There are drug substances do not contain a functional group that can form a stable salt but many others do. Drug discovery chemists frequently plan to incorporate a salt forming functional group into their candidate structures because making pharmaceutical salts can modulate the critical bioavailability a successful drug product.
Because finding highly preferred salt forms of drug candidates is a frequent undertaking, efficient protocols for identifying preferred compositions are in place among the firms that search for new drugs. Many of the steps in the screening have been automated. The evidence makes it difficult to argue against the proposition that the tools, steps and essential considerations for deciding upon the best pharmaceutical salt candidates are well known to skilled salt selection practitioners and are taught in the primary and secondary literature for all who are interested.
P. Heinrich Stahl and Camille G. Wermuth have edited a book, Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002 hereafter H&W, which bring together a great deal of material about pharmaceutical salts already in the literature, particularly in patents.
The editorial stance however may be a little annoying to readers from the generic drug industry because the authors imply an exaggerated idea about the difficulties encountered in making them. In particular at pg. 250 they write, ¡°The preparation of pharmaceutical salts is usually not a matter of university teaching, and so most of the organic chemists are not trained to prepare salts.¡± Taken strictly literally what they say is true but I do not think the authors¡¯ purpose is sarcasm. The authors are implying a requirement for inventive ingenuity only accessible to graduates when in reality with perhaps rare exceptions, preparing pharmaceutical salts is too simple to be the subject matter of university teaching.
Pharmaceutical salts typically are more soluble and more rapidly soluble in stomach and intestinal juices than non-ionic species and so are useful in solid dosage forms. Furthermore, because their solubility often is a function of pH, selective dissolution in one or another part of the digestive tract is possible and this capability can be manipulated as one aspect of delayed and sustained release behaviours. Also, because the salt-forming molecule can be in equilibrium with a neutral form, passage through biological membranes can be adjusted.
It is true that selection patents for particular pharmaceutical salts are used to extend the monopoly on many important medicines even though it is difficult to imagine the inventive step in the development of these salts. In the patent literature a great fuss is made about the millions of possible permutations of process variables that may need to be explored in order to devise a practical procedure for making a particular salt. Indeed, there are unusual cases where making any pharmaceutical salt turns out to be difficult. In such an instance, after the exhaustive trials, which would be the result of such an instance, it would be a simple matter to document, the difficulties and to justify a patent for the solution to that particular problem. In general however, once a compound is known, its pharmaceutical salts become readily available without further inventive steps to persons of ordinary skill in the art.
The work-horse cited document concerning pharmaceutical salts is S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. This work listed the pharmaceutical salts from which a pragmatic choice might be made. This work was updated by L.D. Bighley, S.M. Berge, D.C. Monkhouse, in ¡°Encyclopedia of Pharmaceutical Technology¡¯. Eds. J. Swarbrick and J.C. Boylan, Vol. 13, Marcel Dekker, Inc., New York, Basel, Hong Kong 1995, pp. 453-499. In this most recent compilation they found 113 different anions (13 inorganic) and 38 different cations (11 inorganic). About 75% of the basic drugs had been combined with one of just eight anions: chloride, sulfate, bromide, mesylate, maleate, citrate and phosphate. About 50% of all pharmaceutical salts were just hydrochlorides. There was an even more significant concentration for cations with acid drugs. Nearly 90% of the pharmaceutical salts were made with sodium, calcium, potassium, magnesium, meglumine or ammonia with more than 55% made with sodium.
An important point that Stahl and Wermuth¡¯s book brings out is that finding an appropriate pharmaceutical salt has become easier because the choices are to-day more limited. Referring to the Berge, Bighley and Monkhouse references the statement is made on pg. 331.
¡°While these authors presented the results of a survey on the approval status of drug salts 25 years ago, the present day situation is different. Accumulated knowledge and experience has led to a reduction of the number of acids and bases regarded as innocuous. Moreover, national health authorities reacted in different ways to certain findings in the area. Therefore, it was deemed timely to put up a revised list of useful salt-forming acids and bases.
In the following tables, an attempt has been made to group the salt-forming acids and bases into classes of first, second and third choice. The following criteria for assignment to the respective classes were applied.
1. First Class salt-formers are those of unrestricted use for that purpose because they form physiologically ubiquitous ions, or because they occur as intermediate metabolites in biochemical pathways. The first group is typically and quite impressively represented by the past and present use frequency of hydrochloride/chlorides and sodium salts. The second group comprises many acids present in food or vegetable origin, or those generated in the body¡¯s metabolic cycles.
