PHARMACEUTICAL
`
`PREFORMULATION:
`The Physicochemical Properties
`of Drug Substances
`
`JAMES I. WELLS, 3‘ch M.Sc.. Ph.D.. M.l'.S.. Mlnstl’kg.
`Development Group Leader
`Pharmaceutical Research and Development
`Pfizer Central Research, Sandwich, Kent
`
`ELLIS HORWOOI) LIMITED
`Publishers - (Thichcstcr
`
`Halstcd Press: a division of
`
`JOHN WILEY & SONS
`New York - Chichcsler - Brisbane - Tomnlu
`
`ApoteX Exhibit 1011.001
`
`Apotex Exhibit 1011.001
`
`

`

`First published in 1988 by
`
`‘6‘? 8
`
`ELLIS HORWOOD LIMITED
`Market Cross House, Cooper Street,
`Chichester, West Sussex, P019 1EB, England
`guts ublirher’s Colophon is reproduced from James Gilliron's drawing of the ancient Market Cross,
`IC ester.
`
`Distributors:
`
`Australia and New Zealand:
`JACARANDA WILEY LIMITED
`GPO Box 859, Brisbane, Queensland 4001, Australia
`Canada:
`
`JOHN WILEY & SONS CANADA LIMITED
`22 Worcester Road, Rexdale, Ontario, Canada
`Europe and Africa:
`JOHN WILEY & SONS LIMITED
`Baffins Lane, Chichester, West Sussex, England
`North and South America and the rest of the world:
`Halsted Press: a division of
`JOHN WILEY & SONS
`
`605 Third Avenue, New York, NY 10158, USA
`South-East Asia
`
`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 1. (James Ingram), I950—
`I’hannaceutical prefonnulation.
`1. Drugs. Physiochernical aspects .
`I. Title
`615’.l9
`
`Library of Congress Card No. 88—9233
`
`ISBN 0-7458-0276—1 (Ellis Horwood Limited)
`ISBN 0—470—21 114-8 (Halsted Press)
`
`Phototypcsct in Times by Ellis Horwood Limited
`Printed in Great Britain by Hannolls, Bodmln
`
`COPYRIGHT NOTICE
`
`All Rights Reserved. No part of this publication may be reproduced, stored in a retrieval system, or
`transmitted, in any term or by any means. electronic, mechanicahphotocopying, recording or otherwise.
`téwthoul gm ransom of 131115 Horwood Ltmited. Market Cross ouse, Cooper Street, Chichester, West
`usscx,
`ng an .
`
`ApoteX Exhibit 1011.002
`
`Apotex Exhibit 1011.002
`
`

`

`2 S
`
`olubility
`
`in_—_._.vaml,_w~V
`
`1
`
`‘
`
`When a preformulation programme begins, the availability of bulk is always limited
`and the scientist may only have 50 mg. Thus, it is imperative that the best use 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
`compound is new, the quality is invariably poor, so that a number of impurities may
`be present and often the first seeding comes down as a metastable polymorph
`(Chapter 3). Accordingly if nothing else is measured, the solubility and pKu must be
`determined since these largely control all future work. The solubility dictates the
`ease with which formulations for gavage and intravenous injection studies in animals
`are obtained. The pKd 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 improve stability (Chapter 5) and powder properties (Chapter 6).
`Kaplan (1972) suggested that, unless a compound has an aqueous solubility in
`excess of 1% (10 mg [Ill—l) over the pH range 1—7 at 37°C, then potential adsorption
`problems may occur. He also found that if the intrinsic dissolution rate (lDR. section
`2.7) was greater than 1 mg cm“2 min”1 then adsorption was unimpeded, while less
`than 0.1 mg cm‘2 min'l gave dissolution rate-limited adsorption. This ten-fold
`difference in dissolution rate translates to a lower limit for solubility of 1 mg ml'1
`since under sink conditions, dissolution rate and solubility are proportional (Hamlin
`et 01., 1965). A solubility of less than 1 mg ml" indicates the need for a salt,
`particularly if the drug is to be formulated as a tablet or capsule. In the range 1-10
`mg ml”1 , serious consideration should be given to salt preparation. These guidelines
`are shown graphically in Fig. 2.1. Where the solubility of the drug cannot be
`manipulated in this way (a neutral molecule: glycoside, steroid, alcohol or where the
`pK,, 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 coconut oil) in a soft gelatin
`capsule, or as a paste or semisolid (dissolved in oil or triglyceride) in a hard gelatin
`capsule may be necessary.
`
`2.1
`
`INTRINSIC SOLUBILITY (C,,)
`
`First examine the chemical structure, or determine the solubility in 0.1 N HCl, 0.1 N
`NaOH and water by UV. An increase in acid over aqueous solubility suggests a weak
`
`Apotex Exhibit 1011.003
`
`Apotex Exhibit 1011.003
`
`

