2. BASIC CONCEPTS IN SALT FORMATION

Salts are formed when a compound is ionized in solution and forms a strong ionic interaction with an oppositely charged counterion, leading to crystallization of the salt form². In the aqueous or organic phase, the drug and counterion are ionized according to the dielectric constant of the liquid medium. The charged groups in the drug's structure and the counterion are attracted by an intermolecular coulombic force. During favorable conditions, this force crystallizes the salt form (Fig 1.0). All acidic and basic compounds can participate in salt formation¹. However, the success and stability of salt formation depends upon the relative strength of the acid or base or the acidity or basicity constants of the species involved³.

The salt form is separated into individual entities (ionized and counter ion) in dissolution medium, and its solubility depends upon the solvation energy in the solvent. The solvent must overcome the crystal lattice energy of the solid salt and create space for the solute. Thus, the solubility of a salt depends on its polarity, lipophilicity, ionization potential, and size. A salt's solubility also depends on the properties of solvent and solid such as the crystal packing and presence of solvates⁴.

Figure 1: Schematic illustration representation of salt formation

3. SALT SELECTION IN DRUG DEVELOPMENT

Pharmaceutical companies previously selected salts at various stages in drug development. However, companies now tend to move the salt selection process to the research phase to make the process more fool proof ⁵. Ideally speaking, the salt form should be chosen before long term toxicology studies are performed i.e., at the start of Phase I clinical trials⁶. This is important in the early stages of new drug development because changing the salt form at a later stage may force a repetition of toxicological, formulation, and stability studies thus increasing development time and cost⁷. A new salt form introduced at a later stage must also be evaluated for potential impurity changes, bioequivalence, pharmacokinetic equivalence and toxicity equivalence.

4. OBJECTIVES OF SALT SELECTION:

Innumerable salt forms are available to pharmaceutical scientists. The selection process must therefore be rational and streamlined. A lack of proper planning may lead to the synthesis of several salt forms of the drug candidate for preformulation testing. Moreover, this hit or miss approach results in many failures and may cause the loss of test substance and time. These considerations underscore the need for a well formatted decision tree to help scientists choose a suitable salt form in an efficient and timely manner depending upon the intended use with a minimum number of failures and expended resources.

The main objective of a salt selection study is to identify the salt form most suitable for drug development. The parameters often considered primary or essential criteria for the selection of a particular form are aqueous solubility measured at various pH values depending upon the intended pharmaceutical profile, high degree of crystallinity, low hygroscopicity (i.e., water absorption versus relative humidity), which gives consistant performance and optimal chemical and solid state stability under accelerated conditions (i.e., minimal chemical degradation or solid state changes when stored at 40°C and 75% relative humidity). A serious deficiency in any of these characteristics should exclude that form for further development. In addition to these essential criteria, the desirable criteria which influences salt form selection are limited number of polymorphs or absence of variability because of polymorphism and ease of synthesis, handling and formulation development⁸. A single salt form generally cannot satisfy all the requirements for developing suitable dosage forms. However, introducing a second or third salt form consumes additional developmental resources and increases the cost of manufacturing, handling, storing, and characterizing the additional salt forms. Therefore, the dosage form is developed with a single salt form whenever possible⁹. The major drug development issues are addressed by choosing the appropriate salt form. Minor issues can be addressed using other development tools. Decreasing development timelines intensify the pressure to select the right salt form the first time. Salt selection is a critical step in the preformulation stage of drug development. The balance required in assessing the correct salt form to progress into drug development makes it a difficult semi empirical exercise¹⁰. This statement emphasizes the need to prioritize the salt selection process so that various development issues are addressed as early as possible.

5. PHYSICOCHEMICAL ASPECTS OF SALTS:

5.1 Solubility:

Solubility is a key determinant of bioavailability and alteration of solubility by salt formation may be used to improve biopharmaceutical performance¹¹. Typical counterions, cations, and anions used to prepare salts of acidic drugs and basic drugs are summarized. Development of more soluble salt forms of a drug with a view to improve drug bioavailability or ease of formulation are among the principal motives for salt formation^12-13. Several studies have compared the solubilities of different salt forms of a parent compound with that of the free acid or base. In Fig 1.0, the arrows indicate the equilibrium solubility of the specific salts. Deviations from the theoretical pH-solubility profiles may reflect the ability of some of the salts to form micelles¹⁴. Among the examples of the dramatic enhancement in solubility of a basic drug achievable through salt formation is that of the lactate salt of the antimalarial drug, (2-piperidyl)-3, 6-bis(trifluoromethyl)-9-phenanthrenemethanol, which is approximately 200 times more soluble than the hydrochloride salt¹⁵. In a study to select an appropriate salt form for RS-82856,¹⁶ the hydrogen sulfate salt is found to be more soluble than the parent drug over a wide pH range and is shown to result in an approximately 2-fold increase in bioavailability. Salt formation does not always confer greater solubility. There are many examples in the literature of the preparation of salts to reduce the water solubility of the parent compound^17-18. Reasons for lowering the aqueous solubility of a drug include the attainment of dissolution controlled absorption for controlled release from oral dosage forms.

5.2 Determination of solubility:

The solubilities of various salts under simulated gastric and intestinal pH conditions are determined by equilibrating excess of drug in the solubilising medium at room temperature and placed in a shaker and equilibriated for 24 - 48hrs. The filtered solution is assayed for drug concentration using a suitable analytical method. The pH values of the solution is recorded prior to their filtration through 0.45 pm port size Millipore filters.