2.Second Class salt formers are considered those that are not naturally occurring, but, so far, during their profuse application have shown low toxicity and good tolerability.
3. Third Class salt-formers might be interesting under particular circumstances in order to achieve special effects such as ion-pair formulation, or for solving particular problems. some of them are assigned to this class because they have their own pharmacological activity. Also some of the acids and bases were used much less frequently in the past¡.
¡It is recommended to search for the latest safety records in the RTECS inventory and in literature at the time when a Class 3 acid or base would be considered for salt formation with a NCE.¡±
There are just 30 First Class and 27 Second Class acids listed. There are only 9 First Class bases and 10 Second Class bases listed.
The First Class Acids are alphabetically: acetic acid, adipic acid, L-ascorbic acid, L-, capric, carbonic, citric, fumaric, galactaric, D-glucoheptanoic, D-gluconic, D-glucuronic, Glutamic, glutaric, glycerophosphoric, hippuric, hydrochloric, DL-lactic, lauric, maleic, (-)-L-malic, phosphoric, sebacic, succinic, sulphuric, (+)L-tartaric, and thiocyanic. Glycolic aspartic, palmitic and stearic are First Class acids also but they are used almost exclusively to make ester derivatives which are actually pro-drugs. Glycolic acid is used to make ether pro-drugs not a pharmaceutical salt per se.
The Second Class acids are alphabetically: alginic, benzenesulfonic, benzoic, (+)camphoric, caprylic, cyclamic, dodecylsulfuric, ethane-1,2-disulfonic, methanesulfonic, ethanesulfonic, 2-hydroxy-, gentisic, 2-oxo glutaric, isobutyric, lactobionic, malonic, methanesulfonic, naphthalene-1,5-disulfonic, naphthalene-2-sulfonic, 2-napthoic 1-hydroxy, nicotinic, oleic, orotic, oxalic, pamoic, propionic, (-)-L-pyroglutamic and p-toluenesulfonic acids.
The First Class acids, which are also among the most frequently used 15 acids are: hydrochloride, sulfate, tartrate, maleate, citrate, phosphate, acetate, lactate, and fumarate. Those which are not First Class acids but are among the top 15 salt formers are: hydrobromide (3), mesylate (2), pamoate (2), hydroiodide (not listed), nitrate (3), and methylsulfate(not listed). The class is listed in brackets. The pamoate salt is frequently quite insoluble in water. It finds particular use in making sustained release formulations. It also can be used to make quite insoluble salts to dibasic materials. Nitrate salts in former times were popular but are now recognized to have their own physiological effects and so are unlikely to be accepted today. S&W states at page 298 that the nitric acid salts should no longer be considered for formation of salts for internal use. Methyl sulfate salts are exclusively salts of quartenary ammonium ions with at least one methyl. The salt is created by methylation of the tertiary amine with dimethylsulfate. Kilomentor could find no other structures in which it was the pharmaceutical salt form.
What is evident from this is that there are only 9 acids which are both First-Class and in the top 15 historically. Among the top 15 acids there are some used exclusively in special situations and which need not be considered at all for regular screening applications.
Aspartate is characterically used to make salts with other amino acids. Kilomentor found no salts of drug substances.
Glycolic acid is not used to make pharmaceutical salts; covalent ether derivatives have been made to improve water solubility.
Palmitic and caproic acids are used only to make steroid esters.
D-glucoheptanoic: bisguanidine sebacic stearic
There are other sources of advice on preparing crystalline salts of complex basic substances. R. H. F. Manske writing about the isolation of alkaloids in sources of Alkaloids and their isolation, wrote at pg. 12,
¡°Should both fractional crystallization and distillation fail [to get the crystalline free base] in the resolution of these mixtures then they may be converted into any one of a number of salts in the hope that one of the component salts may be insoluble. There are a number of cases where certain special salts crystallize remarkably well but preliminary trials should be limited largely to the use of such acids as hydrochloric, hydrobromic, perchloric, picric, and oxalic, although sulphuric acid frequently affords acid or neutral sulfates that are sparingly soluble in alcohol or water. Instead of aqueous hydrochloric or hydrobromic acid absolute methanolic solutions of the reagents are recommended, since methanol is a good solvent for many bases. The methanol solutions offer the added advantage that the excess hydrogen halide is readily removed by precipitating the salt with an excess of dry ether. Hydrochlorides, thus prepared, often crystallize readily from boiling acetone, or acetone containing just enough methanol to effect solution¡±.
