope = 0%
`Intercept = 13.05 mg g@'
`
`
`
`
`
`.
`SOLVENT:
`ISOPROPANOL
`
`
`
`
`= 10
`®&
`
`5
`
`> 9
`
`w
`Oo
`o
`
`£ > 52A
`
`Chlordiazepoxide hydrochioride
` Slope 0.23%
`
`
`Intercept 2.53 mg g''
`
`
`
`
`20
`40
`60
`80
`100
`
`Concentration of sample in solvent
`
`Fig. 2.5 — Phase—solubility analysis for chlordiazepoxide and hydrochloride salt.
`
`By convention, ionization constants are now expressed as the corresponding acid
`pX, where:
`
`PA,+pK,=pKy (the ionization product of water)
`and
`
`pH + pOH
`
`pky
`
`Substituting in (2.1) and rearranging gives the Henderson—Hasselbalch equation:
`
`pH = pK,+108(-L-)
`
`
`
`(2.2)
`
`A similar equation can be derived for a weak acid (HA):
`
`Apotex Exhibit 1011.009
`
`Apotex Exhibit 1011.009
`
`

`

`
`
`28
`
`Solubility
`
`_
`
`[Ch. 2
`
`2 mg ml~'. Thesolubilities at pH 4 and 6 were measured as 14.6 (0.048 M) and 2.13
`mg ml~? respectively. Then using equation (2.4):
`
`and
`
`pk, = 4+ log4S)
`
`= 4.799
`
`pK, = 6 + log)
`
`= 4.813
`
`(Theliterature value is given as 4.6).
`The measuredsolubilities should not exceed 0.1M because of activity effects
`governed bythesalt’s lattice energy in the solid state. Use a higher pHifthis occurs.
`When morebulkis available a more precise value for the pK, can be obtained by
`constructing a seven-point pH-solubility profile within the range pk, +1. From
`equation (2.4), the solubility will double (2C,) when the pK, equals the pH.
`Alternatively, plotting pH against log(CJ(C, — Cy)) gives a straightline with the pK,
`as intercept. In the antilog form [H*] = (K,/C,)C, — Kg. Plotting C, against [H* ]
`gives a y-intercept of — K,, an x-intercept of C,, anda slope of K,/C, (Green, 1968).
`Other methods are available to determine pK,: potentiometry, spectroscopy
`(Chapter 4) and conductivity (see Albert and Serjeant, 1984). Once the pK, and
`intrinsic solubility are known, the solubility or pH can be predicted.
`For example: an injection of diamorphine (pK, = 7.60, C, = 0.59 mg ml!~!)
`contains 10 mgml~', What
`is the maximum pH consistent with maintaining
`solubility?
`From equation (2.4),
`
`Maximum pH = 7.60 -log
`
`(10 - 0.59)
`0.59
`
`6.4
`
`2.3 SALTS
`The improvementin solubility by pH changecanalso he achievedbythe selection of
`a salt. Acceptable pharmaceuticalsalt formers are shown in Table 2.1 which includes
`their corresponding pK,, whosesignificancewill now be explained.
`If the acid orbaseis ‘strong’ (K, and K,, both greater than 10 ~2), it is completely
`ionized in solution so that:
`
`pH
`
`I
`
`—log C, for an acid or
`log C, — pK,, for a base
`
`(2.6a)
`(2.6b)
`
`Apotex Exhibit 1011.010
`
`Apotex Exhibit 1011.010
`
`

