`
`Pharmaceutical
`Sciences
`
`JANUARY 1977
`
`VOLUME 66 NUMBER I
`
`REVIEW ARTICLE
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`Pharmaceutical Salts
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`STEPHEN M. BERGE**, LYLE D. BIGHLEY *, and
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`DONALD C. MONKHOUSE"'
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`Salt-forming agents are often chosen empirically. Of the
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`physicoKeyphrases □ Pharmaceutical salts-general pharmacy,
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`many salts synthesized, the preferred form is selected by
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`chemical properties,
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`bioavailability, pharmaceutical properties, toxi
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`cology, review Cl Salts, pharmaceutical-general pharmacy, physico
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`pharmaceutical chemists primarily on a practical basis:
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`chemical properties
`, bioavailability
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`, pharmaceutical properties, toxi
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`cost of raw materials, ease of crystallization, and percent
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`cology, review Cl Physicochemical properties-dissolution, solubility,
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`yield. Other basic considerations include stability, hy
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`stability, and organoleptic properties of pharmaceutical salts, review CJ
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`groscopicity, and flowability of the resulting bulk drug.
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`Bioavailability-formulation effects, absorption alteration and phar
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`macokinetics of pharmaceutical salts, review □ Toxicology-pharma
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`Unfortunately, there is no reliable way of predicting the
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`ceutical salts, review
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`influence of a particular salt species on the behavior of the
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`parent compound. Furthermore, even after many salts of
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`the same basic agent have been prepared, no efficient
`CONTENTS
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`screening techniques exist to facilitate selection of the salt
`Potentially Useful Salts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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`2
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`most likely to exhibit the desired pharmacokinetic, solu
`4
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`Physicochemical Studies
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`bility, and formulation profiles.
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`Dissolution Rate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`5
`. . . . .
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`Some decision-making models have, however, been de
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`Solubility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`7
`. . . . . .
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`Organoleptic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`8
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`veloped to help predict salt performance. For example,
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`Stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`9
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`Walkling and Appino (1) described two techniques, "de
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`Miscellaneous Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
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`cision analysis" and "potential problem analysis," and
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`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
`Bioavai/ability
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`applied them to the selection of the most suitable deriva
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`Formulation Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
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`Absorption Alteration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
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`tive of an organic acid for development as a tablet. The
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`Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
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`derivatives considered were the free acid and the potassi
`. . . . . . . . . . . . . . . . . . . . . . . . . . . • . . . . . . . . . . .
`14
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`General Pharmacy
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`um, sodium, and calcium salts. Both techniques are based
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`Pharmacological Effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
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`on the chemical, physical, and biological properties of these
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`Dialysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
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`specific derivatives and offer a promising avenue for de
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`Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`15
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`Toxicological Considerations
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`veloping optimal salt forms.
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`Toxicity of Salt Ion . . . .. . . . . . . . . . . . . . . . . . . . . . . . .. . .. . . . . 15
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`Information on salts is widely dispersed throughout the
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`Toxicity of Salt Form . .. . . . . . . .. . . . . . . . . . . . . . . . .. . .. . . . . 15
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`pharmaceutical literature, much of which addresses the
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`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
`Conclusions
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`use of salt formation to prolong the release of the active
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`16
`References
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`component, thereby eliminating various undesirable drug
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`properties (2-6). This review surveys literature of the last
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`The chemical, biological, physical, and economic char
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`acteristics of medicinal agents can be manipulated and,
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`25 years, emphasizing comparisons between the properties
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`of different salt forms of the same compound. Included also
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`hence, often optimized by conversion to a salt form.
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`is a discussion of potentially useful salt forms. Our purpose
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`Choosing the appropriate salt, however, can be a very
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`is twofold: to present an overview of the many different
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`difficult task, since each salt imparts unique properties to
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`salts from which new drug candidates can be chosen and
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`the parent compound.
