(cid:11)(cid:12)(cid:14)(cid:13)(cid:12)(cid:15)(cid:16)(cid:4)(cid:10)(cid:15)(cid:5)(cid:4)(cid:7)(cid:6)(cid:8)(cid:9)(cid:4)
`(cid:12)(cid:13)(cid:14)(cid:4)(cid:13)(cid:17)(cid:21)(cid:18)(cid:21)(cid:18)(cid:20)(cid:19)(cid:4)(cid:6)(cid:4)(cid:16)(cid:15)(cid:13)(cid:4)(cid:9)(cid:5)(cid:8)(cid:7)(cid:9)(cid:5)(cid:11)(cid:10)(cid:11)(cid:4)
`
`Apotex Exhibit 1012.001
`
`

`

`Pharmacy Library
`University of Wisconsin - Madison
`2130 Chamberlin Hall
`425 N. Charter Street
`Madison,WI 53706-1608
`
`Library of Congress Cataloging in Publication Data
`Main entry under title:
`
`Encyclopedia of Pharmaceutical Technology.
`editors: James Swarbrick, James C. Boylan.
`
`Includes index.
`
`1. Pharmaceutical technology—Dictionaries.
`II. Boylan, James C.
`2. Drugs—
`[DNLM: 1. Chemistry, Pharmaceutical-encyclopedias.
`encyclopedias.
`3. Technology, Pharmaceutical—encyclopedias. QV 13 E565].
`RSI92.E531988 615’.1’0321-dc19
`
`I. Swarbrick, James.
`
`COPYRIGHT © 1996 BY MARCEL DEKKER, INC. ALL RIGHTS RESERVED.
`
`Neither this book nor any part may be reproduced or transmitted in any form or by any
`means, electronic or mechanical, including photocopying, microfilming, and recording,
`or by any information storage and retrieval system, without permission in writing from
`the publisher.
`
`MARCEL DEKKER, INC.
`270- Madison Avenue, New York, New York 10016
`
`LIBRARY OF CONGRESS CATALOG CARD NUMBER 88-25664
`ISBN: 0—8247—2812—2
`
`Current printing (last digit):
`10
`9
`8
`7
`6
`5
`4
`3
`
`2
`
`1
`
`PRINTED IN THE UNITED STATES OF AMERICA
`
`Apotex Exhibit 1012.002
`
`Apotex Exhibit 1012.002
`
`

`

` This material may be protected by Copyright law {Title ”l"? US. Code}
`
`Salt Forms of Drugs and Absorption
`
`Introduction
`
`Salt formation is frequently performed on weak acidic or basic drugs because it is a
`relatively simple chemical manipulation which may alter the physicochemical, formu-
`lation, biopharmaceutical, and therapeutic properties of a drug without modifying the
`basic chemical structure. Salt selection has been largely semi-empirical, based on con-
`sideration of cost of raw materials, yield, ease of preparation and purification, etc. Al—
`though attempts have been made to apply “decision analysis” and “potential problem
`analysis” to select salts and help predict salt performance [1], the choice of which salt
`to use remains a difficult decision.
`
`The ideal characteristics of a salt are that it is chemically stable, not hygroscopic,
`presents no processing problems, dissolves quickly from solid dosage forms (unless it
`is formed with the intent to delay dissolution), and exhibits good bioavailability.
`The literature contains a large amount of information on salts; however, much of
`the early research addresses the use of salt formation to prolong the release of the active
`component, thereby eliminating various undesirable drug properties[2—6]. This article
`supplements an extensive review published in 1977 [7], providing a literature overview
`of approximately 40—45 years. Its objectives are to present potentially useful salts, their
`effect on the properties of the parent drug, and a decision tree for choosing the most
`desirable salt form(s) for development.
`
`Potentially Useful Salts
`
`Salt formation is one of the simplest chemical reactions, involving either a proton transfer
`or a neutralization reaction between an acid and a base. The relative strength of the acid
`or base, or the acidity and basicity constants of the species involved, significantly in-
`fluences the occurrence of the reaction and provides a measure of the stability of the
`resulting salt. Theoretically, every compound possessing acidic and/0r basic properties
`can participate in salt formation.
`Salt forms that have been clinically evaluated in humans or were commercially
`marketed through 1993 are shown in Tables 1 and 2, compiled from the drug mono—
`graphs listed in Martindale, The Extra Pharmacopoeia, 30th'ed. [8]. Table 1 gives all
`anionic salt forms, Table 2 all cationic forms. The relative frequency (as a percentage)
`of use for each salt type was calculated based on the total number of anionic or cat~
`ionic salts used through 1993.
`The monoprotic hydrochlorides are by far the most frequent choice of an anionic
`salt—forming radical, probably for physiological reasons and simple availability. For simi—
`lar reasons, sodium is the most predominate cation. These findings are identical to those
`reported in a‘similar survey [7] from 1977, even though they are based on twice the
`number of salts as the earlier study. Other comparisons between this and the previous
`review show an increase of approximately 40% in the types of anionic salts and approxi—
`453
`
`Apotex Exhibit 1012.003
`
`Apotex Exhibit 1012.003
`
`