It must be born in mind that Manske is trying to get one alkaloid to precipitate from a mixture of alkaloids and he is not constrained to making pharmaceutically acceptable salts. this is why he advocates perchloric, picric and oxalic acid but his recommendations of other preferred salts that are pharmaceutical and his solvent recommendations based on a massive alkaloid experience are worth noting.
Hydrochloride salts frequently exhibit less than desirable solubility in gastric and other physiological fluids because of the common ion effect. Because hydrogen chloride is a volatile gas, salts with weak bases may lose acid over time when combined with weak bases. Hydrochlorides can be corrosive to machine surfaces, when somewhat hygroscopic.
Sulfuric acid can make two kinds of salts a sulfate and a bisulfate. The second pKa is 1.92. H¨¦l¨¨ne Perrier and Marc Labelle in J.Org. Chem. 1999, 64, 2110-2113 had the goal of choosing a salt form to be used to precipitate or crystallize a large number of different substrates whose only common feature was the presence of a quinoline base. Their first choice was the bisulfate salt using a standard procedure or a modification of it. There procedure was for precipitating the quinoline substrates from a reaction mixture in one of the solvents:ethyl acetate, methylene chloride, chloroform, dimethoxyethane, acetonitrile, dimethyl formamide, methanol, ethanol, and tetrahydrofuran. A solution in one of these solvents was diluted to 0.2 molar with ether and one equivalent of sulphuric acid was slowly added with vigorous stirring. With a few exceptions this produced a solid phase. Difficulties were experienced with compounds dissolved in DMF or alcohol solvents. This problem was solved in two different ways. In a first procedure, an extraction method was applied where the mixture was diluted with an ethyl acetate-water mixture, the organic phase was separated, and the compound was precipitated from that phase after dilution with ether. a second procedure applied to DMF simply involved a 4-fold dilution with methylene chloride (from 0.5M in DMF to 0,12M) followed by the standard ether dilution to 0.08M and acid precipitation.
The pharmaceutical form, (+)-L-tartaric acid has pKas of 3.02 and 4.36. A mixture of forms might be formed in bitartrates. Tartrates as a group show augmented solubility. where solubility is a problem the tartrates may be candidates for solution for the problem. A problem might arise using L-tartaric acid as the counterion with a racemic drug substance, because partial resolution might occur by selective crystallization of one enantiomer of the API. Among the compounds in USAN 1993, only metraprolol is a racemic free base. The other partners were either single enantiomers or achiral. There seems to be a preference for the stronger bases as partners of tartaric acid such as guanidines, amidines, thiuronium (in furazolium tatrate) and the predominant form is the hydrogen tartrate (1:1 stoichiometry). Tartrates are also more frequent when the basic structure contains alcohol and phenol as additional functionality. Kilomentor hypothesizes that there may be other hydrogen bonds between cation and anion. The amine functionality can be without other hydrogen bond donors such as in the compounds:ditrimeprazine , phendimetrazine and altanserin (all tert-alkylamines).
Maleic acid has two pKas 1.92 and 6.23. They are distinctly different because of the rigid structure which holds the first anion close to the site of the second deprotonation. For comparison the pKas of the geometric isomer fumaric acid are 3.03 and 4.38. In arecent report maleic acid could be made responsible for acute tubular necrosis in dogs after a single peroral dose of a test substance supplied as a maleate (pravadoline maleate) corresponding to a dose of 9 mg/kg maleic acid. [R.M. Everett, G. descotes, M. Rollin, Y. greener, J.C. Bradford, P.D. Benziger, S.J. Ward, Fundam. Appl. Toxicol. 1993, 21, 59-65.]
Maleic acid as a counter ion can be reactive with nucleophilic primary and secondary amines when heated strongly together or for an extended duration. The amines can undergo a Michael addition to the activated double bond. Nucleophiles can open any small amounts of maleic anhydride that might form making a conjugate with the maleic acid. These problems are more frequently encountered in the preparation of the API itself.Because maleic acid is a diprotic acid, there is the possibility of producing chains of cations and anions associated together by reaction with free bases that have more than one basic site. In fact examination of the compositions in the USAN 1993 that form salts with maleic acid 26 of them have a second basic site at least as basic as pyridine and 23 of them are effectively mono basic APIs. Although the second pKa of maleic acid is not going to protonate something like a pyridine substructure, there is a good chance for a strong stabilizing hydrogen bond.