`

`Sec. 2.3]
`
`Salts
`
`29
`
`Table 2.1 — Potential pharmaceuticalsalts
`NNeeom]
`Basic drugs
`Acidic drugs
`NN
`pK,
`pK,
`
`(%) Cation
`Usage*
`
`(%)
`Usage*
`
`Anion
`
`ydrochloride —-6.10
`Sulphate
`— 3.00, 1.96
`Tosylate
`— 1.34
`Mesylate
`~- 1.20
`Napsylate
`0.17
`Besylate
`0.70
`Maleate
`1.92, 6.23
`Phosphate
`2.15, 7.20, 12.38
`Salicylate
`3.00
`Tartrate
`3.00
`Lactate
`3.10
`Citrate
`3.13, 4.76, 6.40
`Benzoate
`4.20
`Succinate
`4.21, 5.64
`Acetate
`4.76
`Alternatives
`
`Potassium
`43
`7.5 Sodium
`0.1 Lithium
`2.0 Calcium
`0.3 Magnesium
`0.3 Diethanolamine
`3.0 Zinc
`3.2 Choline
`0.9 Aluminium
`3.5 Alternatives
`0.8
`3.0
`0.5
`0.4
`1.3
`30.2
`
`With thesalt of a weak acid and weak base (pK,(acid) >2 and pK, (base) < 12),
`
`aH
`
`10.8
`16.00
`14.77 62
`13.82
`1.6
`12.90
`10.5
`11.42
`1.3
`9.65
`1.0
`8.96
`3.0
`8.90
`0.3
`5.00
`0.7
`8.8
`
`* Martindale (1982).
`
`Knowing the pX, and concentration (molar) gives the pH of the solution. For
`example:
`
`pH of 0.01 N HCl = —log 0.01
`= 2
`
`Forthe salt of a weak base (pK, < 12) and a strong acid (pK, < 2):
`
`pH = (pK,—logC,) (2.7)
`
`
`and for a salt of a weak acid (pK, > 2) and strong base (pK, > 12):
`
`pH = i(pK,+ pK,+ logC,)
`
`(2.8)
`
`In each case the pK,refers to the weaker component,since the pH is modified byits
`extent of ionization, measured by its pX,, whereas the stronger reactant is com-
`pletely ionized.
`
`Apotex Exhibit 1011.011
`
`Apotex Exhibit 1011.011
`
`

`

`FS\
`
`30
`
`Solubility
`
`(Ch. 2
`
`both participating reactants moderate the overall pH of the stoichiometric product
`(salt):
`
`pH = 3(pK,(acid) + pK, (base))
`
`(2.9)
`
`i.e, the pH ofa salt solution of a weak acid and base (monovalent)is the meanoftheir
`respective pK,, because whenK,is small relative to C, the solution pH is indepen-
`dentof concentration. This equationis often expressed in the antilog form:
`
`[H*}? = K, (acid) x K, (base)
`
`Forthe salt of a dibasic acid (H,A) by analogy:
`
`[H*} = 2K,(acid) x K, (base)
`
`Herethe K, refers to the second acidity function (HA ~') which is weaker, and for
`any acid (H,A):
`
`[H*}? = » x K, (acid) x K, (base)
`
`(2.10)
`
`The equations which define ionic equilibria for a range of acids, bases andsalts are
`shownin Table 2.2. Their derivation is given by Martin etal. (1983).
`The effect of changing the salt form of chlordiazepoxide on the acidity of the
`solution and the solubility of the drug is shown in Table 2.3. In many cases,salts
`preparedfrom strong acidsor basesare freely soluble but also very hygroscopic. This
`can lead toinstability in tablet or capsule formulations since some drug will dissolve
`in its own adsorbedfilms of moisture (wateris the usual prerequisite or vector for
`breakdown), andin thecaseofthe salt of a weak base and strong acid, the strongly
`acidic solution may increase hydrolysis due to an unfavourable PH.pH,in, the pH of
`maximum hydrolytic stability for chlordiazepoxideis pH 2.75. From Table 2.3, it can
`be seen thatall the strong acids (HCI, H,SO,, besylate and maleate) give potentially
`moreacidic solutions at saturation. Applying equation (2) in Table 2.2, the most
`stable solution at pH,,;, (2.75) would contain 134 mg _ml—! active as these salts.
`Accordingly it is often better to use a weaker acid or base to form thesalt provided
`any solubility/biopharmaceutical requirements are met. A salt which is muchless
`solublewill probably be less hygroscopic (Chapter 5) and produce muchlessacidic or
`basic solutions (Table 2.2). This may also be importantin physiological terms:
`injections shouldlie in the pH range 3-9 to preventvesselortissue damageand pain
`at the injection site, and oral syrups should not be too acidic to enhance palatability.
`Packaging mayalso be susceptible: undue alkalinity will attack glass, and hydrochlo-
`ride salts should not be used in aerosol cans since a propellant-acid reaction will
`corrode the cannister.
`Onthis basis,it is possible to identify five key attributes of a selected salt form and
`these are shown in Table 2.4. While solubility and dissolution are discussed in detail
`here,further information on hygroscopicity andstability will be found in Chapter5.
`
`Apotex Exhibit 1011.012 |
`
`|
`
`Apotex Exhibit 1011.012
`
`