`

`22
`
`Solubility
`
`[Ch. 2
`
`10
`
`
`
` Codeine X
`
`SALT FORM
`RECOMMENDED
`
`
`
`HIGH SOLUBILITY 0R
`
`HIGH BASICITY REGION
`
`
`
`
`X Chlordiazepoxide
`
`0.5
`
`0.2
`
`0.1
`
`X Diamorphine
`
`SALT FORM
`REQUIRED
`
`X Morphme
`
`0-05
`
`X Diazepam
`
`0.02
`
`0.01 ~
`
`E E:
`
`g
`2:
`
`g
`.3
`8
`.2
`:3
`'3
`_
`
`MAY NOT REQUIRE SALT
`
`
`
`
`.
`.
`
`Dugoxm (no pig)
`
`
`Prochlorperazine X
`X Promazine
`
`
`0.005
`
`0002
`
`0.001
`
`Co = 101 + amilog (pK, - 7)
`
`
`pK, : 7 4
`log (10H:u -U
`
`
`x
`.
`
`Trifluoroprornazme
`
`4
`5
`5
`7
`8
`9
`10
`11
`
`0K.
`
`Fig. 2.1 — Relationship between drug {HQ and solubility. Solubility>10 mg ml" at < pH?
`(Kaplan. 1972) is required to ensure good bioavailability.
`
`ApoteX Exhibit 1011.004
`
`Apotex Exhibit 1011.004
`
`

`

`Sec. 2.1]
`
`Intrinsic solubility (Co)
`
`23
`
`neutral molecule with no measurable pKa. Here solubility manipulation will require
`either solvents or complexation.
`When the 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 (Co), 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
`chemical stability until more definitive data are available. The density of water is
`maximum at 4°C and this imposes the greatest challenge to saturated aqueous
`solubility.
`(2) 37°C: to support biopharmaceutical evaluation, since this is body temperature.
`
`
`
`..—._.._.___-_.._...__.__..mi“
`
`Self association; complexation
`or solubtltzatlon by impurities
`
`Solubility
`
`C0
`
`Pure and No interaction
`l.—
`-. ‘
`-—._——————____—_—_-.
`
`Suppression by common ion
`effect of slating out
`
` 1
`
`8
`
`2
`
`4
`
`":9.5'33“3."
`
`1 1
`
`Drug : solvent phase ratio
`
`Fig. 2.2 — Effect of drug : solvent ratio on solubility when the drug is impure.
`
`Assuming the compound is a base and the estimate in 0.1 N NaOH gave 1 mg ml”,
`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 shown in Fig. 2.1. Three millilitres is the
`smallest volume which can be manipulated, by either centrifugation or filtration,
`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 phase ratio, where the ‘solubility’ will be independent of solvent level
`
`ApoteX Exhibit 1011.005
`
`Apotex Exhibit 1011.005
`
`