Looking into ASAN 1993 to see the structures of the free base form of APIs that form citrate salts there is no primary or secondary amine in any of the structures. Each structure has a tert-alkylamine with occasionally a n additional aryl heterocyclic amine. The pipeazine substructure is frequent. Kilomentor would not recommend trying to make a citrate salt with an organic base containing any hydrogens on a basic amine functionality. Citric acid binds magnesium and calcium ions, which may appear in the formulation excipients. Because it complexes polyvalent metals which can operate catalytically, citric acid may have some antioxidant properties
Fumaric acid has both its pKas close together: 3.03 and 4.38. Because the pKas are close together, a mixture of 1:1 and 2:1 salts is possible. The same concern about Michael addition impurities arises as it did with maleic acid.
Phosphates of aliphatic sec-and tert- amines and of heterocyclic bases are likely to exhibit low water solubility but phosphoric acid is a syrupy liquid and is difficult to work with. In addition, phosphates have a tendency to form hydrates. Perrier and Labelle considered phosphates the second best salt to consistently precipitate from organic structures containing the substructure quinoline.
Kilomentor thinks that it is important to point out that simple salts of dihydrogenphosphate mono anion are actually rare. Clindamycin, metronidazole, rosaramicin, etoposide, fludarabine, tricirabine phosphates are actually phosphate esters. Other phosphates are often disodium phosphate esters. Where regular phosphates have been selected as a preferred pharmaceutical salt, the API is almosr always a structure with two or three basic groups, for example, clomacran (2 groups), chloroquine (3 groups), venpiroline (3 groups), primaquine (3 groups),disopyramide (2 groups) or histamine (3 groups). Usually one of these basic groups is a heterocycle. Only octryptoline is monobasic from among the drugs in USAN 1993. Klomentor recommends that phosphate salts be preferentially attempted only of substrates more than monobasic or that contain the quinoline substructure tested by Perrier and Labelle.
It may be that phosphates are insoluble in aqueous organic media. Easily handled sources of phosphate may be mono and dibasic ammonium phosphates: NH4 H2PO4, (NH4)2 HPO4. These compounds have good water solubility and the former has some alcohol solubility. In the presence of stronger less volatile bases, it may be possible to drive out the ammonia.
Because the acid is a weak one good salts are only formed with strong bases. The free acid is a liquid and excess can easily be removed. It is volatile again explaining the need for a strong base partner to keep its stoichiometric integrity. The low molecular weight could be useful in high load solid dosage forms where the size of the drug product could be an issue.
Both (+)-L-Lactic acid and racemic (¡À)-DL-lactic acid can be used for salt formation as the enantiomers of lactic acid are interconvertible in biological systems. The pKa is 3.86. Although the solids are known they are most readily available as aq. solutions. It is reported [P.H. Stahl, Ciba-Geigy AG, Basel, Switzerland unpublished ] that otherwise sparingly soluble and weak bases can be advantageously dissolved with these acids. Aqueous lactic acid is a complex solution with varying amounts of oligomeric esters present such as lactoyllactic acid depending upon the concentration and age of the solution. This may make the preparation of pure salts difficult not just in the crystallization but in stoichiometric preparation. Pure (+)-L-lactic acid should be used to form salts with a chiral base.
Although it is not a First Class acid, methanesulfonic acid is among the top 15 acid salt formers. It deserves special consideration because is a strong acid with a low molecular weight and excellent aqueous solubility properties Methanesulfonic acid has the advantages of a low molecular weight, a high acidity and it is a liquid miscible with some solubility in organic solvents even as non-polar as toluene as well as being totally soluble in water and a liquid at ambient temperatures. It can be obtained inexpensively in an anhydrous form. There has been a warning to be careful about the possible formation of methyl, ethyl or isopropyl mesylate from the use of the acid in these alcohol solvents. The main risk is from small amounts of methanesulfonyl halide in the acid that can react with alcohols. Methanesulfonate salts have no tendency to form hydrates.
Among basic salt-forming substances as designated in the First Class bases are alphabetically: ammonia, L-arginine, calcium hydroxide, choline, N-methylglucamine, lysine, magnesium hydroxide, potassium hydroxide, sodium hydroxide.
Among basic salt-forming substances the Second Class bases are alphabetically: Benethamine, benzathine, betaine, deanol, diethylamine, 2-diethylaminoethanol,hydrabamine, 4-(2-hydroxyethyl) morpholine, 1-(2-hydroxyethyl)- pyrrolidine, and tromethamine.