`

`Sec. 2.3]
`
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`Apotex Exhibit 1011.013
`
`Apotex Exhibit 1011.013
`
`

`

`rr
`
`32
`
`Solubility
`
`[Ch. 2
`
`Table 2.3 — Theoretical solubilities and pH ofsalts of chlordiazepoxide (molecular
`weight = 299.75)
`
`Salt
`
`Acid
`
`strength
`
`pK,
`
`pH of
`
`saturated
`salt solution
`
`Calculated
`
`solubility
`(mg ml ~')
`
`|
`
`2.0 (intrinsic)
`8.30
`Base
`4.80
`Chlordiazepoxide
`|
`165* Eq. 5t
`2.53
`Strong —6.10
`Hydrochloride
`
`
`
`Sulphate -—=2.53-3.00 = 165 |
`
`Besylate
`0.70
`2.53
`= 165
`}
`Maleate
`1.92
`3.36
`57.1 Eq. 10
`Tartrate
`3.00
`3.90
`17.9
`Benzoate
`4,20
`4.50
`6.0
`Acetatet
`4.76
`4.78
`4.1
`
`Weak
`
`i
`
`* Maximum solubility: governed by drug lipophilicity; melting point (236°C) and crystal lattice energy;
`and commonion effects. Achicved at < pH 2.89.
`+Maynot form: pX, (acid) and (base) too close.
`Table 2.2.
`
`!
`
`Property
`
`1. Solubility
`
`2. Dissolution
`
`3. Hygroscopicity
`
`4. Stability
`
`5. Processing
`
`Table 2.4 — Attributes of a selected drug salt form*
`
`Attribute
`
`Control
`
`Purpose
`
`Good
`>10>>>I1mgmi7
`pH !-7
`High
`LD.R>
`1 mg cm? min
`Low
`<0.5% €95% RH
`
`High
`fyg = 5 years
`at room temperature
`(> 2 years)
`Simple
`Good compression
`Non-sticky
`Good flow
`
`Jonic cquilibria
`ApK, |acid-base|
`Common ion?
`pHmicroenvironment
`Commonion?
`
`Solutions
`Oraland parenteral
`
`Bioavailability
`
`By (1) and (2) and
`drugstructure
`
`Structure,
`(1) and (3)
`
`Solid-state
`stability
`Tablets and capsules
`Shelflife
`
`Melting point, crystal
`form and (3)
`
`Manufacture of
`solid dosege
`forms
`
`* A single salt form for all routes of administration simplifies efficacy and safety evaluation, manufacture
`and analytical clearance and the regulatory documentation.
`
`Some aspects of processing will be found in Chapter 7, melting point in Chapter 3 and
`crystallography in Chapter 6. The majority of this investigational work can be
`undertaken with the formulation technologist’s active involvement.
`
`Apotex Exhibit 1011.014 -
`
`Apotex Exhibit 1011.014
`
`