`

`24
`
`Solubility
`
`[Ch. 2
`
`and a true estimate of the intrinsic solubility. Since any deviation front the horizontal
`(at saturation) is indicative of impurities, as higher drug loading either promotes or
`suppresses solubility, the USP uses this method to estimate the purity of meeamyia-
`mine hydrochloride.
`in the case of a pure sample then the phase—solubility diagram will approximate
`to Fig. 2.3. Up to point C along the solubility linc 0C all the solute dissolves in the
`
`Saturated solubilities
`
`
`
` C, True solubility
`
`
`Saturation
`
`
`point
`
` Pure substance
`
` Solubility
`
`
`ll solute dissolves
`
`
`
`_..__.....,__
`
`\ A
`
`Weight of solute per volume ml solvent
`
`Fig. 2.3 — Phase—solubility diagram for a pure substance.
`
`available solvent. At C saturation occurs and then there is no further dissolution, and
`the slope of line CC'
`is zero. Extrapolation back to the ordinate yields 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 shown in Fig. 2.4. From 0 to
`A all solutes dissolve, when at A, the solute that is most soluble and/or present in the
`highest proportion reaches saturation. Along AB, the other two solutes dissolve, at
`B the second solute reaches saturation, and along BC the third component dissolves
`to reach saturation at C. CD has zero slope because all components have reached
`saturation. Since the tie lines 0A, AB and BC reflect the fraction dissolving, their
`slopes give the preponion in the mixture and the intercepts yield the arithmetic sums
`of their solubilities. Isolation of pure components is also possible since beyond A,
`dissolution proceeds leaving excess pure solid (component i) 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
`
`pK. from solubility data
`
`Is.) LII
`
`
`
`mixture
`
`Solubility
`
`C.+C.,+Cc_____________.
`
`
`
`Slopes = proportion in mixture
`
`Weight of solute per volume 01 solvent
`
`Fig. 2.4 -— Phase—solubility diagram for a mullieomponent mixture.
`
`Theselectionofsolventisgovernedbysolubilityandusuallytherangel—lflmgml"l
`
`is most convenient. Chemical stability is also important since hydrolysis will change
`the measured solubility. Although chlordiazepoxide and the hydrochloride are pure,
`the positive slope for the hydrochloride indicates the acid-catalysed hydrolytic
`instability of chlordiazepoxide even in a non-aqueous solvent. This analysis linds
`most use in the study of complexation. Here phase diagrams allow the sloichiometry
`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 cent of all drugs are weak bases (of the rest 20% are weak acids and
`the remaining 5% made up of non-ionics, amphoterics or alcohols). it is therefore
`more appmpriate to consider the ionic equilibria of a weak base (B):
`
`B+ H20 = BH+ +Ol-l’
`
`and
`
`_ [BH*][OH"]
`K" ‘
`[13]
`
`taking logarithms:
`
`
`
`pr = p0H+log([B[:]+])
`
`(2.1)
`
`Apotex Exhibit 1011.007
`
`1
`
`! i '
`
`'
`
`l
`
`Apotex Exhibit 1011.007
`
`

`

`Sec. 2.2]
`
`pK. from solubility data
`
`pH = pKa+ 104%)
`
`These equations (2.2) and (2.3) are used:
`
`or A
`
`(1) to determine the pKa by following changes in solubility,
`(2) to allow the prediction of solubility at any pH provided the intrinsic solubility
`(Co) and pKa are known,
`(3) to facilitate the selection of suitable salt-forming cempounds.
`(4) to predict the solubility and pH properties of salts.
`
`Albert and Serjeant (1984) give a detailed account of how to obtain precise pKa
`values. The following method gives an acceptable estimate.
`From equations (2.2) and (2.3), when the pH is 2 units either side of the p K“, then
`the drug will be either completely ionized (BH+, A”) or unionized (B, HA):
`
`pH
`
`pH
`
`pKa—Z—sBH*orHA
`
`pKa+2—+ B
`
`To have any chance of significant pH solubility manipulation, the p [(0 for a base must
`be greater than 3 and for an acid less than 11. Consequently, if the solubility of the
`drug is measured in either 0.1 N HO (HA) or 0.1 N NaOH (B) then the solubility will
`be intrinsic (C0), solely due to the unionized free acid or base. if the solubility is then
`measured at pH 4 and 6 for buses (pH 6 and 8 for acids), the resultant saturated
`solubilities (Cs) can be used in equations (2.2) and (2.3) to calculate the pKa:
`
`since
`
`Q, = [B]
`
`and
`
`then
`
`C5 = [B]+[BH+]
`
`[BH+] = (Cs—C“)
`
`Substituting in equation (2.2)
`
`pKa = pH+|og(c‘(’7 C")
`
`
`
`or antilog (2.4)
`
`C“ = Co(1+ antilog(pK¢, — pH))
`
`(2.4)
`
`(2.5)
`
`For example:
`
`the intrinsic solubility of chlordiazepoxide (a weak base) is
`
`ApoteX Exhibit 1011.008
`
`-mzuur
`
`Apotex Exhibit 1011.008
`
`