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`Table 1-FDA-Approved Commercially Marketed Salts
`
`Anion
`
`Acetate
`Benzenesulfonate
`Benzoate
`Bicarbonate
`Bitartrate
`Bromide
`Calcium edetate
`Camsylateh
`Carbonate
`Chloride
`Citrate
`Dihydrochloride
`Edetate
`Edisylatec
`Estolated
`Esylate"
`Fumarate
`Gluceptatef
`Gluconate
`Glutamate
`Glycollylarsanilatell
`Hexylresorcinate
`Hydrabamine;,
`Hydro bromide
`Hydrochloride
`Hydroxynaphthoate
`
`Cation
`
`Organic:
`Benzathinek
`Chloroprocaine
`Choline
`Diethanolamine
`Ethylenediamine
`Meglumine 1
`Procaine
`
`Percent a
`
`Anion
`
`Percent a
`
`1.26
`0.25
`0.51
`0.13
`0.63
`4.68
`0.25
`0.25
`0.38
`4.17
`3.03
`0.51
`0.25
`0.38
`0.13
`0.13
`0.25
`0.18
`0.51
`0.25
`0.13
`0.13
`0.25
`1.90
`42.98
`0.25
`
`Iodide
`Isethionatei
`Lactate
`Lactobionate
`Malate
`Maleate
`Mandelate
`Mesylate
`Methylbromide
`Methylnitrate
`Methylsulfate
`Mucate
`Napsylate
`Nitrate
`Pamoate (Embonate)
`Pantothenate
`Phosphate/diphosphate
`Polygalacturonate
`Salicylate
`Stearate
`Subacetate
`Succinate
`Sulfate
`Tannate
`Tartrate
`Teoclatej
`Triethiodide
`
`Percent a
`
`Cation
`
`0.66
`0.33
`0.33
`0.98
`0.66
`2.29
`0.66
`
`Metallic:
`Aluminum
`Calcium
`Lithium
`Magnesium
`Potassium
`Sodium
`Zinc
`
`2.02
`0.88
`0.76
`0.13
`0.13
`3.03
`0.38
`2.02
`0.76
`0.38
`0.88
`0.13
`0.25
`0.64
`1.01
`0.25
`3.16
`0.13
`0.88
`0.25
`0.38
`0.38
`7.46
`0.88
`3.54
`0.13
`0.13
`
`Percent a
`
`0.66
`10.49
`1.64
`1.31
`10.82
`61.97
`2.95
`
`a Percent is based on total number of anionic or cationic salts in use through 1974. b Camphorsulfonate. c 1,2-Ethanedisulfonate. d Laury! sulfate.
`c Ethanesulfonate. f Glucoheptonate. 11 p-Glycollamidophenylarsonate. h N,N' -Di(dehydroabietyl)ethylenediamine. ' 2-Hydroxyethanesulfonate.
`j 8-Chlorotheophyllinate. k N,N'-Dibenzylethylenediamine. 1 N-Methylglucamine.
`
`to assemble data that will provide, for the student and
`practitioner alike, a rational basis for selecting a suitable
`salt form.
`
`POTENTIALLY USEFUL SALTS
`Salt formation is an acid-base reaction involving either
`a proton-transfer or neutralization reaction and is there(cid:173)
`fore controlled by factors influencing such reactions.
`Theoretically, every compound that exhibits acid or base
`characteristics can participate in salt formation. Particu(cid:173)
`larly important is the relative strength of the acid or
`base-the acidity and basicity constants of the chemical
`species involved. These factors determine whether or not
`formation occurs and are a measure of the stability of the
`resulting salt.
`The number of salt forms available to a chemist is large;
`surveys of patent literature show numerous new salts being
`synthesized annually. Various salts of the same compound
`often behave quite differently because of the physical,
`chemical, and thermodynamic properties they impart to
`the parent compound. For example, a salt's hydrophobicity
`and high crystal lattice energy can affect dissolution rate
`and, hence, bioavailability. Ideally, it would be desirable
`if one could predict how a pharmaceutical agent's prop(cid:173)
`erties would be affected by salt formation.