5.3 Solid-State Properties:

Because solubility within a series of structurally related salts can be attributed to changes in the crystal lattice free energy, relationships between solubility and crystal properties are considered. Many pharmaceutical solids exhibit polymorphism which is defined as the ability of a compound to exist as two or more crystalline phases that have different arrangements of the molecules in the crystal lattice. Polymorphs of a drug salt will be different in crystal structure but identical in the liquid or gaseous states. The process of transformation from one polymorph to another i.e., a phase transition may occur on storage or during processing. If the phase transition is reversible, the two polymorphs are enantiotropes. Likewise, salts may form a range of solvates also called solvatomorphs or pseudopolymorphs depending on the recrystallization solvent used and the conditions employed. As these have different energies, they may have significantly different solubilities, dissolution rates, and stabilities. Within a series, the propensity to form hydrates increases with increasing ionic potential of the counter ion.

5.4 Determination of solid state stability:

Accurately weighed samples of salts (10 mg each) are stored at 40 and 50°C in closed 4 cm³ glass vials and at 4O˚c/75% RH in open glass vials. For photostability studies, samples stored in closed clear glass vials are exposed to 900 foot candle fluorescent light. The vials are stored under a similar condition with aluminium foil wrappers around them to served as controls. The stability samples are then assayed at different intervals by suitable analytical method.

5.5 Counterion pKa:

Successful salt formation generally requires that the pKa of the conjugate base be greater than that of the conjugate acid to ensure sufficient proton transfer from the acid to the base. Consideration of the relationships governing the pH solubility behaviour of weak acids suggests that, in general, it is advantageous to select conjugate bases having pKa values well above the pKa of a weakly acidic drug. However, factors such as solubility product (Ksp) of the salt, common ion effects and hygroscopicity may disfavour the salts of first choice using the above criterion e.g., hydrochloride or sodium salts. The formation of hydrochloride salts does not always enhance solubility above that of the free base. The lower solubility of a hydrochloride salt in dilute HCl, relative to that of the free base, is attributed to the common ion effect of the chloride ion on the solubility product equilibrium of the salts. The common ion effect suppresses the solubility product equilibrium. This is particularly relevant to the HCl salts of drugs administered orally resulting in contact with gastric acid which may result in suppressed solubility, dissolution, and altered bioavailability. Similar effects have been observed for the sodium salts of acidic drugs in the presence of increasing concentrations of sodium chloride. Additional disadvantages of using strong acids or bases in salt preparation have been reported. Salts prepared from strong acids or bases are freely soluble but can be very hygroscopic leading to instability in solid dosage forms as some of them dissolve in its own adsorbed films of moisture. In the case of salts of weak bases and strong acids, the strongly acidic solution may increase hydrolysis as a result of unfavourable pH. An excessively low or excessively high solution pH can lead to physiological compatibility problems in the case of injectable formulations. Injections should lie in the pH range 3-9 to prevent vessel or tissue damage and pain at the injection site. Packaging incompatibilities can also result from strongly acidic or basic formulations. Thus HCl salts in solution may have a low pH causing irritation, pain and inflammation requiring a change in salt form when formulating a parenteral product. Hydrochloride salts may also show incompatibilities with metal aerosol containers.

The use of pKa of the counter ion as a criterion for predicting salt solubility is complicated by the difficulty in discriminating between the energy required to remove ions from the crystal lattice and the energy of solvation. Consideration of ionic equilibria alone fails to account for the stereochemistry of the drug, counter ion size or other polar groups which can interact. The relationship between apparent solubility and solution pH is very important since the differences in solubility of the salts do not appear to be solely due to pH effect, thus compromising a simple predictive relationship. In particular, the salts with ammonium based cations i.e., ethanolamine and ammonium are more soluble than metallic salts of p-amino salicylic acid at similar pH values. The authors postulated that these salts may have an increased solubility because of the ammonium based cations exerting a hydrotropic and a structuring effect on water molecules. Similarly, the ethanolamine salt of an acidic antiallergic drug is more soluble than the salts prepared from inorganic cations.

