KiloMentor: Preparation of Pharmaceutical Salts

There are drug substances that 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 offer a simpler means to modulate the critical bioavailability of 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 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.

However, their editorial stance will be annoying to readers involved with the generic drug industry. The authors do exaggerate the difficulties encountered selecting and making pharmaceutical salts. 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 literally what they say is true, but I do not think the authors’ purpose is sarcasm which would be required to preserve this truth. 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 for solid dosage forms. Moreover, because their solubility is usually related to pH, selective dissolution in one part or another of the digestive tract is possible and this capability can be manipulated as one aspect of delayed and sustained release behaviors. Also, because the salt-forming molecule can be in equilibrium with a neutral form, passage through biological membranes can be adjusted.

Selection patents claiming 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. In fact, there are unusual cases where making some 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 solving that particular problematic case. In general, however, once a particular chemical structure is discovered to display a useful medicinal utility, its pharmaceutical salts become readily available without further inventive steps to persons of ordinary skill in the art.

Most Cited Papers for Making Pharmaceutical Salts

The most widely cited document concerning pharmaceutical salts is S.M. Berge, L.D. Bighley, and D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19 which lists the pharmaceutical salts from which a pragmatic choice can 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 the more recent compilation, they list 113 different anions (13 inorganic) and 38 different cations (11 inorganic). This appears to be a challenging selection except that about 75% of the drugs which have a base functional group have been beneficially combined with one of just eight anions: chloride, sulfate, bromide, mesylate, maleate, citrate and phosphate. About 50% of all pharmaceutical salts were hydrochlorides. There was an even more significant dominance for cations mated with drugs that contained acid functionalities. 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 does bring out is that finding an optimal pharmaceutical salt has become easier today because the choices are more limited. Berge, Bighley and Monkhouse state on pg. 331:

“.... 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 used to make salts 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 also First Class acids but they are used essentially 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 top 15 First Class acids, which are by far the most frequently used 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 actual class of salt former is listed here in brackets.

The pamoate salt is frequently quite insoluble in water. It finds particular use in making sustained-release formulations. It is for example particularly well known for providing quite insoluble salts with 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 on page 298 that nitric acid salts should no longer be considered for the 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 characteristically 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.
Such covalently bonded adducts are actually prodrugs.

Other Salt Selecting Advice

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 also 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.

Hydrochloric acid

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. Using hydrochloric acid in methanol has caused concern with regulatory authorities because they worry about the possible presence of trace amounts of the carcinogen methyl chloride.

Sulfuric acid

Sulfuric acid can make two kinds of salts a sulfate and a bisulfate. The second pKa of sulfuric acid is 1.92. Hélène 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. Their procedure precipitated the quinoline substrates from a reaction mixture in one of the solvents:ethyl acetate, methylene chloride, chloroform, dimethoxyethane, acetonitrile, dimethylformamide, methanol, ethanol, or 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 experienced with compounds dissolved in DMF or alcohol solvents were solved in two different ways. In a first procedure, an extraction method was applied wherein 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 when DMF was 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.

(+)-L-Tartaric acid

The pharmaceutical form, (+)-L-tartaric acid has pKas of 3.02 and 4.36. Since hydrogen tartrates are possible the formation of mixtures must always be taken into consideration.
Tartrates as a group show augmented solubility. Where solubility is a problem the tartrates may be a solution.
A complication might arise using L-tartaric acid as the counterion with a racemic drug substance, because a 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 tartrate) 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

Maleic acid has two pKas 1.92 and 6.23. They are distinctly different because of the cisoid double bond 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 a recent 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. Alternately, 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, in an 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 were effectively monobasic 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.

Citric acid

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 an additional aryl heterocyclic amine. The piperazine substructure is frequent. Kilomentor would not recommend trying to make a citrate salt with an organic base containing any hydrogens on an 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

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 reaction derrived impurities arises as with maleic acid.