`

`
`
`Sec. 2.3}
`
`Salts
`
`33
`
`Returning to the use of pX, for predicting salt solubility, further modification is
`required since the interpretation of salt solubility is complicated by the difficulty in
`discriminating between the energy required to remove ions from the crystal lattice
`and the energy of solvation. This can be measured by dissolving the salt in an inert
`hydrocarbon, for example hexane, since structurally similar solutes dissolve at rates
`solely related to crystalline energies (Rytting et al. 1972). However, it is aqueous
`solubility which remains the central concern, and although there is a strong
`correlation between melting point (7,,) and solubility (equations (3.1) and (3.7)),
`this does not preclude the influence of counterion hydrophilicity. Thus the intuitive
`and attractive relationship between pX, and hydrophilicity (see Berge and Bighley,
`1977; and -Table 2.2) neglects the existence of stronger interactions when the
`counterion becomes more polar (Anderson and Conradi, 1985), or weaker interac-
`tions whentheionis large and/or hydrophobic, for example pamoate (Benjamin and
`Lin, 1985; Table 2.5). Ionic equilibria (Table 2.2) fails to account for the stereo-
`
`Table 2.5 — Salt solubility for an experimental antihypertensive base demonstrating
`poorcorrelations with ionic equilibria calculations
`Salt
`pK,
`pH,..*
`Solubility (mg ml ~')
`TCC)
`
`Calc.7
`Found
`
`
`97-99
`0.32
`_
`9.75
`8.5
`Base
`81-90
`24.20
`22.97
`6.65
`4.8
`Acetate
`150-153
`25.61
`202.22
`5.70
`2.9
`Tartrate
`160
`5.04
`180.27
`5.75
`3.0
`Salicylate
`185-190
`0.24
`320.32
`5.50
`2.5
`Pamoate
`
`
`pH = (pK, + pXp).
`*C, =
`C,(1 + antilog(pX, — pH)).
`From the data of Benjamin and Lin (1985).
`
`Seeeaeeteaadcanedneeeee:bhree
`
`chemistry of the drug, counterion size or other polar groups (—OH) which can
`interact, e.g. citrate. A more general
`treatment is given in Table 2.6 and in
`combination with pK,, ionic equilibria prediction and the Henderson—Hasselbalch
`equation can be usedto identify a shorterlist of suitable salt-forming candidates.
`These have been organized into four subgroupsin Table 2.7 in orderto facilitate a
`rational choice whenthe definedattributes of a salt (Table 2.4) have not been met by
`the preliminary screen, or specific formulation goals need to be addressed, e.g.
`topical, i.m., controlled release, taste. The whole processis highly interactive since
`decisions will have to be based on the drug stereochemistry; the melting point of the
`drug and the acid counterions (Chapter 3); on the stability of the drug (Chapter 5)
`andits lipophilicity and basicity (Chapter 2).
`Rigid planar and flexible molecules behave differently. Rigid molecules form
`salts with a lower melting point andthe solubility rises, whereas aromatic bases form
`oer
`salts with a higher melting point due to an increase in crystallinity. Hydroxy acids
`Apotex Exhibit 1011 015 |
`
`b a
`
`3 4:
`
`a:
`
`Apotex Exhibit 1011.015
`
`

`

`EEES
`
`34
`
`Solubility
`
`[Ch. 2
`
`Table 2.6 — Salt-form selection based on physicochemical properties
`
`Property
`
`Attribute
`
`Methods
`
`1. Melting point
`(+) Increase Processing
`Reducesolubility
`
`(—) Decrease Form oil (7, < 25°C)
`
`Increase solubility
`
`2. Solubility
`(+) Increase Bioavailability
`Aqueous formulations
`
`(—) Decrease Suspensions
`Taste
`Controlled release
`
`3. Stability
`(+) Increase Chemical (shelf life)
`
`Processing (physical)
`
`4. Wettability
`(+) Increase Dissolution rate
`Bioavailability
`
`(—) Decrease Influence hygroscopicity
`
`Use small counterions e.g. Ci- , SO7
`Use aromatic acids with aromatic
`basic drugs
`Use hydroxyacidsif drug will
`hydrogen bond
`Useflexible aliphatic acids with
`aromatic bases
`Use highly substituted acids to destroy
`crystal symmetry
`
`Increase acidity of counterion (< pK,)
`Decrease melting point
`Use hydroxy acid conjugates
`For commonion effects move to small
`organic acids
`Increase melting point
`Use hydrophobic counterions
`Reduce acidity of conjugate acid
`(> pK,)
`
`Reduce hygroscopicity by increasing
`hydrophobicity of acid
`Change from mineral or sulphonic
`acids to carboxylics
`Use weaker acid (> pK,) to raise pH
`of surface moisture
`Decrease C, and increase crystallinity
`by raising 7,,
`
`Lower pK, of acid
`Use hydroxy acids and increase
`polarity
`Recrystallize from other solvents to
`change habit
`Use more hydrophobic acids
`
`increase rigidity in flexible bases by hydrogen bonding. Although the melting point
`then increases, the solubility is not compromised due to the hydrophilicity of the
`acid.
`
`Apotex Exhibit 1011.016
`
`Apotex Exhibit 1011.016
`
`