5.6 Counter ion Structure:

The influence of salt structure on solubility within a series of counter ions should be considered in terms of their separate contributions to the crystal lattice energies and solvation energies. The lattice energy and the hydration energy both increase with an increase in cation/anion charge and decrease with an increase in ionic radius. Both are also expected to increase with an increase in polarity or hydrogen bonding nature of the counter ion. The overall change in solubility with a change in the counter ion will depend on the hydration energies or the lattice energy which are most sensitive to the change in structure. In a study on sodium, potassium, calcium and magnesium salts of three organic acids, the solubilities of the salts at a pH are compared¹⁹. The order of decreasing solubility of naproxen salts is K>Na> Mg> Ca, the order for 7-methylsulfinyl- 2-xanthonecarboxylic acid salts is K >Na>Ca>Mg and the order for 7-methylthio-2-xanthonecarboxylic acid salts is Na> K>Ca>Mg. Thus, the qualitative trends between structure and water solubility reported for inorganic alkali and alkaline earth metal salts²⁰ could not be used for organic carboxylic acids. It can be noted from the results that the salts of the divalent cations consistently exhibit lower water solubility than those of the monovalent cations suggesting that the crystal lattice energy effects dominate²¹. Rank order comparison of metallic p-amino salicylic acid salts obtained for other carboxylic acids indicate a general trend with salts of divalent cations being less soluble than salts of monovalent cations. The rank order solubilities for the antiallergic drug, N-[4-(1,4-benzodioxan- 6-yl)-2-thiazolyl]oxamic acid (Na>K>Ca) provides further support to this trend. It is suggested that a more precise prediction of the effect of the salt forming agent on the solubility of organic carboxylic acids is not possible because of the modification of the solubilities of the salts as a result of different degrees of hydration²². This explanation is further supported by the observation that the log solubilities of a series of sodium salts are inversely related to both the melting point and stoichiometric amounts of water in the crystal hydrates. Rubino²³ based on aqueous solubilities of a number of sodium salts of weekly acidic drugs proposed an equation relating salt solubility (Cs) to the salt melting point (MP) and the stoichiometric amounts of water in the hydrate forms like density and variation in flow behavior. There may be batch to batch variability in the potency of dosage forms if care is not taken to ensure that the bulk drug substance maintained its declared potency prior to batching. The change in moisture content may also affect the physical and chemical stability of salts. The go/no go decision depends on the consideration of both the physical stability of crystalline structure at different humidity conditions as well as the solubility. The criteria for the selection of salts at tier 2 may depend on the judgment of the drug development scientists in consideration of the type of dosage form and the expected dose of the compound. A salt with lower solubility which can still provide good dissolution rate in the judgment of a formulation scientist could be selected over a salt which is highly soluble but prone to crystalline changes. On the other hand, if the solubility is not acceptable in consideration of the dissolution rate or if a solution with high drug concentration is required for oral or parenteral use, another salt with some propensity for changes in crystal properties under extremes of humidity may be considered. Compatibility screening with selected excipients are conducted at tier 3. The number of salt forms available and the physicochemical properties considered important for the bulk drug substance as well for the expected dosage forms will dictate how many tiers would be necessary to select a salt form. There may also be rare situations where all salts progressed from a lower tier to a higher one are unacceptable for development. For example, the solubility of all salts at tier 2 may be unacceptable or chemical stability of all the salts at tier 3 may be poor. If this happens, additional salt forms or free acids/ bases should be considered prior to revaluating any salt that is dropped at an earlier tier. Also, the criteria of progression from a lower tier to the next higher one may also depend on the physicochemical properties of the available salts. If for example, all salts arc found to be highly hygroscopic, it is necessary to progress some of them to a higher tier, keeping in mind that, if selected, might require special manufacturing and storage conditions.

6. BIOPHARMACEUTICAL ASPECTS:

6.1 Bioavailability:

As a consequence of the effect of salt formation on solubility and dissolution rate, there are many examples of altered bioavailability i.e., alteration in rate and extent of absorption, between parent drugs and their salt forms and also between the salt forms. As mentioned, different salts of the same drug are not likely to differ qualitatively in pharmacological response. Quantitative differences is normally expected depending on their dissolution profile at the administration site. For example, the magnesium and calcium salts of indomethacin shows improved bioavailability compared to the free acid form of the drug. The sodium and potassium salts of ampicillin show a faster rate of absorption than ampicillin trihydrate, consistent with a higher dissolution rate of the salt forms. The extent of absorption is not apparently altered. Formation of soluble hydrochlorides of basic drugs does not necessarily result in improved bioavailability. Tetracycline free bases gave higher plasma levels than their hydrochloride salts, while lincomycin hydrochloride had a lower bioavailability than the hexadecylsulfamate salts.

These differences are attributed to common ion effect with gastric HCl following oral administration. The oral administration of tolbutamide sodium resulted in a rapid and pronounced reduction in blood glucose whereas the free acid is found to produce a more gradual hypoglycemic effect. This is attributed to the dissolution rate of the sodium salt being about 275 times greater than that of the free acid. Therefore it is concluded that the more slowly dissolving free acid is more useful form of the drug for the treatment of diabetes. Salts of aminosalicylic acid reports better bioavailabilities than the free acid. This drug exhibits non linear pharmacokinetics and a higher rate of absorption from the salt forms is considered to lead to saturation of the metabolic process leading to a higher proportion of drug escaping metabolism. The citrate salt of naftidrofuryl gives more rapid drug absorption than the oxalate but the extent of absorption is not affected. The rectal rate of absorption of phenobarbitone appears greater when amino acid or choline salts are employed rather than the free acid drug form. The sodium salt of novobiocin is unstable in aqueous solution while the crystalline free acid is inadequately absorbed from the gastrointestinal tract. Consequently, the amorphous Ca salt of novobiocin is employed in liquid formulations because of its stability and bioavailability attributes. Ion exchange resins are used to produce insoluble polymeric drug salts both for taste masking and controlled drug release. Ion exchange containing vehicles with bound basic drugs are shown to have advantages over comparable simple hydrogel vehicles in their versatility and in their capacities to store the drug and to control both its delivery rate and the pH of the vehicle during iontophoresis. Pamoic acid and alginic acid have also been used to prolong the action of basic drugs (e.g., streptomycin, pilocarpine) by forming salts of low solubility. A number of salt forms of drugs have surfactant properties which may contribute to their high solubility, membrane transport, and drug absorption. Examples include diclofenac, N-(2 hydroxyethyl) pyrrolidone (DHEP), and DDNL used in topical products. The use of the lauric acid salt of propranolol for extended release also resulted in increased bioavailability possibly linked to micellar solubilization, ion pair formation, and preferential lymphatic uptake.