`

`
`
`26
`
`Solubility
`
`[Ch. 2
`
`15
`
`
`
`
`Chlordiazepoxide
`
`Slope = 0%
`
`
`Intercept = 13.05 mg g'I
`
`
`.
`
`SOLVENT:
`ISOPROPANOL
`
`
`
`
`10
`
`75‘
`
`0> T
`
`0)
`:
`
`
`
`5
`
`7,,
`a,
`£5.
`
`2 E2 5
`
`’,
`
`Chlordiazepoxide hydrochloride
`
`
`
`Intercept 2.53 mg g' ‘
`
`
`
` Slooe 0.23%
`
`
`20
`
`40
`
`60
`
`80
`
`100
`
`Concentration of sample 5
`
`n solvent
`
`Fig. 2.5 — Phase-solubility analysis for chlordiachoxide and hydrochloride salt.
`
`By convention, ionization constants are now ex
`pKa where:
`
`pressed as the corresponding acid
`
`PKa + pr
`
`pKW (the ionization product of water)
`
`and
`
`pH + pOH
`
`pKW
`
`Substituting in (2.1) and rearranging gives the Henderson-Hassclbalch equation:
`
` )
`pH = pKa + log(
`
`[3]
`[311+]
`
`(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' ‘. The solubilities 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
`
`pKa = 4+log-(L'6222
`
`= 4.799
`
`pKa = 6+log(2'123—2)
`
`
`
`= 4.813
`
`(The literature value is given as 4.6).
`The measured solubilities should not exceed 0.1 M because of activity effects
`governed by the salt’s lattice energy in the solid state. Use a higher pH if this occurs.
`When more bulk is available a more precise value for the pKa can be obtained by
`constructing a seven-point pH-solubility profile within the range pKai 1. From
`equation (2.4), the solubility will double (2C0) when the pit], equals the pH.
`Alternatively, plotting pH against log (Co/(C, — C0)) gives a straight line with the pKa
`as intercept. In the antilog form [11*] = (IQ/Co) C, — K3. Plotting C, against [H+]
`gives a y-interccpt of — K3, an x-intercept of Co, and a SIOpe of KalCo (Green, 1968).
`Other methods are available to determine pKa: potentiometry, spectroscopy
`(Chapter 4) and conductivity (see Albert and Serjeant, 1984). Once the pKa and
`intrinsic solubility are known, the solubility or pH can be predicted.
`For example: an injection of diamorphine (pKu = 7.60, Cn = 0.59 mg ml '1)
`contains 10 mg ml “. What
`is the maximum pH consistent with maintaining
`solubility?
`From equation (2.4),
`
`.
`Maxrmum pH
`
`_
`
`7.60
`= 6-4
`
`_
`
`(IO—0.59)
`log—-—0.59
`
`2.3 SALTS
`
`The improvement in solubility by pH change can also be achieved by the selection of
`a salt. Acceptable pharmaceutical salt formers are shown in Table 2.1 which includes
`their corresponding pKa, whose significance will now be explained.
`It the acid or base is ‘strong’ (Ka and Kb both greater than 10 ‘2), it is completely
`ionized in solution so that:
`
`pH = — log Ca for an acid or
`=
`log Cb — pKW for a base
`
`(2.63)
`(2.6b)
`
`ApoteX Exhibit 1011.010
`
`Apotex Exhibit 1011.010
`
`