Phosphoric acid

Phosphates of aliphatic sec- and tert- amines and of heterocyclic bases are likely to exhibit low water solubility which might encourage their selection but phosphoric acid is a syrupy liquid and discourages working with it. In addition, phosphates have a tendency to form hydrates. Perrier and Labelle considered phosphates the second-best salt to consistently precipitate organic structures containing the quinoline substructure.

Kilomentor thinks that it is important to point out that simple salts of dihydrogen phosphate mono anion are actually rare. Clindamycin, metronidazole, rosaramicin, etoposide, fludarabine, tricirabine phosphates are actually phosphate ester prodrugs. Other phosphates are often disodium phosphate esters. Where regular phosphates have been selected as a preferred pharmaceutical salt, the API is almost 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. Kilomentor recommends that phosphate salts be preferentially attempted only of substrates more than monobasic or that contain the quinoline substructure tested by Perrier and Labelle.

Acetic acid

Because the acid is a weak one, good salts only form with strong bases. Its volatility further explains the need for a strong base partner to keep its stoichiometric integrity. Advantageously, however, the free acid is a volatile liquid making excess reagent easy to remove. The low molecular weight could be useful in high load solid dosage forms where the size of the drug product can become an issue.

Because acetic acid is a liquid fairly volatile acid it can be used in unusual ways. In Org. Process Res. Dev. 2012, 16, 518-523 there is presented the problem of making a monohydrochloride from a substrate that has two basic groups with widely different pKas, one a strong base and one a weak base. The molecule also has another acid sensitive group, a formamide, that under stronger acid conditions could lead to decomposition.
The solution was to take the compound in methyl ethyl ketone and acidify with an excess of acetic acid. The liquid acid is miscible in the solvent and forms the acetate of the stronger base only. The 2-butanone is then extracted with an aqueous solution of sodium chloride. The organic ketone solvent and the aqueous phase are not miscible. Sodium acetate prefers the aqueous phase and the chloride prefers the more hydrophobic ketone phase. After several brine washes, the 2-butanone phase can be thoroughly dried by azeotroping water and the monoacetate can be isolated from the organic layer. The substrate has not been exposed to strong mineral acid.

Lactic acid

Both (+)-L-Lactic acid and racemic (±)-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 these substances can exist as solids, 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.

Methanesulfonic acid

Although it is not a First Class acid, methanesulfonic acid is among the top 15 acid salt formers. It deserves special consideration because it is a strong acid with a low molecular weight and excellent aqueous solubility properties. Methanesulfonic acid has the advantage of a high acidity that mens it can form quantitative salts with weak bases. Also, it is a liquid miscible in many organic solvents and has some solubility in solvents even as non-polar as toluene. It is totally soluble in water. It is a liquid at ambient temperatures. It can be obtained inexpensively in an anhydrous form.... all important advantages. Methanesulfonate salts have no tendency to form hydrates.

Nevertheless, 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 alcohols. The main risk is from small amounts of methanesulfonyl halide in the acid that can react with alcohols.

Basic Salt Formers

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.

Sometimes 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 adsorbent. 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.

Sodium Salts

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 salts

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 salts

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.

Magnesium salts

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.

Ammonium salts

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.

N-methylglucamine

Soluble in ethanol at 70ºC 21 g/ 100 ml. Recrystallized from hot methanol. Salts are very soluble in water. Complexes metal ions.

Cholinate

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 base

Tromethamine 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.

Practical Hints and Example Procedures

Hydrochloride Salts

The diatomic molecule hydrogen chloride can exist either in a covalent form which is a gas soluble in non-polar aprotic solvents and as an ionized substance hydrochloric acid, soluble in polar protic and aprotic solvents. Both of these forms readily react with pharmaceutical bases to create the hydrochloride salts.

HCl for making salts can be provided as a reagent in concentrated aqueous solution of controlled normality where the protons are all present as hydronium ions and the chloride all as solvated chloride ions. The HCl can also be provided as an anhydrous solution in a lower alcohol such as methanol, ethanol or isopropanol. The solution of anhydrous HCl in IPA is more stable than solutions in the lower alcohols. An anhydrous solution in ethanol is readily and conveniently made by the addition of acetyl chloride to anhydrous ethanol, wherein the HCl is created in situ by reaction of the acetyl chloride with the ethanol to give some by-product ethyl acetate. HCl in anhydrous ether is also a very common reagent in the laboratory. The reagent contains the very strong acid diethyloxonium chloride.