6.2 Pharmacological Considerations:

In some cases a counterion may be used which itself has a pharmacological action complementary to that of the primary drug. Thus the formation of the benzhydralamine salt of penicillin is designed as an antiallergic and benzhydralamine having antihistamine activity²⁴. Drug salts using xanthenes or theophylline derivatives as the counter ion may be prepared for their stimulant effects to overcome drowsiness of. The demulcent property of polygalacturonic acid is the rational for its use as a salt former for the irritant quinidine, the quinidine polygalacturonate having lower oral toxicity than the sulphate. The antifungal activity of a series of salts of 9- aminoacridine and its derivatives is shown to correlate with the length of the carbon chain of the anion. The effect is thought to be related to increased lipid solubility and ion pair formation²⁵. Macromolecular salts using as counter ions like polyacrylic acids, sulfonic or phosporylated polysaccharides are used to alter drug distribution for example, by promoting lymphatic uptake of antibiotics²⁶.

6.3 Organoleptic Properties

Taste acceptability is a particular issue with oral liquid dosage forms, lozenges, and chewable tablets. The problem may be overcome by the preparation of poorly soluble salts. Thus the bitterness of erythromycin and of bacitracin can be ameliorated by the use of estolate (lauryl sulphate) and zinc salts, respectively²⁷. Propoxaphene may be taste masked by forming the napsylate, the solubility of which may be further reduced and the taste improved by adding a common ion salt such as sodium or calcium napsylate. Water insoluble salts may also be prepared using ion exchange resins. Metal drug salts, in contrast to organic salts, may be problematic with respect to taste because of their alkalinity. Salts incorporating the sweet tasting N-cyclohexylsulfamic acid (cyclamate) as the counter ion can render bitter drugs such as dextromethorphan and chlorpheniramine palatable²⁸.

6.4 Toxicological Considerations

A wide range of potential counter ions exist with potential for salt formation. However, the actual choice is restricted because of the known or uninvestigated toxicity of many potential counter ions. Therefore, consideration must be given to any likely pharmacological and toxicological actions of the counter ion. Examples of counter ions in use, which have pharmacological actions and potential for toxicity are lithium, copper, aluminium, calcium, and ammonia. The bromide ion, which has inherent sedative action also has a 12-day half-life may accumulate in the body and cause bromism while iodide can produce iodism. Frequently provided, the counter ion is nontoxic. The observed toxicity differences between salts may be linked to solubility and its impact on rate and extent of absorption.

7. PROCESSING AND FORMULATION ISSUES:

7.1 Melting Point:

Low melting point drugs or salts tend to be soft and plastic rather than hard and brittle and these properties impact on frictional heating, on comminution, and ultimately limit the ability to produce a free flowing powder. They also impact on interparticulate binding during tablet compression, affecting tablet hardness and friability. The solubility of a drug frequently decreases by an order of magnitude with an increase of 100˚C in its melting point. Relationships have been identified between salt melting points and the melting point of the conjugate acid or base. These indicate that those structural features leading to high melting (e.g., planarity, symmetry) or low melting (e.g., chain flexibility, asymmetry) of salt-forming agents may be carried over in determining the crystal lattice energies of the salt. In a study on a series of salts of a basic experimental drug candidate, Gould²⁹ explored the dependence of salt melting point on the conjugate anion crystallinity. Salts prepared from planar, high-melting aromatic sulfonic or hydroxycarboxylic acids yielded crystalline salts of correspondingly high melting point³⁰ whereas flexible aliphatic acids such as citric and dodecyl benzene sulfonic yielded oils. So, it is concluded that the comparative planar symmetry of the conjugate acid appeared to be important for the maintenance of high crystal lattice forces. Hydroxyl acids increase rigidity in flexible bases by hydrogen bonding resulting in an increase in melting point while the solubility may not be compromised because of the hydrophilicity of the acid. Dissociation of HCl or HBr from drug salts may occur, resulting in the release of the hydrohalide gas. These gases in turn may interact with excipients or corrode tableting tooling. Such dissociation with gas loss may be induced and/or facilitated by processing, e.g., freeze-drying. High-melting point crystalline salts will generally be the most stable, in contrast to amorphous or liquid/oil salt forms.

7.2 Stability:

The stability of organic compounds in the solid state is related to the melting point or strength of the crystal lattice. Before selecting a salt, its chemical and physical stability under stressed heat and humidity conditions should be assessed. The chemical and physical stability of a drug may be enhanced or retarded by salt formation. For example solid dosage forms of diclofenac contain salt forms rather than the less stable free acid. Although salt formation may result in improved dissolution rate and bioavailability of a poorly water soluble compound, the preparation of stable salt forms for some drugs may not be feasible and the free acid or base forms may be preferred. For example, the base form of a-pentyl-3-(2-quinolinylmethoxy) benzene methanol is selected for dosage form design because of the physical instability of its hydrochloride salt. The selection of an optimal salt form in terms of stability requires consideration of counterion related factors such as crystal lattice energy (stronger crystal lattice forces generally result in superior solid-state stability), pH of the liquid microenvironment (a function of counter ion pKa), and the possibility of counter ion participation in the degradation of the drug. The stability of organic compounds in the solid state is related to the melting point or strength of the crystal lattice.