`

`Sec. 2.3]
`
`Salts
`
`29
`
`Table 2.1 — Potential pharmaceutical salts
`___—______—_.__.__————————
`
`Acidic drugs
`Basic drugs
`__________—__————
`Anion
`pKa
`(%) Cation
`pKa
`(%)
`Usage‘
`Usage."
`___________———————
`Hydrochloride
`- 6.10
`43
`Potassium
`16.00
`10.8
`Sulphate
`-— 3.00, 1.96
`7.5 Sodium
`14.77 62
`Tosylate
`— 1.34
`0.1 Lithium
`13.82
`1.6
`Mesylate
`-- 1.20
`2.0 Calcium
`12.90
`10.5
`Napsylate
`0.17
`0.3 Magnesium
`11.42
`1.3
`Besylate
`0.70
`0.3 Diethanolamine
`9.65
`1.0
`Maleate
`1.92, 6.23
`3.0 Zinc
`8.96
`3.0
`Phosphate
`2.15, 7.20, 12.38
`3.2 Choline
`8.90
`0.3
`Saiicyiate
`3.00
`0.9 Aluminium
`5.00
`0.7
`Tartrate
`3.00
`3.5 Alternatives
`8.8
`Lactate
`3.10
`0.8
`Citrate
`3.13, 4.76, 6.40
`3.0
`Benzoate
`4.20
`0.5
`Succinate
`4.21, 5.64
`0.4
`Acetate
`4.76
`1.3
`Alternatives
`30.2
`__________—_—_————-——-—-—
`
`- Martindalc (1932).
`
`Knowing the pit], and concentration (molar) gives the pH of the solution. For
`example:
`
`pH of 0.01 N HCl = — log 0.01
`= 2
`
`For the salt of a weak base (pKa < 12) and a strong acid (pKa < 2):
`
`pH = £63K. - 103 C.)
`
`and for a salt of a weak acid (pKa > 2) and strong base (pK,2 >12):
`
`pH = 5(pKa + pKW + long)
`
`(2.7)
`
`(2.8)
`
`With the salt of a weak acid and weak base (pKa (acid) >2 and pKa (base) < 12),
`
`In each case the pK‘7 refers to the weaker component, since the pH is modified by its
`extent of ionization, measured by its pKa, whereas the stronger reactant is com-
`pletely ionized.
`
`ApoteX Exhibit 1011.011
`
`Apotex Exhibit 1011.011
`
`

`

`55——l
`
`30
`
`Solubility
`
`[Ch. 2
`
`both participating reactants moderate the overall pH of the stoichiometric product
`(salt):
`
`t
`
`i l
`
`i
`
`For the salt of a dibasic acid (HzA) by analogy:
`
`[H‘]2 = 2 Ka (acid) x Ka (base)
`
`Here the K, refers to the second acidity function (HA “ ') which is weaker. and for
`any acid (HnA):
`
`[n+12 = n x Ka (acid) x K. (base)
`
`(2.10)
`
`The equations which define ionic equilibria for a range of acids, bases and salts are
`shown in Table 2.2. Their derivation is given by Martin et a1. (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
`prepared from strong acids or bases are freely soluble but also very hygroscopic. This
`can lead to instability in tablet or capsule formulations since some drug will dissolve
`in its own adsorbed films of moisture (water is the usual prerequisite or vector for
`breakdown), and in the case of the salt of a weak base and strong acid, the strongly
`acidic solution may increase hydrolysis due to an unfavourable pH. pHmin, the pH of
`maximum hydrolytic stability for chlordiazepoxide is pH 2.75. From Table 2.3 . it can
`be seen that all the strong acids (HCl, H2504, besylate and maleate) give potentially
`more acidic solutions at saturation. Applying equation (2) in Table 2.2, the most
`stable solution at pHmin (2.75) would contain 134 mg ml‘1 active as these salts.
`Accordingly it is often better to use a weaker acid or base to form the salt provided
`any solubility/biopharmaceutical requirements are met. A salt which is much less
`soluble will probably be less hygroscopic (Chapter 5) and produce much less acidic or
`basic solutions (Table 2.2). This may also be important in physiological terms:
`injections should lie in the pH range 3—9 to prevent vessel or tissue damage and pain
`at the injection site, and oral syrups should not be too acidic to enhance palatability.
`Packaging may also 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.
`On this 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 and stability will be found in Chapter 5.
`
`ApoteX Exhibit 1011.012 1l
`
`i.e. the pH of a salt solution of a weak acid and base (monovalent) is the mean of their
`respective pKa, because when Ka is small relative to C, the solution pH is indepen-
`dent of concentration. This equation is often expressed in the antilog form:
`
`pH=é(pK,,(acid)+pKa(base))
`
`[14“]2 = K, (acid) x K3 (base)
`
`(2.9)
`
`Apotex Exhibit 1011.012
`
`