`

`
`
`Table 2.7 — Counterion cluster groups to manipulate basic drug salt performance:
`melting point, solubility, stability, hygroscopicity, processing and organoleptic
`properties
`
`Grouping
`Tn(°C)
`Application
`
`
`Increase T,,, of aromatic
`bases
`Processing and stability
`
`Increase T,,, by hydrogen
`bondsin flexible bases.
`Decrease T,,, for planar
`symmetrical aromatic
`bases and increase C,
`
`_
`_—
`_
`_
`
`20
`
`43
`70
`
`124
`
`131
`122
`158
`
`16.6
`100
`185
`13]
`80
`17
`205
`153
`191
`
`GROUP A
`Organic acids
`Hydrobromide
`Hydrochloride
`Sulphate
`Nitrate
`
`Sulphonic acids
`Methane sulphonate
`Ethanesulphonate
`Benzenesulphonate
`Toluene sulphonate
`'Naphthalenc-2-
`sulphonate
`Carboxylic acids
`Maleate
`Benzoate
`Salicylate
`GROUP B
`Acétate
`Malate
`Succinate
`Gluconate
`Glycollate
`Lactate
`Tartrate
`Citrate
`Ascorbate
`
`| w
`
`eeee
`
`—3.4
`16.7
`31.4
`24
`
`Reduce 7, producing
`oils (ion pairing?) for
`im. injections, topicals
`or soft gelatin capsules
`
`ne,-
`“arteae
`1epeeRETrraeeepeeoe
`Lahaottage
`aeteeonae
`
`GROUP C
`Hexanoate
`Octanoate
`Decanoate
`Undecylenate
`Dodecyl sulphate
`(& D)
`Oleate
`Stearate (& D)
`GROUP D
`Insoluble salts
`(suspensions)
`'Napsylate
`5,5’-methylene
`disalicylate
`Pamoate
`Polystyrene sulphonate
`(resinate)
`Bitter taste-masking
`Saccharinate
`229
`
`Aspartamate 246
`
`4
`69
`
`124
`
`238
`280
`
`Reduce solubility for taste
`masking and suspensions
`
`Apotex Exhibit 1011.017
`
`Apotex Exhibit 1011.017
`
`