The HCl for making a pharmaceutical salt can also be provided by reaction of ammonium chloride with the target free base so long as the intended base is substantially stronger than ammonia. The reaction is an equilibrium, which can be driven towards the hydrochloride salt of the drug by driving off the volatile ammonia.

Hydrochloride salts can also be prepared dissolved in homogeneous aqueous solution and then adding sodium chloride to precipitate them taking advantage of the common ion effect to reduce the solubility. This can be done with or without additional cooling.

Another source of in situ generated hydrogen chloride is t-butyl chloride, which reacts with bulky amine bases by elimination to produce isobutene vapour and the hydrochloride.

It is usually most desirable to have the free base from which the hydrochloride is to be made, present as a homogeneous solution before beginning the salt-forming procedure. The solvent can be selected to be compatible with the solubility of the base, but it would seem to be a good idea if that solvent had more rather than fewer of the following properties:

some few percent water solubility
miscibility with the solvent of the HCl reagent
low viscosity
moderate or low boiling point

It is usually most desirable to add the HCl reagent gradually to the free base because the very strong acid solution can give rise to by-products when present in excess. If for some reason reverse addition seems to provide a potential advantage use the ammonium chloride process because it will avoid excess strong acid.

When any procedure fails to produce a crystalline salt, an experienced laboratory worker will take the further steps of diluting the solution with diethyl ether. Hydrochlorides tend to be particularly insoluble in diethyl ether or solvent mixtures containing diethyl ether as a major component. The solution that is not producing crystals can be alternately concentrated under vacuum somewhat before attempting the diethyl ether dilution. On scale diisopropyl ether is preferred as a precipitant because the vapor pressure is lower reducing the risk of fire.

Producing free base from the hydrochloride

Sometimes 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 adsorbent. On a 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

An ammonium salt upon evaporation to dryness and/or drying under vacuum hydrolyzes and the ammonia can be removed leaving the free acid.

The Sulfate Salts

Sulfuric acid is a diprotic acid. It can form two different stoichiometric salt types the 1:1 bisulfate salt and the 2:1 sulfate salt in which two moles of amine are protonated by H2SO4. The pKas of sulphuric acid are –3 and 1.92 with almost five orders of magnitude difference between the acidity of the first and second hydrogen. Most pharmaceutical salts are of the 1:1 bisulfate type. Sulfates are most often made by the addition of an at least partially aqueous solution of acid because it is not soluble in apolar solvents and has some dehydrating capability which can lead to by-products when the acid is in excess. Typical organic solvents used in making sulfates are methanol, ethanol, 1-propanol, 2-propanol, acetone and mixtures thereof. An excess of acid causes the oligomerization of acetone and the development of color in the solution.

US7230016

PREPARATION OF PIOGLITAZONE SULFATE

24 g of sulfuric acid was added slowly, at room temperature, to 250 ml of methanol followed by addition of 80 g of pioglitazone base with stirring. The mixture turned into a clear solution. 250 ml of ether was slowly added followed by 500 ml of heptane. A solid precipitated and the suspension was stirred for 3 hours. The solid (98.4 g, yield was 96.5%) was collected by filtering and washed once with ether. The solid had a mp: 113.5-116.5° C. (recrystallized from methanol).

WO06040728A1

Preparation of 1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea

Example 1

1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea

(1 equivalent) is dissolved in ethanol at a concentration of 25% w/w and the mixture is heated at 50°C. Aqueous sulfuric acid (1M, 1.1 equivalents) is added. Optionally, the crystallization is initiated by a wet seed of Example 1 (0.5%). The suspension is cooled to 0°C with a cooling rate of 15 C°/ h and maintained at this temperature at least 1 hour before filtration and washing with aqueous ethanol (50 % W/V). The solid is dried at 30°C under a wet stream of nitrogen (50% RH) to provide the title compound with a purity of 97.7% with a yield of approximately 90%.