`

`Sec. 2.3]
`
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`ApoteX Exhibit 1011.013
`
`1
`
`Apotex Exhibit 1011.013
`
`

`

`_ 3
`
`Solubility
`
`[Ch. 2
`
`2
`
`Table 2.3 —- Theoretical solubilities and pH of salts of chlordiazepoxide (molecular
`weight = 299.75)
`
`Salt
`
`Acid
`
`strength
`
`pKa
`
`pH of
`saturated
`salt solution
`
`Calculated
`solubility
`(mg ml “1)
`
`Chlordiazepoxide
`Hydrochloride
`Sulphate
`Besylate
`Maleate
`Tartrate
`
`Benzoate
`Acetate'l
`
`Base
`Strong
`
`Weak
`
`4.80
`— 6.10
`- 3.00
`0.70
`1.92
`3.00
`
`4.20
`4.76
`
`‘
`
`8.30
`2.53
`2.53
`2.53
`3.36
`3.90
`
`4.50
`4.78
`
`2.0 (intrinsic)
`165* Eq. 51:
`S. 165
`£ 165
`57.1 Eq. 10
`17.9
`
`6.0
`4.1
`
`' Maximum solubility: governed by drug lipophilicity; melting point (236°C) and crystal lattice energy;
`and common ion eitects. Achieved at 5. pH 2.89.
`tMay not form: pK, (acid) and (base) too close.
`tTable 2.2.
`
`i
`.
`i
`
`3
`i
`i
`,
`4‘
`
`1
`f
`
`§
`1
`
`Table 2.4 — Attributes of a selected drug salt form“
`
`Property
`
`Attribute
`
`Control
`
`Purpose
`
`1. Solubility
`
`2. Dissolution
`
`Good
`> 10 >>> 1 mg ml '1
`pH 1—7
`
`Ionic equilibria
`ApK, Iaeid-basel
`Common ion?
`
`Solutions
`Oral and parenteral
`
`High
`I.D.R >
`1 mg cm2 min "'
`
`pll microenvironment
`Common ion?
`
`Bioavailability
`
`3. Hygroscopicity
`
`Low
`< 0.5% S 95% RH
`
`By (1) and (2) and
`drug structure
`
`Solid-state
`stability
`Tablets and capsules
`
`Shelf life
`
`Structure,
`(I) and (3)
`
`4. Stability
`
`5. Processing
`
`High
`:90 = 5 years
`at room temperature
`(> 2 years)
`
`Simple
`Good compression
`Non-sticky
`Good flow
`
`Melting point. crystal
`form and (3)
`
`Manufacture of
`solid dosage
`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 .1
`
`Apotex Exhibit 1011.014
`
`

`

`
`
`Sec. 2.3]
`
`Salts
`
`33
`
`Returning to the use of pKa 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 er a1. 1972). However, it is aqueous
`solubility which remains the central concern, and although there is a strong
`correlation between melting point (Tm) and solubility (equations (3.1) and (3.7)),
`this does not preclude the influence of counterion hydrophilicity. Thus the intuitive
`and attractive relationship between pK. 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 when the ion is large and/or hydrophobic, for example pamoatc (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
`poor correlations with ionic equilibria calculations
`
`Salt
`
`pK,
`
`prfi
`
`Solubility (mg ml ")
`
`Tm(°C)
`
`
`
`Calei Found
`
`Base
`
`8.5
`
`9.75
`
`——
`
`0.32
`
`97-99
`
`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
`
`
`
`
`
`2.5 5.50 320.32 0.24Pamoatc 185—190
`
`‘ pH = é(pK,, + pr).
`fC, = C..(1 + antilog(pK,— pH)).
`From the data of Benjamin and Mn (1985).
`
`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 13K“, ionic equilibria prediction and the Henderson—Hasselbalch
`equation can be used to identify a shorter list of suitable salt-forming candidates.
`These have been organized into four subgroups in Table 2.7 in order to facilitate a
`rational choice when the defined attributes 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 process is highly interactive since
`decisions will have to be based on the drug stcreochemistry; the melting point of the
`drug and the acid counterions (Chapter 3); on the stability of the drug (Chapter 5)
`and its lipophilicity and basicity (Chapter 2).
`Rigid planar and flexible molecules behave differently. Rigid molecules form
`salts with a lower melting point and the solubility rises, whereas aromatic bases form
`salts with a higher melting point due to an increase in crystallinity. Hydroxy acids
`
`'u-u'h-_nun-u—.-nu-
`
`.nnnl-5-.!'
`
`. .
`
`“é;‘d
`
`l i
`
`ApoteX Exhibit 1011.015 '
`
`
`
`...m..._
`
`
`
`
`
`--r'-:a:nnrrne!mmunwautupwm..amquu__...-.
`
`Apotex Exhibit 1011.015
`
`