`Tables I and II list all salts that were commercially
`marketed through 1974. The list was compiled from all
`agents listed in "Martindale The Extra Pharmacopoeia,"
`
`2 I Journal of Pharmaceutical Sciences
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`26th ed. (7). Table I categorizes all salt forms approved by
`the Food and Drug Administration (FDA), while Table II
`lists those not approved by the FDA but in use in other
`countries. (Only salts of organic compounds are considered
`because most drugs are organic substances.) The relative
`frequency with which each salt type has been used is cal(cid:173)
`culated as a percentage, based on the total number of an(cid:173)
`ionic or cationic salts in use through 1974. Because of
`simple availability and physiological reasons, the mono(cid:173)
`protic hydrochlorides have been by far the most frequent
`choice of the available anionic salt-forming radicals, out(cid:173)
`numbering the sulfates nearly six to one. For similar rea(cid:173)
`sons, sodium has been the most predominant cation.
`Knowledge that one salt form imparts greater water
`solubility, is less toxic, or slows dissolution rate would
`greatly benefit chemists and formulators. In some cases,
`such generalizations can be made. Miller and Heller (8)
`discussed some properties associated with specific classes
`of salt forms. They stated that, in general, salt combina(cid:173)
`tions with monocarboxylic acids are insoluble in water and
`lend themselves to repository preparations, while those of
`dicarboxylic acids confer water solubility if one carboxylic
`group is left free. Pamoic acid, an aromatic dicarboxylic
`acid, is an exception since it is used as a means of obtaining
`prolonged action by forming slightly soluble salts with
`certain basic drugs. Saias et al. (9) reviewed the use ofthis
`salt form in preparing sustained-release preparations.
`More recently, latentiation of dihydrostreptomycin (10)
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`Table li-N on-FDA-Approved Commercially Marketed
`Salts
`
`Anion
`
`Adipate
`Alginate
`Aminosalicylate
`Anhydromethylenecitrate
`Arecoline
`Aspartate
`Bisulfate
`Butylbromide
`Camphorate
`Digluconate
`Dihydrobromide
`Disuccinate
`Glycerophosphate
`Hemisulfate
`Hydrofluoride
`Hydroiodide
`Methylenebis(salicylate)
`Napadisylateb
`Oxalate
`Pectinate
`Persulfate
`Phenylethylbarbiturate
`Picrate
`Propionate
`Thiocyanate
`Tosylate
`Undecanoate
`
`Cation
`
`Organic:
`Benethamine"
`ClemizoJed
`Diethylamine
`Piperazine
`Tromethamine e
`Metallic:
`Barium
`Bismuth
`
`Percent a
`
`0.13
`0.13
`0.25
`0.13
`0.13
`0.25
`0.25
`0.13
`0.13
`0.13
`0.13
`0.13
`0.88
`0.13
`0.13
`0.25
`0.13
`0.13
`0.25
`0.13
`0.13
`0.13
`0.13
`0.13
`0.13
`0.13
`0.13
`
`Percent a
`
`0.33
`0.33
`0.33
`0.98
`0.33
`
`0.33
`0.98
`
`a Percent is based on total number of anionic and cationic salts in use
`through 1974. b 1,5-Naphthalenedisulfonate. c N-Benzylphenethylamine.
`d 1-p-Chlorobenzyl-2-pyrrolidin-1'-ylmethylbenzimidazole. e Tris(hy(cid:173)
`droxymethyl)aminomethane.
`
`using pamoic acid resulted in the formation of a delayed(cid:173)
`action preparation. Numerous studies using pamoate salts
`are dispersed throughout the literature (11-15).
`Alginic acid also has been used to prepare long-acting
`pharmaceuticals. Streptomycin alginate was prepared (16)
`and shown to be effective in sustained-release prepara(cid:173)
`tions. A striking example of a long-acting alginate salt is
`that of pilocarpine. When dispersed in sterile water and
`. dried to a solid gel, this compound was found useful in the
`preparation of long-acting ophthalmic dosage forms (17).
`While liquid preparations of the alginate and hydrochlo(cid:173)
`ride salts possess similar miotic activity, studies showed
`that solid pilocarpine alginate flakes constricted pupil size
`more effectively and increased the duration of miosis sig(cid:173)
`nificantly when compared with the liquid preparations.