Example 2

1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea sulfate trihvdrate.
To a suspension of 1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea (21.36 kg) in CH₃OH (178 L) is added aqueous H2SO4 (6 L, 9.91%) during 10 min. The clear solution is filtered and further aqueous H2SO4 (33.8 L, 1.07 M) is added during 45 min. The solution is cooled to -2°C during 1.5 h and stirred at -5 to -9°C for 1 h. The formed precipitate is filtered, washed with cooled CH30H (- 5°C, 54 L) and dried under a stream of nitrogen provide 1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea sulfate of formula l as a non-defined hydrate. A slurry of the so obtained salt in H2O (16.2% w/w) is stirred for 3 days at 25°C. Filtration and drying at 30°C under a wet stream of nitrogen (50% RH) provides the title compound.

Example 3

1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea sulfate dihvdrate

To a suspension of 1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea (21.36 kg) in CH3OH (178 L) is added aqueous - H2SO4 (6 L, 9.91%) during 10 min. The clear solution is filtered and further aqueous H2SO4 (33.8 L, 1.07 M) is added during 45 min. The solution is cooled to -2°C during 1.5 h and stirred at -5 to -9°C for 1 h. The formed precipitate is filtered, washed with cooled CH3OH (- 5°C, 54 L) and dried under a stream of nitrogen provide 1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea sulfate of formula I as a non-defined hydrate. The so obtained salt is exposed to humid atmosphere (70 % RH) at 25°C to provide the title compound.

Example 5

1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea sulfate dihvdrate

1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea (1.01 kg, 1 equivalent) is dissolved in ethanol (3.05 kg) under stirring (200±20 rpm) and the mixture is heated at 50°C. Aqueous sulfuric acid (1 M, 1.1 equivalents) is added during 20 minutes. The crystallization is initiated by a wet seed of Example 1 (1 %) as described below. The obtained mixture is maintained at 50°C for about 15 minutes, then it is cooled to 0°C with a cooling rate of 15°C/h and maintained at this temperature for least 1 hour before filtration and washing with aqueous ethanol (50 % W/W, 3 kg). The solid is dried in a conductive agitated dryer at a temperature of 35± 3°C under a wet stream of nitrogen (45±5% RH), optionally under stirring (max. rpm) in case the cake humidity is below 25%, to provide the title compound with a purity of 99.8% with a yield of approximately 94%.
The wet seed used in the above procedure is added in two shots and is prepared by mixing 1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea sulfate dihvdrate (Example 1, 6.5 9) with a saturated solution (13.9 9 for the first shot, plus 15.6 9 for subsequent rinsing and second shot) of 1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea sulfate dihvdrate (Example 1, 7.0 9) in aqueous ethanol (50 % W/W, 50.0 9) for about 2 minutes. The first shot of wet seed is prepared at least 5 minutes before use to ensure that the seed is correctly wetted.

US20060194833A1:

Crystalline 1H-imidazo[4,5-b]pyridin-5-amine, 7-[5-[(cyclohexylmethylamino)-methyl]-1H-indol-2-yl]-2-methyl, sulfate (1:1), trihydrate and its pharmaceutical uses

According to the method, ER807447 is first suspended in water to form an aqueous suspension. Sulfuric acid is added to the aqueous suspension to form a solution while keeping the internal temperature of the solution below 25° C. The solution typically has a yellow color. The solution may optionally be filtered to remove particulates from the solution. Other techniques for removing particulates known in the art, centrifuging, etc. may be used as the filtering step. The solution is then slowly warmed until E6070 crystallizes from solution. The solution may be warmed to about 100° C. Typically crystal formation occurs at temperatures of about 70° C. Preferred rates of warming typically range from about 30 minutes to 5 hours. Longer or shorter times may be used, particularly depending upon the batch size. E6070 may not crystallize as readily from highly dilute solutions.