`

`454
`
`Salt Forms of Drugs and Absorption
`
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`Apotex Exhibit 1012.004
`
`Apotex Exhibit 1012.004
`
`

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`Apotex Exhibit 1012.005
`
`
`
`
`
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`
`Apotex Exhibit 1012.005
`
`

`

`456
`
`Salt Forms of Drugs and Absorption
`
`TABLE 2 Cationic Pharmaceutical Salt Forms Currently in Use
`
` Organic Cation Percenta Metallic Cation Percenta
`
`
`
`
`
`
`
`Aluminum
`Bismuth
`
`Calcium
`
`Lithium
`
`Magnesium
`Neodymium
`Potassium
`
`Rubidium
`Sodium
`Strontium
`Zinc
`
`1 .35
`0.30
`
`12. 18
`
`0.90
`
`4.51
`0. 15
`9.77
`
`0.15
`57.74
`0.30
`1 .05
`
`,7
`
`1 .95
`O. 15
`
`0.45
`
`0.15
`
`O. 15
`0. 15
`0. 15
`
`0.60
`0. 15
`0.45
`0.60
`0. 15
`0. 15
`
`0. 15
`
`0. 15
`0. 15
`
`0. 15
`
`0. 15
`0.30
`2.41
`
`p
`
`.
`
`Ammonium
`Benethamine
`(N—Benzylphenethylamine)
`Benzathine
`(N, N’ —Dibenzylethylenediamine)
`Betaine
`((Carboxymethyl)trimethylammonium hydroxide)
`Carnitine
`»
`Clemizoleb
`Chlorcyclizine
`1—(4—Chorobenzyhydryl)—4—methylpiperazine)
`Choline
`Dibenzylamine
`Diethanolamine
`Diethylamine
`Diethylammonium
`Eglumine
`(N—Ethylglucamine)
`Erbumine
`(t—Butylamine)
`Ethylencdiamine
`Heptaminol
`(6~Amino—2—methylheptan—'2—ol)
`Hydrabamine
`(N, N' —Di(dihydroabietyl)ethylenediamine
`Hydroxyethylpyrrolidone
`Imidazole
`Meglumine
`(N-Methylglucamine)
`0.45
`Olamine
`0.90
`Piperazine
`0.5 1
`4—Phenylcyclohexylamine
`0. 15
`Procaine
`0. 15
`Pyridoxine
`O. 15
`Triethanolamine
`0.90
`Tromethamine ‘
`(Tris(hydroxymethyl)aminomethane)
`
`“Percent based 011 total number of cationic salts in use through 1993.
`b1~p—Chlorobenzyl—Z-pyrrolidin—1’ —y1methylbenzimidazole
`
`mately 80% in the types of cationic salts in use. This may be indicative of a trend to
`modify or optimize the properties of a substance through salt formation as opposed to
`more complex molecular modifications. In addition, the interest in polymer—drug salts
`for controlling drug release is indicated by the appearance of polistirex and policrilix
`salts.
`
`It is well documented that due to differences in physical, chemical, and thermody—
`namic properties imparted by the salt—forming species, various salts of the same com-
`
`Apotex Exhibit 1012.006
`
`Apotex Exhibit 1012.006
`
`