`Solid dose pilocarpine may be more uniformly available,
`because it diffuses more slowly through the gel matrix
`which holds the drug in reserve. In contrast, drops of the
`commonly employed solution dosage form release the dose
`immediately to the conjunctival fluid.
`Malek et al. (18) devised a unique way of prolonging
`action through salt formation; they showed that the dis(cid:173)
`tribution of several antibiotics could be markedly altered
`by merely preparing macromolecular salts. Since macro(cid:173)
`molecules and colloidal particles have an affinity for the
`lymphatic system, streptomycin, neomycin, viomycin, and
`
`streptothrycin were combined with high molecular weight
`compounds such as polyacrylic acids, sulfonic or phos(cid:173)
`phorylated polysaccharides, and polyuronic derivatives.
`Parenteral administration of these compounds produced
`low blood levels of the antibiotic for long periods, while
`lymph levels were high. (In comparison, streptomycin
`sulfate gave high blood levels but low lymph levels.) This
`alteration in distribution caused the streptomycin to
`prolong its passage through the body, since lymphatic
`circulation is quite slow.
`The appropriate choice of a salt form has been found to
`reduce toxicity. It can be rationalized that any compound
`associated with the normal metabolism of food and drink
`must be essentially nontoxic. The approach of choosing
`organic radicals that are readily excreted or metabolized
`opened up a new class of substances from which to select
`a salt form. For example, certain salts of the strong base
`choline have proven to be considerably less toxic than their
`parent compound. The preparation and properties of
`choline salts of a series of theophylline derivatives were
`reported (19), and it was shown that choline theophyllinate
`possessed a greater LD50 than theophylline or its other
`salts (20). It was postulated that this agent would be less
`irritating to the GI tract than aminophylline, because "its
`basic constituent, choline, is an almost completely non(cid:173)
`toxic substance of actual importance to the physiologic
`economy." This evidence led to the preparation of choline
`salicylate (21) as an attempt to reduce the GI disturbances
`associated with salicylate administration. Clinical studies
`indicated that choline salicylate elicited a lower incidence
`of GI distress, was tolerated in higher doses, and was of
`greater benefit to the patient than was acetylsalicylic acid
`(aspirin).
`Amino acids and acid vitamins also have been used as
`salt-forming agents. Based on the evidence that coad(cid:173)
`ministration of amino acids with aminoglycoside antibi(cid:173)
`otics reduced their toxicity, a series of amino acid salts of
`dihydrostreptomycin was prepared (22). In all but one
`case, the acute toxicities of these salts were lower than the
`toxicity of the sulfate. The ascorbate and pantothenate
`also were synthesized and shown to be less toxic than the
`sulfate. Of the salts prepared, the ascorbate had the highest
`LDso.
`The vitamins most commonly used for forming salts
`exhibiting reduced toxicity are ascorbic and pantothenic
`acids. Keller et al. (23) were the first to use pantothenic
`acid as a means of "detoxifying" the basic streptomyces
`antibiotics. Parenteral administration of the pantothen(cid:173)
`ates of streptomycin and dihydrostreptomycin had a sig(cid:173)
`nificantly reduced incidence of acute neurotoxicity in cats
`as compared with the sulfates. Subsequent studies (24-28)
`supported this finding and showed that the pantothenates
`of neomycin and viomycin also are less toxic. The ascorbate
`of oleandomycin was synthesized and its pharmacological
`properties were reported (29). Upon intramuscular injec(cid:173)
`tion in rats, it produced less irritation than the phos(cid:173)
`phate.
`p-Acetamidobenzoic acid, an innocuous metabolite of
`folic acid present in normal blood and urine, has been used
`in preparing salts. In particular, it yields stable salts with
`amines that otherwise tend to form hygroscopic products
`with conventional f!Cid components (30).