`

`F—fi
`
`34
`
`Solubility
`
`[Ch. 2
`
`Table 2.6 —- Salt-form selection based on physicochemical properties
`
`Property
`
`Attribute
`
`Methods
`
`l. Melting point
`(+) Increase Processing
`Reduce solubility
`
`(—) Decrease Form oil (Tm < 25°C)
`
`Use small counterions e.g. Cl ' , SO4—
`Use aromatic acids with aromatic
`
`basic drugs
`Use hydroxy acids if drug will
`hydrogen bond
`Use flexible aliphatic acids with
`aromatic bases
`
`Increase solubility
`
`Use highly substituted acids to destmy
`crystal symmetry
`
`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
`
`Increase acidity of counterion (< pKa)
`Decrease melting point
`Use hydroxy acid conjugates
`For common ion effects move to small
`
`organic acids
`Increase melting point
`Use hydr0phobic counterions
`Reduce acidity of conjugate acid
`(> pKa)
`
`Reduce hygroscopicity by increasing
`hydrophobicity of acid
`Change from mineral or sulphouic
`acids to carboxylics
`Use weaker acid (> pKa) to raise pH
`of surface moisture
`
`Decrease Cs and increase crystallinity
`by raising Tm
`
`Lower pKu of acid
`Use hydroxy acids and increase
`polarity
`Recrystallizc 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
`Tm(°C)
`Application
`
`
`GROUP A
`
`Organic acids
`Hydrobromidc
`Hydrochloride
`Sulphate
`Nitrate
`
`Sulphonic acids
`Methane sulphonate
`Ethane sulpbonatc
`Benzene sulphonate
`Toluene sulphonatc
`INaphthalene-2-
`sulphonate
`
`Carboxylic acids
`Maleate
`Benzoate
`Salicylate
`GROUP B
`
`Acetate
`Malatc
`Suocinatc
`Gluconate
`Glycollate
`Lactate
`Tanrate
`Citrate
`Ascorbatc
`
`GROUP C
`
`Hexanoate
`Octanoate
`Decanoatc
`Undecylcnatc
`Dodccyl sulphate
`(& D)
`Oleate
`Stearale (& D)
`GROUP D
`Imaluble salts
`(suspensions)
`'Napsylare
`5,5'emetltylene
`disalicylate
`Pamoate
`
`Polystyrene sulphonatc
`(resinate)
`
`Bitter taste-masking
`Saccharinate
`
`Increase Tm of aromatic
`bases
`Processing and stability
`
`Increase T... by hydrogen
`bonds in flexible bases.
`Decrease Tm for planar
`symmetrical aromatic
`bases and increase C,
`
`Reduce 7),, producing
`oils (ion pairing?) for
`i.m. injections, topicals
`or soft gelatin capsules
`
`Reduce solubility for taste
`masking and suspensions
`
`—
`—
`—
`—
`
`20
`
`43
`70
`
`124
`
`131
`122
`158
`
`16.6
`100
`185
`131
`80
`17
`205
`153
`191
`
`— 3.4
`16.7
`31.4
`24
`
`4
`69
`
`124
`
`238
`280
`
`229
`
`
`
`Aspartamate 246
`
`ApoteX Exhibit 1011.017
`
`44,-41--”
`
`1::LL”:
`-3m?'3
`_.____.__—'V.—I‘-“A
`
`i l
`
`-—w.-vnmm—~r3<-v.a”q.v«...
`
`m9“!'
`
`Apotex Exhibit 1011.017
`
`