`

`Salt Forms of Drugs and Absorption
`
`457
`
`pound often behave differently. Knowledge that a particular salt form imparts enhanced
`water solubility, reduced toxicity, or slow dissolution rate to a drug molecule greatly
`benefits chemists and formulators. Although some generalizations such as the statement
`by Miller and Heller on water solubility associated with carboxylic acid salts [9] can
`be followed, drug use and history frequently dictate the salt form selected. For example,
`most contrast agents requiring water solubility are meglumine salts, whereas many of
`the newer therapeutic peptides (i.e., buserelin, nafarelin, octreotide) are acetates. Many
`of the antibiotics administered intravenously are sodium salts. This indicates that the
`drug class, history of use and local tolerance, and possibly regulatory acceptability
`influence the selection of the salt form.
`Both pamoic acid and alginic acid have been shown to prolong action by forming
`slightly soluble salts with certain basic drugs. The incorporation of pamoate salts in
`sustained-release preparations has been reviewed by Saias et a1. [10]; numerous examples
`can be found in the literature [11—16]. Alginic acid salts of streptomycin [17] and pilo-
`carpine [18] have been prepared and shown to provide sustained action.
`A unique way of prolonging action through salt formation was demonstrated by
`Malek and co—Workers [l9]. Utilizing the knowledge that macromolecules have an af-
`finity for the lymphatic system, salts of four antibiotics were prepared with high-mo—
`lecular—weight polyacrylic acids, sulfonic or phosphorylated polysaccharides, and poly-
`uronic derivatives. Parenteral administration of these macromolecular salts produced low
`antibiotic blood levels for long periods while lymph levels were high. Since lymphatic
`circulation is slow, the preferential distribution of the antibiotics to the lymphatic sys-
`tem prolonged the passage through the body.
`The lauric acid salt of propranolol was studied as an alternative to polymeric for—
`' mula'tions for sustaining the release of propranolol HCl. The findings indicated that the
`laurate salt increased the bioavailability. This was attributed to micellar solubilization
`or ion-pairing which could lead to lymphatic absorption or lower efficiency of extrac-
`tion by the liver [20].
`Toxicity is reduced by choosing the appropriate salt form; two different strategies
`have been utilitzed to accomplish this. One is based on organic radicals that occur natu—
`rally and are readily excreted or metabolized. Using this approach, salts formed with
`choline [21—23], amino acids [24,25], and vitamins [24, 26—32] have been prepared that
`exhibit lower toxicity and fewer side effects than the parent molecule or other salts. The
`second strategy is to select a salt component that pharmacologically overcomes an un-
`favorable property or properties of the principal agent. Salts incorporating N—cyclo-
`hexylsulfamic acid, better known as cyclamates, can make bitter—tasting drugs accept-
`able because of their characteristic sweet taste. Cyclamate salts of dextromethorphan
`and chlorpheniramine [33] raise the bitterness thresholds compared to commonly oc—
`curring salts. The preparation and characterization of other cyclamic acid salts have been
`reported [34—37].
`Other examples include the preparation of the benzhydralamine salt of penicillin [38]
`and the 8—substituted theophylline salts of several antihistamines [39—42]. Benzhy—
`dralamine is an antihistamine. The preparation of the benzhydralamine salt of penicil—
`lin was an attempt to produce a repository form of penicillin with antiallergic proper-
`ties. The synthesis of the xanthine salts of several antihistamines was an attempt to
`counteract the drowsiness caused by the antihistamines with the stimulant properties of
`the xanthines. A number of other 8—substituted theophyllines have been prepared [21,
`43—49].
`
`Apotex Exhibit 1012.007
`
`Apotex Exhibit 1012.007
`
`