`Often the salt form is chosen by determining a salt
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`component that will pharmacologically antagonize an
`unfavorable property or properties exhibited by the basic
`agent. Salts of N -cyclohexylsulfamic acid are an example
`of the practical application of this approach. N -Cyclo(cid:173)
`hexylsulfamic acid salts, better known as cyclamates, have
`a characteristic sweet, pleasing taste. Although presently
`under investigation by the FDA for potentially carcino(cid:173)
`genic properties, salts incorporating this compou,_nd can
`render unpleasant or bitter-tasting drugs acceptable. For
`example, the cyclamates of dextromethorphan and
`chlorpheniramine exhibit greatly improved bitterness
`thresholds compared to commonly occurring salts (31).
`Furthermore, their stability in aqueous solution was de(cid:173)
`scribed as good when maintained at a pH not greater than
`4.
`
`N -Cydohexylsulfamic acid salts of thiamine hydro(cid:173)
`chloride and lincomycin also have been synthesized. Thi(cid:173)
`amine N -cyclohexylsulfamate hydrochloride was reported
`to have a more pleasant taste than other thiamine salts
`while having an equal or greater stability (32). Lincomycin
`cyclamate, shown to possess an enhanced thermal stability
`over its hydrochloride, was prepared (33) to test the hy(cid:173)
`pothesis that reduced lincomycin absorption in the pres(cid:173)
`ence of small quantities of cyclamates was due to a simple
`metathetic reaction. However, this assumption was found
`not to be true. An extensive study of the preparation and
`characterization of cyclamic acid salts of several widely
`used classes of drugs including antihistamines, antibiotics,
`antitussives, myospasmolytics, and local anesthetics was
`reported (34, 35).
`Various salts of penicillin and basic amine compounds
`have been formulated in an effort to produce a long-acting,
`nonallergenic form of penicillin. Since antihistamines
`appear to mitigate the symptomatology of penicillin re(cid:173)
`actions in some patients, coadministration of the two has
`been advocated. The preparation of the benzhydralamine
`salt of penicillin was an attempt to produce a repository
`form of penicillin with antiallergic properties (36). Blood
`levels achieved with this salt were comparable to those of
`penicillin G potassium; however, its antiallergic properties
`were not evaluated. In fact, the investigators noted that
`antihistamines can actually cause sensitization at times
`and stated that "despite their occasionally favorable in(cid:173)
`fluence on the symptoms of penicillin sensitivity, they
`contribute directly to the potential of drug sensitivity when
`co-administered with penicillin."
`Silver salts of sulfanilamide, penicillin, and other anti(cid:173)
`biotics have been prepared and represent cases where the
`species (ions) are complementary. When aqueous solutions
`of the salts were applied topically to burned tissue, they
`yielded the combined benefits of the oligodynamic action
`of silver and the advantages of the antibacterial agents
`(37).
`The use of 8-substituted xanthines, particularly the
`8-substituted theophyllines, as salt-forming agents was
`first reported in the preparation of a series of antihistamine
`salts (38-41). Synthesis of these xanthine salts was an at(cid:173)
`tempt to find a drug to counteract the drowsiness caused
`by the antihistamines with the stimulant properties of the
`xanthines. When an electronegative group is introduced
`into the xanthine molecule at the 8-position, the elec(cid:173)
`tron-drawing capacity of the substituent results in the
`creation of an acidic hydrogen at position 7. Thus, these
`
`4 I Journal of Pharmaceutical Sciences
`
`moderately strong acidic compounds can undergo salt
`formation with various organic bases.
`The 8-halotheophyllines were the first group of xan(cid:173)
`thines studied as potential salt-forming agents. Since the
`report on the preparation of the 8-chlorotheophylline salt
`of diphenhydramine (42), synthesis of the 8-halotheo(cid:173)
`phyllinates of a number of organic bases has been at(cid:173)
`tempted. The 8-chlorotheophyliine salts of quinine,
`ephedrine, and strychnine were prepared and character(cid:173)
`ized (43). These salts were less water soluble than the
`corresponding free alkaloidal bases. In a similar report, the
`8-chlorotheophyllinates of three synthetic narcotics,
`meperidine, levorphanol, and metopon, were prepared
`(44).