Liquefaction of the solid generally occurs before degradation begins because the forces between molecules in a crystal are generally small relative to the energy required to break chemical bonds. Consequently, the melting point of a compound can be an important factor in determining stability. A study of the stability of a prostaglandin derivative and its sodium, potassium, and tromethamine salts when stored protected from light at 33˚C, revealed a marked dependence of solid state stability on salt form. In addition, a low melting point of a drug salt can adversely affect its processability. Highly hydrophilic polar ionized groups, such as those in monohydrochlorides, dihydrochlorides, and sulphates present on the salt crystal surface, promote wettability and hygroscopicity with resultant processing difficulties and with the potential for instability often promoting hydrolysis. The source of moisture may not only be the atmosphere but also excipients present in the formulation. The pH of such adsorbed moisture may be extreme often being highly acidic in the case of HCl salts.The use of less soluble salts often overcome these hydroscopicity problems. The tris (hydroxymethyl) amino methane salts of some NSAIDS have superior less hygroscopic properties than their sodium equivalents while generally maintaining good solubility. The calcium salt of penicillin is less hygroscopic and consequently more stable in a moist atmosphere than the sodium salt. The potassium salt of penicillin G is preferred to the sodium salt because it is less hygroscopic. In the case of hydrate salt forms, the stability is critically dependent on the temperature and humidity. The onset temperatures of dehydration for the magnesium and calcium salts are higher than that of the sodium salts consistent with stronger ion dipole interactions in the divalent salts. Examination of the crystal structure of the sodium salt reveals a very open network with an observable channel of water oxygen, not apparent for the divalent salts which is suggested by the authors as a significant factor in the stability of the hydrate. Studies of the potassium, sodium, calcium, and magnesium salts of p-amino salicylic acid indicates a general trend of increasing propensity to form hydrates with increasing ionic potential of the cations. This is evident from the increase in the number of moles of water associated with the salts as the ionic radius decreased and the charge on the cation increased. However, the usefulness of such a generalization is limited because salts may form several stoichiometric hydrates with different amounts of water depending on the crystallization conditions. Therefore, the selection of the optimal salt form with respect to hydrate stability usually required. The base form of a-pentyl-3-(2-quinolinylmethoxy) benzene methanol is selected for dosage form design because of the physical instability of its hydrochloride salt³¹. The selection of an optimal salt form in terms of stability requires consideration of counter ion-related factors such as crystal lattice energy (stronger crystal lattice forces generally result in superior solid-state stability), pH of the liquid microenvironment (a function of counter ion pKa), and the possibility of counter ion participation in the degradation of the drug³². Thus amorphous ethacrynic acid and amorphous sodium ethnacrynate are less stable than the crystalline forms³³. Low solubility tends also to contribute to increased stability, as it will set the upper concentration limit of drug in solution. Cracking of tablets, because of conversion on high humidity storage of the anhydrous HCl drug salt to a hydrate form has been reported³⁴. A study on the stability of hydrate forms of fenoprofen salts³⁵ showed that the dihydrate of the calcium salt was more stable than the dihydrate of the sodium salt, suggesting that the water of hydration was more tightly bound in the calcium salt crystals. Similar trends in relation to the stability of hydrates of p-amino salicylic acid salts were reported³⁶. In the case of hydrate salt forms, the stability is critically dependent on the temperature and humidity. The onset temperatures of dehydration for the magnesium and calcium salts were higher than that of the sodium salts, consistent with stronger ion–dipole interactions in the divalent salts. Examination of the crystal structure of the sodium salt revealed a very open network with an observable channel of water oxygen’s, not apparent for the divalent salts, which was suggested by the authors as a significant factor in the stability of the hydrate. Studies of the potassium, sodium, calcium, and magnesium salts of p-amino salicylic acid indicated a general trend of increasing propensity to form hydrates with increasing ionic potential of the cations. This was evident from the increase in the number of moles of water associated with the salts as the ionic radius decreased and the charge on the cation increased. However, the usefulness of such a generalization is limited because salts may form several stoichiometric hydrates with different amounts of water, depending on the crystallization conditions. Therefore, the selection of the optimal salt form with respect to hydrate stability usually requires experimental evaluation. The issue of equilibrium moisture curves for salt hydrates was reviewed by Carstensen³⁷.

8. DISSOLUTION ASPECTS OF SALTS:

The dissolution is the process by which a solid dissolves in a liquid, and the rate at which the dissolution takes place is referred to as the dissolution rate. There is, however, an important distinction between dissolution and solubility. The latter implies that the process of dissolution has been complete and the solution is saturated.

8.1 General solubility - dissolution rate relationships:

Theories of salt dissolution have been reported in the literature^38,39. The relationship between dissolution rate (J) and solubility (Cs) may be expressed by the Noyes - Whitney

Equation⁴⁰.

J = KA (Cs-C) -------------------------- (1)

K - constant, A - surface area of the dissolving solid, and C - concentration in the dissolution medium.