`

`458
`
`Salt Forms of Drugs and Absorption
`
`A quinidine salt with reduced toxicity has been prepared from polygalacturonic acid,
`a derivative of pectin [50,51]. This substance possesses special demulcent properties
`and inhibits mucosal irritation. It is used to reduce the shock to the gastrointestinal (GI)
`mucosa resulting from the liberation of irritating ions caused by the rapid dissociation
`of the conventional inorganic quinidine salts. Quinidine polygalacturonate is one—fourth
`as toxic orally as the sulfate.
`The N—(2-hydroxyethyl)pyrrolidine salt of diclofenac (DHEP) was prepared as part
`of a study to obtain salts with balanced hydrophilic and hydrophobic properties [52].
`Of the 24 salts synthesized, DHEP had the greatest solubility in both water and octanol.
`In addition, it exhibited surfactant properties and the ability to solubilize lipid materi—
`als above its critical micelle concentrations. These properties suggest that this salt is
`preferable to topical administration since it could promote its own absorption by inter-
`acting with the membrane components. Other compounds reported to be potentially
`useful as pharmaceutical salt forms are shown in Table 3.
`
`Physicochemical Studies
`
`Although different salts of the same drug elicit similar biological responses, the inten—
`sities of response may differ markedly [96,97]. A knowledge of the physicochernical
`properties of a salt and its influence on pharmacokineticsis necessary to understand the
`onset, duration, and intensity of action, relative toxicity, and possible routes of admin—
`istration [2]. The influence of salt form on volatility and hygroscopicity has been in—
`vestigated in preformulation studies [98].
`
`Solubility
`
`Solubility is an important factor in chemical stability, the formation of dosage forms,
`and the overall drug-absorption process.
`
`Common—Ion Efiect
`
`Hydrochloride salts are the most common anionic salt—forming species [7]. However,
`they do not necessarily enhance the solubility of poorly soluble basic drugs in a chlo-
`ride—containing medium because of the common—ion effect which suppresses the solu-
`bility product equilibrium [99—105]. In some instances, the solubility of various hydro—
`chlorides was less than that of the corresponding free base at gastric pH. The practical
`effect of reducing solubility could ultimately be a reduction of the dissolution rate in
`gastric juice. The Setschenow salting—out constants for chloride are highest for these
`slightly soluble hydrochlorides [106]. However, the relationship between the aqueous
`solubility of sparingly soluble salts and the empirical Setschenow saltingout constant
`is valid only at low concentrations of added salt [107].
`Prazosin1s an example of a drug with a strong chloride'1on dependence The hy—
`drochloride saltin water has a solubility of 1 4 mg/mL at 30° C, whereas1n 0 1M HCl
`it is 0.037 mg/mL [108].
`A common—ion effect on the sodium salt of an organic acid has also been reported
`[109]. The solubility and dissolution rates decreased with varying sodium ion concene
`
`Apotex Exhibit 1012.008
`
`Apotex Exhibit 1012.008
`
`