`Pharmacological and clinical studies involving the 8-
`bromotheophylline pyrilamine salt revealed the unusual
`diuretic properties associated with the 8-halotheophylline
`portion of the compound (45, 46). This finding initiated
`an investigation into the preparation of a soluble 8-bro(cid:173)
`motheophylline salt of high diuretic activity. With readily
`available amines, over 30 salts were synthesized and
`screened for diuretic activity (47). When tested against
`theophylline salts of the same amines, the 8-bromotheo(cid:173)
`phyllinates showed greater activity in every case.
`With the successful formation of 8-halotheophyllinates
`of organic bases, Morozowich and Bope (48) proposed that,
`if the halogen moiety was replaced with a more electro(cid:173)
`negative substituent such as a nitro group, a more acidic
`compound would be formed. Presumably, more stable salts
`would result and precipitation of the free xanthine deriv(cid:173)
`ative in the stomach would be less likely to occur. On this
`premise, they successfully prepared pharmacologically
`effective 8-nitrotheophyllinates of several pharmaceuti(cid:173)
`cally useful bases.
`Duesel et al. (19), in their study of choline theophylli(cid:173)
`nate, prepared the 8-chloro-, 8-bromo-, and 8-nitrotheo(cid:173)
`phylline salts of choline. Oral toxicity studies in mice
`showed that the LD~;o of the 8-nitrotheophyllinate was
`much greater than that of either 8-halotheophylline. In
`fact, it remained nonlethal at doses as high as 5 g.
`Polygalacturonic acid, a derivative of pectin, has been
`used to prepare quinidine salts exhibiting reduced toxicity
`(49, 50). The compound possesses special demulcent
`properties and inhibits mucosal irritation. The rationale
`for use of this agent is to reduce the ionic shock to the GI
`mucosa resulting from the flood of irritating ions liberated
`by rapid dissociation of the conventional inorganic quin(cid:173)
`idine salts. Studies have shown that it is four times less
`toxic orally than the sulfate. This difference was attributed
`to the slower release of quinidine from the polygalactu(cid:173)
`ronate.
`Other compounds reported to be potentially useful as
`pharmaceutical salt forms are listed in Table III.
`
`PHYSICOCHEMICAL STUDIES
`
`Biological activity of a drug molecule is influenced by
`two factors: its chemical structure and effect at a specific
`site and its ability to reach-and then be removed from(cid:173)
`the site of action. Thus, a knowledge of the physicochem(cid:173)
`ical properties of a compound that influence its absorption,
`distribution, metabolism, and excretion is esRential for a
`complete understanding of the onset and duration of ac-
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`Table III-Potentially Useful Salt Forms of Pharmaceutical Agents
`
`Salt-Forming Agent
`
`Compound Modified
`
`Modification
`
`Reference
`
`Acetylaminoacetic acid
`N- Acetyl-L-asparagine
`N -Acetylcystine
`Adamantoic acid
`Adipic acid
`N- Alkylsulfamates
`
`Anthraquinone-! ,5-disulfonic acid
`Arabogalactan sulfate (arabino)
`Arginine
`
`Aspartate
`Betaine
`Bis(2-carboxychromon-5-yloxy)alkanes
`Carnitine
`4-Chloro-m-toluenesulfonic acid
`Decanoate
`Diacetyl sulfate
`Dibenzylethylenediamine
`Diethylamine
`Diguaiacyl phosphate
`Dioctyl sulfosuccinate
`Embonic (pamoic) acid
`
`Fructose 1,6-diphosphoric acid
`
`Glucose !-phosphoric acid, glucose
`6-phosphpric acid
`L-Glutamine
`Hydroxynaphthoate
`2-(4-lmidazolyl)ethylamine
`Isobutanolamine
`Laury! sulfate
`Lysine
`
`Methanesulfonic acid
`N-Methylglucamine
`
`N- Methyl piperazine
`Morpholine
`2-Naphthalenesulfonic acid
`Octanoate
`Probenecid
`Tannic acid
`Theobromine acetic acid
`3,4,5-Trimethoxybenzoate
`
`Tromethamine
`
`Doxycycline
`Erythromycin
`Doxycycline
`Alkylbiguanides
`Piperazine
`Ampicillin
`Lincomycin
`Cephalexin
`Various alkaloids