To enhance crystallization, an anti-solvent may be used in the method of making the crystalline E6070 or to recrystallize crystalline E6070. The recrystallization procedure is described in Example 5. In the above method, the anti-solvent may be added to the aqueous suspension before sulfuric acid addition or to the solution after sulfuric acid addition and the optional filtration step. Useable anti-solvents and their use are known in the art. Typical anti-solvents include water-miscible anti-solvents such as, for example, methanol, ethanol, 1-propanol, 2-propanol, acetone and mixtures thereof. When an anti-solvent is used, the solution may become cloudy. It is generally not necessary to warm the solution to as high of temperatures as when just using an aqueous solution.

Sodium Salt of Organic Acids

The update reported by L.D. Bighley, S.M. Berge, D.C. Monkhouse concerning pharmaceutical salts indicated that more than half the time the sodium salt is selected. What is taught about forming sodium salts? The classical approach is to add a strong solution in water such as 50% NaOH to the free acid dissolved in a water-miscible solvent. In favorable cases the salt once formed is insoluble in the predominantly organic medium and crystallizes. An example of this is provided by W.J.

Welstead, H.W. Moran, H.F. Stauffer, L.B. Turnbull and L.F. Sancilio, J. Med. Chem. 1979, 22, 1074.

A stirred solution of 111 g (0.43 mol) of (2-amino-3-benzoylphenyl)acetic acid in 777 ml of tetrahydrofuran is treated with 31.3 g (0.39 mol) of 50% NaOH. After cooling the solution to 0 C for 3 hours, the solid, which precipitates is collected by filtration to yield 64 g (56%) of the expected sodium salt. M.p. 245-25 C. An analytical sample is obtained by dissolving 1.0 g of the crude salt in 10 ml of 95% EtOH and treating the solution with 5 ml of (I-Pr)2O (diiisopropyl ether). The pure sodium salt precipitates slowly to yield 0.9 g of yellow solid. M.P. 254-255.5 C.

In this procedure, the sodium hydroxide is just less than the stoichiometric amount possibly to prevent the inorganic base from itself. Another possibility is that there is a small amount of a weaker base present in the free acid and an effort is being made to exclude it from the salt formation. 95% Ethanol is probably the most common recrystallizing solvent for salts and diisopropyl ether is the most common anti-solvent besides diethyl ether for increasing the yield of precipitant. On scale, where preventing the condensation of water into the cold mixture is possible the temperature is often lowered to about –20 C before filtration of solid and to cool any wash liquid.

More recently the practice has been even with polar protic solvents to try to exclude water, which may inhibit crystallization or reduce the yield. Also, the presence of water can often lead to the preparation of one or another form of hydrate rather than a completely desolvated material. Because Sodium acetate (and potassium acetate more so) is soluble in many organic solvents, such as methanol, ethanol or glacial acetic acid, the base can be added without water as a homogeneous solution in one of these. Most often the carboxylic acid is dissolved in cold methanol or ethanol. When crystallizing from lower alcohols the dissolution should not be done with heating to avoid the formation of a small amount of the ester by-product.

An anhydrous crystalline salt formation can be conducted even in a non-polar solvent if one can find a sodium carboxylate that is soluble in such solvents. 2-ethyl hexanoic aicd is an inexpensive organic acid, which forms salts with many inorganic cations which are soluble in a wide range of organic solvents. The example used Stahl and Wermuth’s book is from U.S. Patent 3,503,967.

“Five litres of dichloromethane were added to a clean dry vessel equipped with stirrer. 7-[α-(4-pyridylthio)acetamido]cephalosporanic acid {proper name: 3-[(acetyloxy)methyl]-8-oxo-7-{[(pyridin-4-ylthio)acetyl]amino}-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid } (1000 grams) was added to the vessel, followed by 350 ml. of triethylamine. The resulting solution was treated with decolorizing charcoal for fifteen minutes and filtered. A solution of sodium 2-ethyl-hexanoate (27.3%) in butanol/methylene chloride was added to the filtrate with stirring. 7500 ml. of acetone was added. Crystallization occurred while stirring was continued several hours under dry conditions. The crystals were collected by filtration, washed with large volumes of acetone, and then dried dried in vacuo at 50 C to yield about 950 g of the title compound.”