`

`ee
`
`36
`
`[Ch. 2
`
`Solubility
`
`PeSPESee
`
`The most popularsalts (group A: inorganic, sulphonic and carboxylic acids) tend
`to increase melting point and improve stability and processing. The extent of
`solubility improvementthen largely dependson any specific commonion interaction
`(section 2.7), particularly with the inorganics, and the size and polarity of the
`sulphonate or carboxylate counterion. Hygroscopicity is less easy to predict, but
`moving throughtheseries, larger ions will reduce solubility and their lower polarity
`will reduce the interaction with water vapour. The sulphonic acids are prone to
`hydrate formation, but this may give a stable, acceptable form, provided the
`solubility is not adversely affected. Prochlorperazine (an oil: T,,, = 25°C) is presented
`as an insoluble maleate salt (7,,, = 198-203°C; C, < 1 mg ml~") in solid dosage forms
`and suppositories, while for solutions (syrup and injection) the required solubility is
`obtained using the mesylate salt (T,,, = 242°C; C, > 2000 mg ml ').
`Group B contains the hydroxy acids which will both increase and decrease
`melting point depending on drug structure. Their majoreffect, however, resides with
`their excess hydroxy groups and this hydrophilicity confers high solubility. However,
`hygroscopicity then becomesa significant problem.In the search for a solublesalt of
`chlorhexidine, a broad spectrum bactericide, Senior (1973) identified the digluco-
`nate salt which gives a ten-thousand-fold improvement over the free base. The
`dihydrochloride by comparison only improvessolubility by about 7.5 and some data
`is shown in Table 2.8. In general, from the acids he evaluated, hydroxy acids
`promotedsolubility. In the search for a more solublesalt, the major lead arose from
`comparingthesolubility of the lactate (a-hydroxypropionate) with the propionate.
`Group C comprises the fatty acids whose application is generally restricted to
`exploiting an oily form in topical preparations, soft gelatin capsules or i.m. injec-
`tions. Some benefits are also possible from improved stability, e.g. erythromycin
`stearate (erythromycin baseis gastric acid labile) and for controlled-release devices.
`For example, fluphenazineis given as the decanoate (T,,, = 25°C; C, = < 10 ug ml~')
`by i.m. injection for monthly therapy in schizophrenia, while the dihydrochloride
`(T,, = 277°C; C, = 100 mg ml~') is formulated as tablets and elixir. Neomycin
`sulphate is used widely in oral therapy, but the undecylenate is applied topically,
`capitalizing on the intrinsic antifungal activity of this acid.
`The miscellancousacids in group D provide a meansof suppressing solubility and
`maskingtaste in suspension formulations. Their low solubility may also be exploited
`in controlled release (Table 2.5). Chlorpromazine is supplied as the freely soluble
`hydrochloride in most dosage forms, including a syrup containing 25 mg per 5 ml. In
`high-dose therapy, however, the insoluble pamoatesalt is formulated as a suspension
`containing 100 mg per 5 ml, and the base is used in suppositories. Dextropropoxy-
`phenehydrochloride is extremely soluble (1 in 0.3) andis used in solid dosage forms.
`However, in compound analgesics, the insoluble napsylatesalt is preferred because
`it is stable when combined with aspirin.
`A range of preferred salt forms for various drugs is given in Tabie 2.9. Armed
`with the information presentedin this section, the interested reader can attempt to
`understand and rationalize their choice. Supplementary information in Martindale
`(1982) or the Merck Index (1983) will be found helpful.
`Returning to chlordiazepoxide (Table 2.3) it is clear that not only does the
`intrinsic pH of the base solution fall significantly from pH 8.3 (pH... = #(pKa+
`pKw+ logC,), where C, is the molar concentration of base) but as a consequence,
`
`Apotex Exhibit 1011.018
`
`<n
`ra
`Fepe
`
`canaryweeener
`
`|
`
`
`Apotex Exhibit 1011.018
`
`

`

`
`
`Sec. 2.3]
`
`Salts
`
`37
`
`Table 2.8 — Salt selection for chlorhexidine, a bis-biguanide bactericide
`
`Salt
`
`Base
`
`Inorganic
`Dihydrochloride
`Sulphate
`Dinitrate
`Di-acid phosphate
`Sulphonic
`Dimesylate
`Di-2-hydroxyethanesulphonate
`(isethionate)
`Di-2-hydroxynaphthoate
`Pamoate
`Carboxylic
`Di-acetate
`Dipropionate
`Di-isobutyrate
`Malonate
`Succinate
`Dibenzoate
`Hydroxy
`Tartrate
`Dilactate («-hydroxypropionate)
`Di-a-hydroxyiso-butyrate
`Digluconate
`Diglucoheptonate
`
`From the data of Senior (1973).
`
`Solubility (mg ml ~')
`
`(SO,?~ sensitive |)
`
`0.08
`
`0.60
`0.10
`0.03
`0.03
`
`12.00
`
`> 500
`0.14
`0.009
`
`18.00
`4.00
`13.00
`0.20
`0.20
`0.30
`
`1.00
`10.00
`13.00
`> 700
`> 700
`
`the solubility increases exponentially (equations (2.2) and (2.3)). The corresponding
`equation for an acid is pH,.ig = 4(pK, — log C,). These have important implications
`in vivo. Intuitively a weak base with an intrinsic solubility > 1 mg m1 —' will be freely
`soluble in the gastrointestinal (GI) tract, especially the stomach.
`Nonethelessit is usually better to formulate with a salt since it will control the