`

`Salt Forms of Drugs and Absorption
`
`459
`
`TABLE 3 Potentially Useful Salt Forms of Pharmaceutical Agents
`
`
`Salt—Forming Agent
`
`Compound Modified
`
`Property Modified
`
`Reference
`
`p—Acetamidobenzoic acid
`Acetylaminoacetic acid
`N—Acetyl—L—asparagine
`N—Acetylcystine
`
`Adamantoic acid
`
`Adipic acid
`
`N—Alkylsulfamates
`
`Anthraquinone—l ,5-
`disulfonic acid
`
`Arabogalactan sulfate
`(arabino)
`Arginine
`
`Aspartate
`Betaine
`
`Bis(2—carboxychr0mon—5-
`yloxy)a1kanes
`Carnitine
`4~Chloro—m—toluenesulfonic
`acid
`Decanoate
`
`Diacetyl sulfate
`Dibenzylethylenediamine
`Diethylamine
`Diguiacyl phosphate
`Dioctyl succinate
`Embonic (pamoic) acid
`
`Fructose—1,6-diphosphoric
`acid
`
`Glucose—l—phosphoric acid,
`Glucose—6—phosphoric acid
`L—Glutamine
`
`Hydroxynaphthoate
`2—(4—Imidazolyl)ethylamine
`Isobutanolamine
`Lauryl sulfate
`Lysine
`
`Mcthanesulfonic acid
`
`N—Methylglucamine
`
`Various amines
`
`Doxycycline
`Erythromycin
`Doxycycline
`
`Alkylbiguanides
`Piperazine
`
`Ampicillin
`Lincomycin
`Cephalexin
`
`Hygroscopicity
`Solubility
`Solubility, activity, stability
`Combined effect useful in
`
`pneumonia
`Prolonged action
`Stability, toxicity, organoleptic
`properties
`Absorption (oral)
`Solubility
`Stability, absorption
`
`53
`54
`55
`56
`
`57
`58
`
`59
`60
`61
`
`Various alkaloids
`
`Prolonged action
`
`62,63
`
`Cephalosporin
`Sulfobenzylpenicillin
`
`Erthromycin
`Tetracycline
`7—Aminoalkyltheophy—
`Hines
`Metformin
`
`Propoxyphene
`
`Heptaminol
`Thiamine
`
`Ampicillin
`Cephalosporins
`Tetracycline
`Vincamine
`
`Kanamycin
`Z—Phenyl—S—methyl-
`morpholine
`Tetracycline
`
`Erthromycin
`Tetracycline
`Erythromycin
`Erythromycin
`Bephenium
`Prostaglandin
`Theophylline
`Vincamine
`
`Sulfobenzylpenicillin
`
`Cephalosporin
`Pralidoxirne (2—PAM)
`Sulfobenzylpenicillin
`
`Toxicity
`Stability, hygroscopicity,
`toxicity
`Solubility
`Gastric absorption
`Activity, prolonged prophylactic
`effect
`
`Toxicity
`Organoleptic properties
`
`Proplonged action
`Stability, hygroscopicity
`Prolonged action
`Reduced pain on injection
`Activity
`Organoleptic properties
`Toxicity
`Toxicity
`
`Solubility
`
`Solubility
`Solubility
`Solubility
`Solubility, activity, stability
`Toxicity
`Prolonged action
`Stability
`Organoleptic properties
`Toxicity, stability, hygroscop—
`icity
`
`Solubility
`Toxicity, stability, hygroscop—
`icity
`
`64
`65
`
`66
`67
`68
`
`69
`70
`
`71
`72
`
`73,74
`75
`76
`77
`78
`79
`
`80
`
`80
`80
`80
`55
`81
`82
`83
`84
`65
`
`64
`85
`65
`
`Apotex Exhibit 1012.009
`
`Apotex Exhibit 1012.009
`
`

`

`460
`
`Salt Forms of Drugs and Absorption
`
`TABLE 3 (Continued)
`
`
`
`
` Salt—Forming Agent Compound Modified Property Modified Reference
`
`
`
`
`
`N—Methylpiperazine
`Morpholine
`2—Naphtha1enesulf0nic acid
`Octanoate
`Probenicid
`Tannic acid
`Theobromine acetic acid
`3,4,5—Trimeth0xybenzoate
`
`Tromethamine
`
`Reduced pain on injection
`Toxicity, faster onset of action
`Reduced pain on injection
`Organoleptic properties
`Prolonged action
`Organoleptic properties
`Prolonged action
`Activity
`Organoleptic properties
`Prolonged action
`Absorption (oral)
`Physical state
`
`75
`86
`75
`87
`71
`88
`89,90
`91
`92
`71
`93
`94
`
`Cephalosporins
`Phenylbutazone
`Cephalosporins
`Propoxyphene
`Heptaminol
`Pivampicillin
`Various amines
`Propoxyphene
`Tetracycline
`Heptaminol
`Aspirin
`Dinoprost
`(prostaglandin F)
`
`Salmeterol Local toleranceXinafoate 95
`
`
`
`
`
`trations. The reduction in solubility product in the presence of NaCl was attributed to
`a decrease in the degree of self—association of the drug in aqueous media.
`
`Formulation
`
`The choice of salt can have significant benefits for the formulation of a drug as, for
`example, with the cytotoxic drug, coralyne sulfoacetate. The solubility of coralyne
`chloride in water is 4.5 mg/mL, and that of the sulfoacetate is 6.5 mg/mL; however,
`solutions containing 25 mg/mL were required for iv infusion [110,111]. The solubility
`of the chloride salt was no higher in weakly alkaline aqueous media than in distilled
`water since it is a salt of a quaternary ammonium ion and the conjugate base of a strong
`acid. Adding sodium hydroxide greatly enhanced the solubility of the sulfoacetate. The
`reason is that the sulfoacetate anion is an acid which is ionized by the added base,
`resulting in an increase in the concentration of coralynium ion in solution.
`The solubility of a salt can influence the use of formulation adjuvants. In the pres—
`ence of methanesulfonic, acetic, and hydrochloric acids, 2,3,4,5—tetrahydro—8-
`(methylsulfonyl)—1-H~3~benzazepin—7—ol had water solubilities of approximately 440,. 320,
`and 1 mg/mL. Addition of sodium chloride to a saturated solution of the mesylate
`(methanesulfonic) salt, reduced the solubility to approximately 60 mg/mL, even with
`a sodium chloride concentration as low as 0.05 M. This was probably due to the rapid
`conversion of the mesylate to the hydrochloride salt and may preclude the use of so—
`dium chloride as an isoosmotic agent or the use of saline as diluent [103].
`In addition to its effect on solubility, the choice of salt is important to the useful-
`‘ ness and efficacy of the formulation. For example, hydrochloride salts in aqueous so—
`lution may lower'the pH, which can adversely affect their use in parenteral dosage forms
`because of the incidence of pain and subsequent venous inflammation [112]. It could
`also lead to incompatibilities with metal aerosol containers [108].
`
`Apotex Exhibit 1012.010
`
`Apotex Exhibit 1012.010
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`