The above equation may be modified according to the Nernst - Brunner diffusion layer model⁴¹. It implies that the outermost layer of the solid drug dissolves instantly into a thin film of solvent to form a saturated solution of concentration (Cs) and the transfer of the dissolved drug to the bulk solution occurs by diffusion of drug molecules through this layer. If the diffusion layer thickness may be denoted by h and the diffusion coefficient of the solute in this layer by D, then K becomes equivalent to D/h and the equation may then be rewritten as

J = DA / h (Cs-C) -------------- (2)

For a constant surface area A and under sink conditions

(Cs≫C) in Eq (2) becomes

J = DACs / h ---------------- (3)

or J / ACs = D / h ------------ (4)

where the left side of Eq (4) may remain constant under a particular experimental condition, that is, when D and h remain constant. Although according to Eq (3), the dissolution rate is proportional to both solubility and surface area, the increase in Cs is the more effective way of improving the dissolution rate of a solid dosage form. For example, if the particle size of a drug substance is lowered by a factor of 5, say, from 25 μm to 5 μm, the surface area A increases by 5 times and consequently the dissolution rate J also increases by a factor of 5. There is also a practical limit how much particle size reduction one can achieve. For solid powders, the lowest particle size that can be achieved by conventional milling i.e; about 2 to 3 μm. On the other hand, the salt formation may be able to increase Cs hundreds of times, and J would also increase by a similar factor. The dissolution rate of drugs is generally diffusion controlled and under sink conditions, the rate per unit surface area (G) may be expressed by:

G = DC_s/ h --------------------- (5)

D - diffusion coefficient of the drug, Cs - solubility and h - hydrodynamic boundary layer thickness.

Therefore, given the effect of salt formation on solubility, it is not surprising that many studies illustrate the positive influence of salt formation on dissolution rate and the beneficial effects on dissolution of changing acidic and basic drugs into salts. A pharmaceutical salt generally exhibits a higher dissolution rate than the corresponding conjugate acid or base at an equal pH by acting as its own buffer and altering the pH of the diffusion layer. Thus, a pharmaceutical salt can exhibit a higher dissolution rate than the corresponding conjugate acid or base at the same pH, although they may have the same equilibrium solubility. The early work on the dissolution of theophylline salts shows a correlation between diffusion layer pH and dissolution rate, concluding that salts often speed up dissolution by a self-buffering action, altering the pH of the diffusion layer. Therefore the dissolution rates of acids and bases are determined by the pH values of the diffusion layers and are in effect independent of the bulk pH of the medium used. The difference in dissolution rates of acids and their salts at different bulk pH was found to be in good conformity with Eq (2) when the saturated solubility (Cs) at the pH at the interface (pH_o) is used rather than the solubility at the bulk solution pH. The pH of the dissolution medium in equilibrium with an excess of the dissolving material is shown to be a good approximation for the pH at the solid-liquid interface.

9.ROLE OF NMR SPECTROSCOPY:

Investigation of the use of solution NMR spectroscopy to determine the effect of organic solvents on chemical shift changes can be useful in the evaluation of solvents and counter ion selection for salt formation. 1H and 15N chemical shift changes in three bases (pyrazine, phthalazine, and pyridine) on the addition of acids (1:1 ratio) in various solvents indicated protonation i.e; salt formation. The media used affected the observed chemical shift changes. Protonation data provides an insight on potential salt formation in different media. Therefore solution NMR spectroscopy appears to be a useful tool to evaluate counter ion and solvent selection for salt formation reaction.

The physicochemical properties of drug candidates often dictate their successful development in pharmaceutical products⁴². For example, many drug candidates fail due to low solubility and/or low stability. Salt formation is routinely employed in modern drug discovery to overcome such failure by changing the physicochemical properties of drug candidates without modifying their chemical structures. There have been numerous literature reports concerning the selection process to achieve an optimal salt form for new drug candidates⁴³ and impact on solubility, dissolution rate and bioavailability^44-46. A common problem during salt screening is that glassy material may form following solvent evaporation. This may result from high solubility of the salt form in the solvent system, insufficient time for nucleation and crystal growth and/or insufficient proton transfer from acid to base in the solvent system. A general rule for appropriate counter ion selection for salt formation for a weak base is that the pKa value of the acid should be 2 units lower than that of the base to ensure proton transfer⁴⁷. The difference between the pKa of the base and the pKa of the acid is known as pKa. Although the pKa is a useful guideline for initial counter ion selection, it is important to remember that pKa values can shift with the solvent system due to differences in dielectric constant and proton donor or acceptor properties. Most pKa values reported in the literature are based on the aqueous phase, whereas organic solvents are usually employed in salt formation. The differences in the pKa values of various compounds in water and DMSO are reported⁴⁸. Even though changes in the pKa values of acids and bases in organic solvents are well known, no guidelines have been reported regarding selection of solvent systems for pharmaceutical salt formation based on protonation between acids and bases. The pKa of ephedrine and acetic acid in water are 9.74 and 4.76 whereas in methanol 8.74 and 9.71 respectively. Thus the pKa values of ephedrine and acetic acid⁴⁹ are 4.98 and −0.97 in water and methanol. Accordingly, there is no pH range to ensure sufficient proton transfer from acid to base in methanol, suggesting that salt formation between ephedrine and acetic acid is unlikely to occur in this solvent. Thus, solution NMR technique can also be used to confirm the pKa in different organic solvents when the complete pKa values in many different organic solvents are available. Since the pKa values of drug candidates may not be available for all solvent systems solution, NMR technique provides useful information and rationale to select suitable solvent system for salt formation reaction in organic solvents.