The thorough washing is likely required to completely remove the 2-ethyl hexanoic acid, which is the co-product.

Potassium Salts

Next in frequency to sodium as a pharmaceutical salt cation is potassium. Potassium salts can also be prepared by the 2-ethyl hexanoate methodology. According to the abstract CA 47, 11899d; Paul N. Cheremisinoff and Martin L., Stumf. Am.Paint J. 27(48) 90, 92, 94 (1953), potassium 2-ethyl hexanoate is soluble in water, acetone, isopropyl alcohol, benzene, carbon tetrachloride and naphtha. The reference is old and the measurements were qualitative. In a widely known example, penicillin free acid in acetone is precipitated by a solution of potassium 2-ethyl hexanoate. In Chem. & Industry, May 18, 1974, the suggestion is made that other less expensive acids can do the job “Studies on the precipitation of Phenethicillin have shown that cheaper potassium salts can be used, giving good product yields and purity after reslurry of the product in an alcoholic solvent” British Patent 877120.

It is important to know the rule of thumb that most potassium salts of carboxylic acids are soluble in hot ethanol.

Reaction of Methyl esters with Metal Silanolates

Another procedure for preparing either the sodium or potassium salts of carboxylic acids in anhydrous media starts with the corresponding methyl ester. The ester is reacted with the commercially available metal silanolate in homogeneous organic solvent:

R-(C=O)-O-Me + K-O-Si(Me)3 → R-(C=O)-O- K+ + Me-O-Si(Me)3

An example is provided in E.D. Laganis, B.L. Chenard, Tetrahedron Lett. 1984 25, 5831.

“Methyl 4-chlorobenzoate (13.65 g, 80 mmol) is added in one portion to a stirred slurry of potassium trimethylsilanolate (10.26 g, 80 mmol) in dry ether (500 ml) at ambient temperature under nitrogen. the reaction mixture is stirred for 4 hours. the white solid is fitered under nitrogen, washed with ether, and dried under a stream of nitrogen, to afford analytically pure potassium 4-chlorobenzoate (13.1 g, 84%).”

Preparation of Salts of Amines by Ion Pair Extraction

As we have seen, the standard method for the preparation of a salt (usually a hydrochloride) of an amine is by the addition of an anhydrous solution of the acid to a solution of the amine in an organic solvent. After chilling and scratching the salt may often be obtained in a crystalline form which can be purified by recrystallization. This method is not usually satisfactory for the preparation of the nitrate, thiocyanate, the iodide or the bromide. with the nitrate there is actually an issue of safety because anhydrous acid should not be mixed with anhydrous solvent. Arne Brandstrom and Klas Gustavii in Acta Chemica Scandinavica 23 (1969) 1215-1218 teach a methodology which is so general that it works also for non-pharmaceutical salts such as perchlorates and tetrafluoroborates. They teach that using such chlorinated solvents as chloroform, 1,2-dichloroethane and methylene chloride, salts of higher molecular weight amines with large “soft” anions can be appreciably extractable into the organic phase from a water phase. The extraction coefficients can be as high as 1010 or as low as 10-1.5. When the constant is high there are of course no difficulties extracting the ion pair quantitatively and organic chemists are widely aware that large ammonium chlorides can be in large part lost in the organic phase when we try to extract them into water. However, in the opposite case of a low extraction constant, it might be concluded that the extraction from an acid solution would be impossible, unsatisfactory or tedious but this need not be so. These amine salts often undergo association in the organic phase

[HAX]org + [HAX]org ↔ [H₂A₂X₂] org

and this equilibrium which is often lies strongly to the right and can be driven further in that direction by making the organic phase concentrated in HAX. Almost paradoxically extracting with smaller amounts of the organic solvent improves the extracting capacity by helping to dimerize the ammonium salts in the organic phase.