`

`Salt Forms of Drugs and Absorption
`
`461
`
`Sciarra et al.[113], using epinephrine as a model compound in an aerosol delivery
`system, points out that the solubility of the salt form in various propellants is impor-
`tant in products intended for local action in the lungs or for systemic therapy; further—
`more, the salt form should be soluble in extracellular fluids.
`
`Complex Salt Formation
`
`Organic acid salt forms of basic drugs, such as amines, frequently have higher aque—
`ous solubilities than their corresponding inorganic salts. Hydrochloric, nitric, sulfuric,
`and phosphoric salts of triamterine form insoluble complex salts [114]. Acetic acid pro—
`duced solubilities higher than those observed with any of the inorganic acids. Although
`acetic acid complexes with triamterine, an insoluble complex was not found. This is im—
`portant in the synthesis and selection of a salt form that exhibits enhanced bioavailability
`and desirable formulation characteristics.
`
`Studies have been conducted on the complexation of some drugs with sodium poly—
`phosphate [115]. Insoluble complex salts formed with amethocaine, amitriptyline, pro-
`pranolol, and verapamil, but not with atropine, ephedrine, and procaine. The complex
`salt formed with verapamil produced a prolonged dissolution profile in acid compared
`to pure verapamil, but because of hygroscopicity it was difficult to process and store.
`The solubility also of organic carboxylic acids is also affected by salt formation,
`in
`some cases adversely. For example, N—[4—(1,4-benzodioxan—6-yl)~2~thiazolyl] oxamic
`acid was less soluble in the presence of sodium, potassium, and calcium ions. How-
`ever, these ions increased the distribution coefficients significantly between water and
`l—octanol, even at low concentrations. The lower solubility was attributed to the for-
`mation of less soluble salts, whereas the increase in distribution coefficients was ex—
`plained by ion-pairing and/0r complexation [116].
`
`Solubility Predictions
`
`The solubility of a salt can be influenced by the structure of the organic moiety or by
`the hydrophilic properties of the anion or cation. A higher crystal lattice energy (crys—
`tallinity) is generally reflected by a higher melting point. An increase in melting point,
`usually by maximizing or encouraging crystal symmetry, reduces solubility. Gould [108]
`reports that the solubility of a drug frequently decreases by an order of magnitude with
`an increase of 100°C in its melting point. Where solubility and resultant pH are major
`issues, a low melting salt of a drug produced from a soluble, fairly weak acid or base,
`probably made in situ, is usually preferred.
`The increase or decrease in melting point of a series of salts of basic compounds
`depends on the controlling effect of crystallinity from the conjugate anion. This is
`exemplified by an experimental drug candidate, UK47880, which has a basic pKa of 8
`[108]. Salts prepared from planar, high melting aromatic sulfonic or hydroxycarboxylic
`acids yield high melting crystalline salts. However, flexible aliphatic acids such as cit-
`ric and dodecylbenzene sulfonic yielded oils. Gould [108] discussed how crystal lattice
`forces of drugs with good hydrogen bonding potential could be built up by consider—
`ing the symmetry and hydrogen bonding potential of the conjugate acid. He used epi~
`nephrine as an example, which gives high melting salts with small, strongly hydrogen-
`bonding acids like malonic and maleic. The larger bitartrate and presumably
`symmetrically unfavored fumarate give lower melting salts.
`
`Apotex Exhibit 1012.011
`
`Apotex Exhibit 1012.011
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`