10. CONCLUSION:

The ability of many drugs to form salts affords the formulation scientist increased scope to optimize drug product performance. The formation of a drug salt can alter physicochemical properties such as physical and chemical stability, solid state characteristics such as crystal form, melting point, enthalpy, solvation, hygroscopicity, which in turn has an impact on processability, dissolution rate, and bioavailability. Unfortunately, our understanding of the physics and chemistry of salt formation is not yet at a stage where we can predict the physicochemical properties of a proposed salt. A particular problem in this regard is the formation of a range of salt polymorphs and/or solvates. While qualitative/semi empirical guidelines have been developed, the selection process is still largely experiment based. It is to be hoped that developments in computational methods will soon lead to the more accurate prediction of biopharmaceutically relevant solid state properties that will ultimately simplify the task of appropriate salt selection.

11. REFERENCES:

1. Bhattachar SN, Deschenes LA, and Wesley JA. Solubility: It's not just for physical Chemists. Drug Discov Today, 2006; 11 (21/22): 1012-1018.

2. Anderson BD, and Conradi RA. Predictive Relationships in the Water Solubility of Salts of a Nonsteroidal Anti-inflammatory Drug, J. Pharm Sci 1985; 74 (8): 815–820.

3. Bighley LD, Berge SM, and Monkhouse DC, Swarbrick J and Boylan JC. Salt Forms of Drugs and Absorption in Encyclopedia of Pharmaceutical Technology, Eds. Marcel Dekker, New York, 1996; 453-499.

4. Florence AT and Attwood D. Properties of the Solid State in Physicochemical Principles of Pharmacy, Eds. Macmillan Press Ltd, London, 3rd ed, 1998; 5–34.

5. Balbach S and Korn C. Pharmaceutical Evaluation of Early Development Candidates-the 100- mg Approach, Int. J. Pharm, 2004; 275 (1–2), 1–12.

6. Hilfiker R, Blatter F, and Raumer MV. Relevance of Solid-State Properties for Pharmaceutical Products in Polymorphism in the Pharmaceutical Industry, Ed. Wiley- VCH, Weinheim, Germany, 2006; 1-19.

7. Davies G. Changing the Salt, Changing the Drug, Pharm. J.2001; 266 (7138), 322–323.

8. Higgins JD and Rocco WL. Pharma Preformulation: A Stop along the Drug Development Highway, Today's Chemist at Work, 2003; 12 (7), 22-26.

9. Stahl PH and Nakano M, Stahl PH and C.G. Wermuth CG. Pharmaceutical Aspects of the Drug Salt Form, Handbook of Pharmaceutical Salts Properties, Selection, and Use, Eds. Wiley–VCH, Weinheim, Germany, 2002;83-116.

10. Gould PL. Salt Selection for Basic Drugs, Int. J. Pharm.1986; 33 (1–3), 201-217

11. Shargel L, Swarbrick J, Boylan JC. Yu, A.B.C. Biopharmaceutics. In Encyclopedia of Pharmaceutical Technology Eds. Marcel Dekker, Inc. New York, 2002; 156-176.

12. Anderson BD, Conradi RA. Predictive relationships in the water solubility of salts of a non-steroidal antiinflammatory drug. J. Pharm. Sci. 1985; 74 (8): 815-820.

13. Connor KM, Corrigan OI. Preparation and characterization of a range of Diclofenac salts. Int. J. Pharm, 2001; 226: 163-179.

14. Chiarini A, Tartarini A, Fini A. pH–solubility relationship and partition coefficients for some anti-inflammatory arylaliphatic acids. Arch. Pharm. Weinh. 1984; 317, 268-273.

15. Agharkar S, Lindenbaum S, Higuchi T. Enhancement of solubility of drug salts by hydrophilic counterions: Properties of organic salts of an antimalarial drug. J. Pharm. Sci, 1976; 65 (5): 747–749.

16. Engel GL, Farid NA, Faul MM, Richardson LA, Winneroski LL. Salt form selection and characterization of LY333531 mesylate monohydrate. Int. J. Pharm, 2000; 198: 239- 247.

17. Dittert LW, Higuchi T, Reese DR. Phase solubility technique in studying the formation of complex salts of triamterene. J. Pharm. Sci, 1964; 53 (11): 1325-1328.

18. Morozowich W, Chulski, T, Hamlin WE, Jones PM, Northam JI, Purmalis A, Wagner JG. Relationship between in vitro dissolution rates, solubilities, and LT50’sin mice of some salts of benzphetamine and etryptamine.J. Pharm. Sci. 1962, 51 (10), 993–996.

19. Haleblian J, McCrone W. Pharmaceutical applications of polymorphism. J. Pharm. Sci, 1969; 58 (8): 911–929.

20. Brittain HG, Swarbrick J, Boylan JC. Polymorphism: pharmaceutical aspects. In Encyclopedia of Pharmaceutical Technology; Eds.; Marcel Dekker, Inc.: New York, 2002; 2239-2249.

21. Higgins JD and Rocco WL. Pharma Preformulation: A Stop Along the Drug Development Highway, Today's Chemist at Work, 2003; 12 (7): 22–26.

22. Miyazaki S, Oshiba M, Nadai T. Unusual solubility and dissolution behaviour of pharmaceutical hydrochloride salts in chloride containing media. Int. J. Pharm, 1980; 6, 77-85.