`Cephalosporins
`a-Sulfobenzylpenicillin
`Erythromycin
`Tetracycline
`7 -(Aminoalkyl)theophyllines
`Metformin
`Propoxyphene
`Heptaminol
`Thiamine
`Ampicillin
`Cephalosporins
`Tetracycline
`Vincamine
`Kanamycin
`2-Phenyl-3-methylmorpholine
`Tetracycline
`Erythromycin
`Tetracycline
`Erythromycin
`Erythromycin
`Bephenium
`Prostaglandin
`Theophylline
`Vincamine
`a-Sulfobenzylpenicillin
`Cephalosporins
`Pralidoxime (2-PAM)
`a-Sulfobenzylpenicillin
`Cephalosporins
`Phenylbutazone
`Cephalosporins
`Propoxyphene
`Heptaminol
`Pivampicillin
`Various amines
`Propoxyphene
`Tetracycline
`Heptaminol
`Aspirin
`Dinoprost (prostaglandin F2.,)
`
`Solubility
`Solubility, activity, stability
`Combined effect useful in pneumonia
`Prolonged action
`Stability, toxicity, organoleptic properties
`Absorption (oral)
`Solubility
`Stability, absorption
`Prolonged action
`Toxicity
`Stability, hygroscopicity, toxicity
`Solubility
`Gastric absorption
`Activity, prolonged prophylactic effect
`Toxicity
`Organoleptic properties
`Prolonged 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, hygroscopicity
`
`Solubility
`Toxicity, stability, hygroscopicity
`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
`
`51
`52
`53
`54
`55
`56
`57
`58
`59,60
`61
`62
`63
`64
`65
`66
`67
`68
`69
`70, 7l
`72
`73
`74
`75
`76
`77
`
`77
`
`52
`78
`79
`80
`81
`62
`61
`82
`62
`72
`83
`72
`84
`68
`85
`86,87
`88
`89
`68
`90
`91
`
`tion, the relative toxicity, and the possible routes of ad(cid:173)
`ministration (2).
`In a review in 1960, Miller and Holland (92) stated that
`"different salts of the same drug rarely differ pharmaco(cid:173)
`logically; the differe-nces are usually based on the physical
`properties." In a subsequent review (93), Wagner ex(cid:173)
`panded upon this statement, asserting that, although the
`nature of the biological responses elicited by a series of
`salts of the same parent compound may not differ appre(cid:173)
`ciably, the intensities of response may differ markedly.
`The salt form is known to influence a number of physi(cid:173)
`cochemical properties of the parent compound including
`dissolution rate, solubility, stability, and hygroscopicity.
`These properties, in turn, affect the availability and for(cid:173)
`mulation characteristics of the drug. Consequently, the
`pharmaceutical industry has systematically engaged in
`extensive preformulation studies of the physicochemical
`properties of each new drug entity to determine the most
`suitable form for drug formulation. Published information
`concerning such studies, however, is sparse. Preformula(cid:173)
`tion studies have been outlined, and the influence of the
`salt form on the volatility and hygroscopicity of an agent
`under investigation was discussed (94).
`
`In one such study, methylpyridinium-2-aldoxime
`(pralidoxime) salts were investigated (95). This study set
`out to prepare a salt with water solubility adequate to allow
`intramuscular injection of a low volume (2-3 ml) thera(cid:173)
`peutic dose. The original compound, the methiodide, had
`the disadvantages of limited aqueous solubility and high
`potential toxicity, since its high iodide content could result
`in iodism. On the basis of physiological compatibility,
`better water solubility, favorable stability, and relatively
`high percentage of oxime, the chloride salt of pralidoxime
`was selected for therapeutic administration; it was claimed
`that "the anion used to form the salt can confer physical
`properties of importance and significance for the formu(cid:173)
`lation and administration of the compound" (95).
`Some physicochemical properties of a series of mineral
`acid salts of lidocaine also were determined (96). While the
`hydrochloride and hydrobromide were more hygroscopic,
`they were more soluble in a number of solvents than the
`nitrate, perchlorate, phosphate, or sulfate salts.