One can further increase the degree of extraction from the water into the organic layer by using an excess of the anion (here X). If for instance, a 0.5 M solution of an amine hydrochloride (Extraction constant=0.1, but dimerization constant 10⁴) in dilute phosphoric acid is shaken with chloroform 60% is extracted, but with an aqueous phase of 1.5M HCl the degree of extraction is increased to about 95%.

From experience, it has been found that:

Tertiary amines are more easily extracted than secondary or primary amines
Salts of most mono-basic acids are extracted as easily or better than the hydrochloride
High molecular weight as well as the absence of hydrophilic groups will support the extractability of the salt, while the presence of polar hydrogen bonding groups disfavor it
The choice of organic solvent is important

The following procedures can usually be applied for the preparation of salts of most secondary or tertiary amines with a molecular weight of 250 or higher. The procedures were used for the base alprenolol.

When an aqueous solution of the acid is available procedure A, here illustrated for making a bromide, is convenient.

When an inorganic salt containing the desired anion is available, illustrated for the perchlorate, procedure B can be applied.

0.5 mole of the free amine is dissolved in a mixture of 250 ml of 48% hydrobromic acid and 250 ml of water is extracted with 200 + 50 ml of methylene chloride. the combined organic layers are dried with anhydrous magnesium sulfate and evaporated using reduced pressure at the end of the evaporation process. The hydrobromide crystallizes spontaneously and is obtained in quantitative yield; it is recrystallized from an appropriate organic solvent such as ethyl acetate for alprenolol bromide.

B. 0.1 mole of the free amine and 35 g of NaClO4 are dissolved in a mixture of 125 ml of 1 M H₃PO₄ and 125 ml of water and extracted with 2 X 100 ml of methylene chloride. The combined organic layers are dried with magnesium sulfate and evaporated under reduced pressure. On scratching the salt will crystallize in a quantitative yield. With alprenolol the product was dissolved in 100 ml of benzene, diluted with pet. ether, and chilled to give pure perchlorate.

Using chloroform for extraction the hydrochloride, hydrobromide, hydroiodide, thiocyanate, nitrate, perchlorate and tetrafluoroborate salts of alprenolol were made in high yield.

Calcium Salt US 3,035,973

88 g of the dioctyl sodium sulfosuccinate (1,4-bis(2-ethylhexyl)sulfobutanedioate sodium) is first dissolved in 100 cc. od isopropanol and 25 grams of calcium chloride is dissolved in 50 cc. of methanol. the solutions are then mixed and stirred for about 3 hours and then cooled with ice. the sodium chloride which precipitates in the cool mixture is removed by filtration and most of the alcohol is evaporated from the resulting filtrate with heat. the liquid remaining is poured into 88 cc. of water, and the resulting precipitate washed with water until free from chloride ion. The washed calcium salt was dried.

Salt Selection

It is a general rule of thumb that the pKa of the acid should be >2 pKa units lower than the pKa of the conjugate base. Similarly for making a salt of an acid the pKa of the conjugate acid of the base should be >2 pKa units higher than the acid being derivatized. The rational for this is that one wants essentially complete formation of a single species, not a mixture of the neutral species and the acid or basic salt.

For an acceptable salt, it is disfavored if several different polymorphic forms or hydrates are within reach under the conditions of a possible wet granulation. If several forms are possible, uniformity of product cannot be guaranteed, since uniform sampling of a heterogeneous solid material is not dependable.

The solubility of the selected salt is preferable sufficient to make an injectable product because the full product line will contain an injectable material and one does not want to need to do clinical trials and stability on two different pharmaceutical salts if it can be avoided. There will also be pre-clinical studies that will require an injectable form.

For a high dose product, the salt counter ion should be a smaller part of the total molecular weight to reduce the tablet or capsule size.

Hygroscopicity of the salt form must be low both for the machinability of the formulation in all production facilities and also for the stability of the solid dosage form and consistency in the bioavailability over time. Hygroscopicity also affects the flow properties of the formulation and the stickiness of the formulation on the tablet punches.

For low dose medicines the size reduction and distribution properties of the solid are important to achieving good sample uniformity during the final mix preparation and the avoidance of de-mixing in the tablet machine hopper and during storage.