`

`462
`
`Salt Forms of Drugs and Absorption
`
`Various salts of oc-(2—piperidyl)—3,6-bis(trifluoromethyl)—9-phenanthrenemethanol
`[102], chlorhexidine [117], erythromycin [118], and the N—alkylsulfamates of lincomycin
`[60] show enhanced solubility which can be attributed to a lower melting point and the
`hydrophilic properties of the anion. Organic salts may increase aqueous solubility
`through decreased crystal lattice energy, lowered melting point, increased hydrogen
`bonding of the salt counterions with water, etc.
`There are exceptions to the solubility—melting point and solubility—hydrophilicity
`relationship. For example, the THAM, tris(hydroxymethyl)aminomethane, salts of
`certain analgesic—anti-inflammat0ry agents showed no simple solubility—melting point
`relationship [119]. Anderson and Condradi, using organic amine salts of flurbiprofen
`to predict water solubility, found a strong dependence of the solubility product on melt—
`ing point; however, there was no significant correlation between solubility product and
`counterion hydrophilicity [120]. The authors concluded that this is in conflict with the
`notion that higher salt solubilities can be achieved by selecting more hydrophilic
`‘ counterions, since such arguments neglect the likelihood that interactions in the crystal
`become stronger as the salt-forming species are made increasingly polar.
`Rubino [121] found that the logarithms of the molar solubilities of a number of
`sodium salts of drugs were inversely related to their melting points, but a good. corre-
`lation was not evident. However, the logarithms of the molar solubilities were inversely
`related to both the melting points and stoichiometric amounts of water in the crystal
`hydrates, but unrelated to the polarity of the corresponding acid forms of the drugs. It
`was concluded therefore that the melting point and the degree of crystal hydration of
`the solid phase are most important in determining the solubilities of the sodium salts
`of some drugs.
`The solubilities of the sodium salts of some weakly acid drugs have been determined
`in mixtures of propylene glycol and water. The solubility in the mixed solvent of com—
`pounds with low temperatures of desolvation had increased, whereas the solubility of
`compounds with high desolvation temperatures had decreased. These data indicate that
`crystal hydrate formation plays a significantrole in determining if a cosolvent can be
`used to enhance the solubilities of certain sodium salts [122].
`The hydrogen ion concentration can significantly affect salt solubility. Anderson
`[123] discussed the influence of pH on the solubility of therapeutically useful weak acids
`and bases and their salts. This was followed a few years later by an extensive study on
`the solubility interrelationships of the hydrochloride and free base of two amines [124].
`Mathematical equations describing the total solubility at an arbitrary pH in terms of the
`independent solubilities of the hydrochloride and free base species and the dissociation
`constant of the salt were derived and fitted to experimental data with good results. This
`report made the point that, although the solubility of an amine hydrochloride generally
`sets the maximum obtainable concentration for a given amine, the solubility of the free
`base and the pKa determine the maximum pH at which formulation as a solution is pos—
`sible. This assumes that the desired concentration exceeds the free base solubility.
`Shifting the pH—solubility profile to higher pH values for formulation purposes may
`require increasing the solubility of the free base with the help of an appropriate co—
`solvent. Because the dissociation characteristics of carboxylic acids and other organic
`species are similar to those of organic hydrochlorides, the pH—solubility profiles could
`be characterized theoretically by the same treatment.
`Chowhan [125] studied the solubilities of three organic carboxylic acids (naproxen;
`7-methylsulfinyl-2~xanthonecarboxylic acid; and 7—methythio—2-xanthonecarboxylic acid)
`and their sodium, potassium, calcium, and magnesium salts as a function of pH. The
`
`Apotex Exhibit 1012.012
`
`Apotex Exhibit 1012.012
`
`