Before moving on to discuss the most common salt forming bases Kilomentor thinks it might be useful to provide some teaching about how to best obtain the free base form from the most common salt form the hydrochloride.
Recovering the Free Base Form from the Hydrochloride Salt
So predominant is the hydrochloride salt among pharmaceutical salts that it is useful to know the easy methods to regenerate the free base from the hydrochloride. The most frequent and least expensive method is to mix the hydrochloride in a mixture of water and a water immiscible organic solvent to which aqueous alkaline sodium hydroxide is added to neutralize the hydrogen chloride irreversibly. The free base is extracted into the organic phase where after optional drying it is recovered.
Sometime there is some reason to neutralize without contact with water. In the laboratory this can be done very simply by passing an organic solution of the hydrochloride through a plug of basic alumina. The material eluted will be the free base. The acid is retained by the adsorbant. On larger scale the hydrochloride salt is reacted with an equivalent of the epoxide of propylene. The 1-chloro-2-propanol can be removed by evaporation.
Example Belgium Patent 775,082 May 9 1972 F. Hoffmann-LaRoche
Insoluble anion exchange resin in the hydroxide form can also be used to neutralize hydrochloride salts. The excess resin can be filtered for removal. These resins however typically contain some residual water.
An ammonium salt upon evaporation to dryness and/or drying under vacuum hydrolyzes and the ammonia can be removed leaving the free acid.
Bases for forming Salts of Acids
Kilomentor will now look at the use of bases to form salts with pharmaceutical acids. The First Class bases, as designated in S&W, which are also among the most frequently used 15 base cations are: sodium, calcium, potassium, magnesium, N-methylglucamine, ammonium, and choline. Again this reduces dramatically the most probably choices of base to those both in the most popular 15 and First Class . The number meeting both criteria is only 7.
Those which are not First Class bases but are among the top 15 salt formers are: aluminum (not listed), zinc(3), piperazine(3), tromethamine(2), lithium(not listed), diethylamine(2), 4-phenylcyclohexylamine(not listed), and benzathine(2). The class as established by S&W is the bracketed number.
Among the most frequently used positive ions that are First Class bases there are only five that are inorganic cations, one quartenary ammonium ion and the simple ammonium ion. The organic cations are choline and N-methylglucamine.
The most popular cation can be produced using a number of reagents of which sodium hydroxide is only the most classic. Sodium salts can also be prepared under anhydrous conditions. Poorly soluble sodium salts are made even less soluble in physiological fluids by the common ion effect.
Potassium hydroxide is a very strong base like sodium hydroxide. Potassium hydroxide solid is just 85% potassium hydroxide because the solid cannot be completely dried. It is hygroscopic, deliquescent and reacts with carbon dioxide in the same way as sodium hydroxide. Potassium salts are somewhat less likely to form hydrates.
Calcium hydroxide is only slightly soluble in water so calcium salts must be made most often by indirect methods since a solution of calcium hydroxide in water is not possible. it is often made by salt exchange between a soluble sodium salt and a solution of a soluble calcium salt. Calcium chloride is often used so as to give the co-product sodium chloride which is both innocuous and easily washed out of the precipitated product.
However, just in case, anyone still feels that there is high art learned by experience rather than just working efficiently and systematically, I will to bring what is out there together.
Magnesium salts are even more insoluble than those of calcium unless the magnesium is bound as a chelate with two functional groups of the drug substance. Magnesium can de solubilized as magnesium ethoxide in ethanol. it is used as such in one preparation of magnesium omeprazole.
The ammonium ion is the only First Class cation, which can be delivered as a gas. Ammonia is a weak base and can only form stable salts with acids of mineral acid strength. Because the ammonium salts are salts of a weak base they can be displaced by srong bases giving ammonia as a coproduct which is easily removed from the reaction.
Soluble in ethanol at 70ºC 21 g/ 100 ml. Recrystallized from hot methanol. Salts are very soluble in water. Complexes metal ions.
N,N,N-trimethyl ethanolamine hydroxide
Choline hydroxide or chloride are soluble in water and alcohol. The salt can make drug substances more effective and less toxic than the parent compound.
Tromethamine baseTromethamine is not a First Class base. It is relatively recently approved for use in the United States and this may account for its less frequent application. Tromethamine is a primary amine and as such should not be used with reducing sugars as excipients because of a possible Maillard reaction. The base is somewhat soluble in a wide range of solvents.