`

`_ 3
`
`6
`
`Solubility
`
`[Ch. 2
`
`The most popular salts (group A: inorganic, sulphonic and carboxylic acids) tend
`to increase melting point and improve stability and processing. The extent of
`solubility improvement then largely depends on any specific common ion 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 through the series, 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: Tm = 25°C) is presented
`as an insoluble maleate salt (’1'm = 198—203°C; Cs < 1 mg ml ‘ l) in solid dosage forms
`and suppositories, while for solutions (syrup and injection) the required solubility is
`obtained using the mesylate salt (Tm = 242°C; C, > 2000 mg ml' 1).
`Group B contains the hydroxy acids which will both increase and decrease
`melting point depending on drug structure. Their major effect, however, resides with
`their excess hydroxy groups and this hydrophilicity confers high solubility. However,
`hygroscopicity then becomes a significant problem. In the search for a soluble salt of
`chlorhexidine, a broad spectrum bactericide, Senior (1973) identified the diglueo-
`nate salt which gives a ten-thousand-fold improvement over the free base. The
`dihydrochloride by comparison only improves solubility by about 7.5 and some data
`is shown in Table 2.8. In general, from the acids he evaluated, hydroxy acids
`promoted solubility. In the search for a more soluble salt, the major lead arose from
`comparing the solubility 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 base is gastric acid labile) and for controlled-release devices.
`For example, flupbcnazine is given as the decanoate ( TI“ = 25°C; C3 = < 10 pg ml ‘ l)
`by i.m. injection for monthly therapy in schizophrenia. while the dihydrochloride
`(Tm = 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 miscellaneous acids in group D provide a means of suppressing solubility and
`masking taste 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 pamoate salt is formulated as a suspension
`containing 100 mg per 5 ml, and the base is used in suppositories. Dextropropoxy-
`phene hydrochloride is extremely soluble (l in 0.3) and is used in solid dosage forms.
`However, in compound analgesics, the insoluble napsylate salt is preferred because
`it is stable when combined with aspirin.
`A range of preferred salt forms for various drugs is given in Table 2.9. Armed
`with the information presented in 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 (prm = £(pKa +
`pKw + log Cb), where Cb is the molar concentration of base) but as a consequence,
`
`ApoteX Exhibit 1011.018
`
`i
`r
`j
`
`.
`
`.-.——-r~
`
`-_"—....__..‘.-.
`
`
`
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`
`
`Apotex Exhibit 1011.018
`
`

`

`
`
`Sec. 2.3]
`
`Salts
`
`37
`
`Table 2.8 — Salt selection for chlorhexidine, a bis-biguanide bactericide
`
`‘va—Av_
`
`
`M.....-._"_.—...-._.u.m-o—Wm
`
`-...
`
`RfiA-w-“—v—<
`
`Salt
`
`Base
`
`Inorganic
`Dihydrochloride
`Sulphate
`Dinitrate
`
`Di-acid phosphate
`
`Sulphonic
`Dimesylate
`Di-Z-hydroxyethanesulphonate
`(isethionate)
`Di-2-hydroxynaphthoate
`Pamoate
`
`Carboxylt‘c
`Di-aeetate
`
`Dipropionate
`Dhisobutyrate
`Malonate
`
`Succinate
`
`Dibenzoate
`
`Hydroxy
`Tartrate
`
`Dilactate (a-hydroxypropionate)
`Di-oz-hydroxyiso—butyrate
`Digluconate
`Diglucoheptonate
`
`From the data of Senior (1973).
`
`Solubility (mg ml '1)
`
`(8042’ sensitive l)
`
`0.08
`
`0.60
`0.10
`0.03
`
`0.03
`
`12.00
`
`> 500
`0. l4
`0.009
`
`18.00
`
`4.00
`13.00
`0.20
`
`0.20
`
`0.30
`
`1.00
`
`10.00
`13.00
`> 700
`> 700
`
`
`
`
`
`"Menu-w.«p.1-44-~
`
`the solubility increases exponentially (equations (2.2) and (2.3)). The corresponding
`equation for an acid is pH,“id = 5(pKa — log Ca). These have important implications
`in viva. Intuitively a weak base with an intrinsic s