`

`Salt Forms of Drugs and Absorption
`
`463
`
`data were fitted to mathematical relationships similar to those used by Kramer and Flynn
`[124]. The results on the solubility of naproxen and its salts were in excellent agree—
`ment with theory. The solubilities of the two xanthone carboxylic acids and their salts
`were higher at higher pH than the values calculated for complete dissociation in solu—
`tion.
`
`Surface Activity
`
`The salts of some compounds are surface active [126—128]. If the saturation solubility
`enables the critical micelle concentration (CMC) to be reached, solubility is enhanced
`significantly via micellar solubilization. A study of the colloidal properties of some
`chlorhexidine salts showed that the counterion can affect the CMC which was usually
`associated with a change in micellar size [126]. For example, the diacetate displays a
`higher CMC than the digluconate [126].
`The hydrochloride salt of 2—butyl-3—benzofuranyl—4—[2-(diethylamino)eth0xy]~3,5-
`diiodophenyl ketone is capable of forming micelles. Anions such as chloride, sulfate,
`acetate, tartrate, and citrate significantly affect the equilibrium solubility of the com—
`pound, which is partly related to the effect on the CMC by the anionic environment
`[127].
`The nonopioid kappa agonist analgesic amine, DuP 747, as the hydrochloride salt,
`exerts surface activity in aqueous solutions; however, the critical micellar concentra—
`tion is not reached at the saturation solubility [128]. On the other hand, the methane-
`sulfonate salt formed a micellar solution and allowed for a solubility of 60 mg/mL as
`opposed to 3 mg/mL for the hydrochloride.
`Zomepirac, an insoluble, carboxylic, non-narcotic analgesic, has a solubility in water
`of 0.02 mg/mL. In a developing zomepirac solution containing 100 mg/mL [129],
`THAM was found to be a satisfactory solubilizer at a concentration where equivalent
`concentrations of sodium or potassium hydroxide were not. The solubility was achieved
`by a micellar mechanism. It is interesting that potassium hydroxide was more effective
`in solubilizing zomepirac than sodium hydroxide. Walkling et al. attributed the difference
`in their performance as solubilizers to the difference in their charge densities [129]. Ad-
`ditional references on the relationship of salt form and solubility are listed in Table 4.
`
`Dissolution Rate
`
`In many cases, the dissolution rate can be a good indicator of bioavailability, especially
`of poorly soluble drugs. A salt form frequently exhibits a higher dissolution rate than
`the corresponding conjugate acid or base at the same pH, even though they may have
`the same equilibrium solubility. In a review article on the biopharmaceutical basis for
`drug design, Nelson [150,151], and later Benet [152], referred to the self—buffering
`action of the salt form in the diffusion layer. The dissolution rates are determined by
`the pH values of the diffusion layer and are independent of the prulk of the media used.
`Therefore, the difference in diffusion—layer pH between a parent compound and its salt
`accounts for the difference in the dissolution rates in a particular medium.
`
`Effect of Salt Form
`
`Nelson, using theophylline salts, was the first to show the correlation between diffu—
`sion—layer pH and dissolution rate [150]. Salts with a high diffusion-layer pH had higher
`
`Apotex Exhibit 1012.013
`
`Apotex Exhibit 1012.013
`
`

`

`464
`
`Salt Forms of Drugs and Absorption
`
`TABLE 4 References on Salt Form and Solubility
`
`
`
` Topic Reference
`
`Mineral acid salts of lidocaine
`Nonionic surfactant effect on rate of release of drugs from suppositories
`Influence of solubility of salicyclic acid on diffusion from ointment bases
`Influence of solubility on rate of GI absorption of aspirin
`Effect of dosage form on G1