Polymorphic change during milling and micronization can be a problem particularly where producing a small physical aggregate is important for uniform distribution as in low dose medicines.

It is essential to develop the same drug product form for all markets in order to minimize the problems and maximize the return. Salt types that will create regional regulatory problems should be avoided if possible. S. & W. makes suggestions of salts that are not universally accepted.

Time Requirement:

“The initial studies described above require ca. 3-4 g of the free base and a similar quantity of each of the salts. The data for the free acid or base, and each of the different salt forms normally can be generated in ca. 4-6 weeks if the samples are available for simultaneous analysis.” S. & W. pg. 183.

CA 21433849

Rosiglitazone Maleate

The reaction between the compound of formula (I) and the source of counterion M- is generally carried out under conventional salt-forming conditions, for example by admixing the compound of formula (I) and the source of counter-ion M-, suitably in approximately equimolar amounts but preferably using a slight excess of the source of counter-ion M-, in a solvent, generally a C 1-4 alkanolic solvent such as ethanol, at any temperature which provides a suitable rate of formation of the required product, generally at an elevated temperature for example at the reflux temperature of the solvent and thereafter crystallizing the required product.

Example 1

5-[4-[2-(N-Methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione maleic acid salt

5-[4-[2-(N-Methyl-N-(2-pyridyl)amino)ethoxy] benzyl] thiazolidine-2,4dione (470g) and maleic acid (1 37g) were dissolved in ethanol (4 1) at a boil. The hot solution was filtered through diatomaceous earth and was then allowed to cool slowly with gentle agitation. After leaving in a refrigerator at 0-5°C for several hours, the maleate salt was filtered off, washed with ethanol and dried in vacuo at 50 C to give 446 g (73%) of product, m.p. 120-121°C.

1H NMR 6 (k-DMSO): 3.0-3.35 (2H, complex); 3.10 (3H, s); 3.95 (2H, t); 4.15 (2H, t); 4.85 (lH, complex); 6.20 (2H, s); 6.65 (lH, t); 6.85 (3H, complex); 7.15 (2H, d) 7.65 (lH, t); 8.05 (lH, complex); 1 1.85- 12.1 (lH, broad, 15 exchanges with D20).

A very broad signal was observed in the range 2-5 ppm which is thought to be due to residual water from the solvent and the exchangeable carboxylic acid protons.

Because of the strategic significance of salt selection patents for extending the monopoly period for a new drug substance, brand pharmaceutical corporations have vigorously defended the position that finding the preferred salt form is an inventive activity yielding something new and patentable. Generic competitors have argued that identifying preferred salts forms is no more than applying standard protocols, doing routine testing, making educated guesses or just after the fact rationalization. With the monetary stakes are so high, one can expect that the assessment on both sides may be clouded by self-interest, professional pride, or small-mindedness; or quite possibly authentic judgments are being suppressed.

Although one may not be able to depend on the testimonials of the protagonists, there are other forms of evidence in the actual behaviors of the people.

The basic drug patent is not a patent for the rights to a group of molecules with promise as possible medicinal treatments. The basic patent protects a composition containing active and at least one excipient, a method of treatment, a use etc. The basic patent protects the final marketed item. The patent is granted because there is a basis of sound prediction that using what is made available in the disclosure and what is already available in the art, a group addressees of ordinary skill could make the claimed medicine without the need for further inventions.

When a subsequent patent is filed selecting a salt from the class of pharmaceutical salts, it can only be considered an inventive contribution where there is actually an unsolved problem in the art. In practice there is no long-unsolved problem. Practitioners of the art do not work on the problem of making pharmaceutical salts of drug substances owned by others that have years of exclusivity left on their basic patent. What is politically unfair is for a national regulatory agency to insist that they will not accept without full clinical data, a generic product containing the same API, unless it is the identical salt as the originator because that forces generics to use the salt selected by the originator rather than any other one taught by the combination of the basic patent and the available prior art.

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Saturday, 11 March 2017

Preparation of Pharmaceutical Salts