`Dissolution Rate-The dissolution rate of a pharma(cid:173)
`ceutical agent is of major importance to the formulator. In
`many cases, particularly with poorly soluble drugs, this
`characteristic best reflects the bioavailability of the com-
`
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`
`Novo Nordisk Ex. 2027, P. 5
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`
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`administration of three different salts and the free acid,
`
`
`
`
`
`pound. As a rule, a pharmaceutical salt exhibits a higher
`was the same as the rank order of their rates of dissolution
`
`
`
`dissolution rate than the corresponding conjugate acid or
`
`
`While the investigators ascribed these differences
`
`
`base at an equal pH, even though they may have the same
`in vitro.
`
`their experiments
`
`
`to the solubility properties of the salts,
`
`
`
`
`equilibrium solubility. The explanation for this result lies
`
`
`
`
`
`actually compared dissolution rates, not solubilities. The
`
`
`in the processes that control dissolution.
`
`
`relative order of dissolution rates and mean maximal blood
`
`
`
`Dissolution can be described by a diffusion layer model1
`
`
`
`
`levels was: potassium salt calcium salt free acid
`
`
`
`in terms of an equation developed by Nernst and Brunner
`
`benzathine salt.
`(97):
`
`Nelson (100) determined dissolution rates for several
` = �S (C, - C)
`weak acids and their sodium salts in media whose pH's
`
`
`represented GI fluids. In all cases, the sodium salt dis
`where W is the mass of the solute dissolved
`at time t,
`
`
`solved more rapidly than the free acid. This finding re
`
`d WI dt is the rate of mass transfer per unit time, D is the
`
`
`
`solved the misconception that absorption of drugs is re
`
`
`
`
`solute molecule diffusion coefficient, S is the surface area
`
`
`
`lated only to solubility in the appropriate medium; rather,
`
`
`
`layer thickness,of the dissolving solid, h is the diffusion
`
`
`
`
`
`solubility affects absorption only to the extent that it af
`
`
`atC is the concentration of the drug in the bulk solution
`
`
`fects dissolution rate. Absorption of drugs is a dynamic
`
`
`
`intime t, and Cs is the .saturation solubility of the solute
`
`
`of a drug in fluid atprocess, and the ultimate solubility
`
`the diffusion layer.
`
`
`
`absorption sites is of limited consequence since absorption
`
`
`The driving force for dissolution in Eq. 1 is the difference
`
`
`
`prevents the attainment of saturated solutions. Therefore,
`
`solubility of the drug and the
`
`between the saturation
`
`
`
`dissolution rate, more than solubility, influences absorp
`
`concentration of the drug in the bulk fluid. If the drug is
`tion since it is a preceding process.
`
`
`not rapidly absorbed after it dissolves, then C, the con
`fur
`
`
`In two subsequent studies, Nelson and coworkers
`
`
`
`centration in the bulk solution, approaches Cs and the
`
`
`ther illustrated the effects of changing
`
`nonionized drugs
`
`
`
`dissolution rate is retarded. When this occurs, absorption
`
`
`
`
`
`into salts. A report concerning tolbutamide (101), a weak
`
`
`
`is "absorption rate" limited (or "membrane transport"
`
`
`showed that the initial dissolution rate of tolbutamide
`acid,
`
`limited). If the absorption rate is rapid ( or if the absorption
`
`
`sodium was approximately 5000 times more rapid than the
`
`
`
`mass transfer coefficient is much larger than DS/h ofEq.
`
`free acid in acidic media and 300 times more rapid in
`
`
`1), however, C becomes negligible compared to Cs and
`
`
`
`
`
`
`neutral media. This difference, measured reflected
`
`
`
`
`
`dissolution occurs under "sink" conditions. Absorption is
`in vitro,
`
`
`
`the differences observed between the free acid and the salt
`
`
`then said to be dissolution rate limited, which is what oc
`
`
`when administered to human subjects. Oral administration
`
`
`
`
`cur