23. Rubino JT. Solubilities and solid state properties of the sodium salts of drugs. J. Pharm. Sci,1989; 78 (6): 485-489.

24. Boger WP, Strickland SC. The penicillinate of benzhydrylamine; its oral administration. Antibiot. Med. Clin. Ther, 1955; 1: 352-376.

25. Viscia SM, Brodie DC. The in vitro antifungal activity of a series of acridine salts. J. Am. Pharm. Assoc. Sci. Ed, 1954; 43: 52-54.

26. Malek P, Kolc J, Herold M, Hoffman J. Lymphotrophic antibiotics. In Antibiotics Annual 1957-8; Welch, H., Mari-Ibanez, F., Eds.; Medical Encyclopedia, Inc.New York, 1958; 546-551.

27. Gruber CM, Stephens VC, Tirrell PM. Propoxyphene napsylate: chemistry and experimental design. Toxicol. Appl. Pharmacol, 1971; 19 (3): 423-426.

28. Campbell JA, Slater JG. Modification of physical properties of certain antitussive and antihistaminic agents by formation of N-cyclohexylsulfamate salts. J. Pharm. Sci, 1962; 51: 931-934.

29. Gould PL. Salt selection for basic drugs. Int. J. Pharm, 1986; 33: 201-217.

30. Wells JI. Pharmaceutical Preformulation-The Physicochemical Properties of Drug Substances; Ellis Horwood: Chichester, UK, 1988.

31. Serajuddin ATM, Sheen PC, Mufson D, Bernstein D, Augustine MA. Preformulation study of a poorly water-soluble drug, a-pentyl-3-(2-quinolinylmethoxy)benzenemethanol: Selection of the base for dosage form design.J. Pharm. Sci, 1986; 75: 492-496.

32. Anderson BD, Flora KP.Preparation of water-soluble compounds through salt formation. In The Practice of Medicinal Chemistry; Academic Press: London, 1996; 739-754.

33. Yarwood RJ, Phillips AJ, Collett JH.The influence of freeze drying on the stability and dissolution of sodium ethacrynate. J. Pharm. Pharmacol, 1983; 35, P4.

34. Yamaoka T, Nakamachi H, Miyata K. Studies on the characteristics of carbochromen hydrochloride crystals. II.Polymorphism and cracking in the tablets. Chem. Pharm.Bull. Tokyo, 1982; 30 (10): 3695-3700.

35. Hirsch CA, Messenger RJ, Brannon JL. Fenoprofen: drug form selection and preformulation stability studies. J. Pharm. Sci. 1978; 67 (2): 231-236.

36. Forbes RT, York P, Fawcett V, Shields L. Physicochemical properties of salts of p- aminosalicylic acid. I. correlation of crystal structure and hydrate stability. Pharm. Res, 1992; 9 (11): 1428-1435.

37. .Carstensen JT, Rhodes CT. Physical characteristics of solids. In Drug Stability, Drugs and the Pharmaceutical Sciences; Eds.; Rhodes: Marcel Dekker, 2000; 107: 209-236.

38. Noyes AA, Whitney WR. The rate of solution of solid substances in their own solutions, J. Am. Chem. Soc, 1897;19: 930-934.

39. Higuchi WI. Diffusional models useful in biopharmaceutics - drug release rate processes, J. Pharm. Sci,1967; 56: 315-324.

40. Pudipeddi M, Serajuddin ATM, Grant DJW, Stahl PH, Stahl PH, Wermuth CG. Solubility and dissolution of weak acids, bases, and salts, in: (Eds.), Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Wiley-VCH, Weinheim, 2002; 19- 39.

41. Pudipeddi M, Serajuddin ATM, Grant DJW, Stahl PH, Wermuth CG. Solubility and dissolution of weak acids, bases, and salts, in: (Eds.), Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Wiley-VCH, Weinheim, 2002.

42. Wenlock M.C, Austin RP. A Comparison of physiochemical property profiles of development and marketed oral drugs. J. Med. Chem,2003; 46: 1250-1256.

43. Morris KR., , (1994). An integrated approach to the selection of optimal salt form for a new drug candidate. Int. J. Pharm., 105, 209-217

44. Serajuddin ATM, Pudipeddi M, Stahl PH, Wermuth CG. Eds. Salt selection strategies. Handbook of Pharmaceutical Salts: Properties, Selection,and Use. Wiley-VCH, Zurich,2002;135-160.

45. Berge, S.M., Bighley, L.D., 1977.Pharmaceutical salts. J. Pharm. Sci.66, 1–19.

46. Engel, G.L., Farid, N.A., 2000. Salt form selection and characterization of Y333531 mesylate monohydrate. Int. J. Pharm. 198, 239–247.

47. Bastin, R.J., Bowker, M.J., et al., 2000.Salt selection and optimisation procedures for pharmaceutical new chemical entities. Org. Process Res. Dev. 4, 427-435.

48. Bordwell FG. Equilibrium acidities in dimethyl sulfoxide solution. Acc. Chem.Res,1988; 21: 456-463.

49. Black SN, Collier EA. Structure, solubility,screening and synthesis of molecular salts. J.Pharm. Sci,2007; 96: 1053-1068.

Received on 19.10.2011

Accepted on 28.10.2011

Research Journal of Pharmaceutical Dosage Forms and Technology. 3(6): Nov.- Dec., 2011, 251-259