Abstract
Within the pharmaceutical research and development field, the selection of a suitable solid-state form represents a crucial step. Selecting a solid-state form comprises several decisions, mainly the selection of a salt form and the selection of a polymorph or pseudo-polymorph of the respective salt. During the last decade, co-crystals have been added to the set of tools available for the Medicinal Chemist, Pharmaceutical Developer or Analytical Chemist. The present summary will address salt selection as an efficient tool to optimize solid-state properties of research compounds. Reviews on screening, evaluation and selection of polymorphs have been discussed intensively in the literature [1] and are – as co-crystals – beyond the scope of the present summary.
Introduction
During a lead optimization program, several properties of research compounds are optimized, typically leading to one or a few candidates that continue into exploratory development programs. Typically as regards assessment and optimization of physical chemical parameters during lead optimization, the main focus is on solubility [2, 3]. 
As research programs approach the development phase, more and more attention is devoted to further physical chemical parameters such as hygroscopicity, crystal habit, thermal behavior and many others besides. At this stage, salt selection represents a powerful tool to optimize properties and avoid pitfalls without changing the pharmacologically active moiety that binds to the target. However, careful assessment of the respective salt form is necessary and certain requirements – which will be discussed below - have to be fulfilled. A broad discussion on pharmaceutical salts is given in [4].
What can be Optimized?
What cannot be Optimized?
In many cases, salt selection is regarded primarily as a tool to optimize solubility. However, one has to bear in mind which aspects of solubility can be optimized and which aspects cannot. Further, solubility is not the only physical chemical property to be considered as, for example, a highly soluble salt form might exhibit unacceptable hygroscopicity or processability. These two aspects will be addressed in the following two sections.
Optimizing Solubility
Solubility represents a key parameter with an influence on bioavailability [5]. The thermodynamic solubility of a drug as well as its dissolution rate becomes crucial parameters. In many cases, the thermodynamic solubility of different salts in gastric fluid does not differ very much from one salt to another. This is due to the fact that gastric fluid presents a high concentration of chloride, e.g. about 0.1 mol/L. As drugs that are introduced into this medium as salt forms in low doses do not add a high concentration of a different counterion, the solubility of the respective drug is defined by the solubility product of the respective hydrochloride, as shown in Figure 1. For example, a 50-mg oral dosage form of a drug with a molecular weight of 500 g/mol would result in 0.0004 mol/L additional concentration of the respective counterion to the stomach, assuming a volume of 250 mL and complete dissolution. Accordingly, the concentration of the drug counterion is considerably lower than the concentration of chloride ions originating from the gastric fluid and thermodynamic solubility. However the dissolution profile might be very diverse if different salt forms are compared. Comparing the intrinsic dissolution of a free base and several salt forms in many cases yields a scenario in which the salts dissolve much faster than does the free base. This can be understood in terms of the crystal structure. As pharmaceutical salts – by definition – comprise charged species in the crystal structure, free bases and acids are made up of uncharged species. To dissolve a crystal, it has to be attacked by water molecules that knock drug molecules or counterions out of the crystal lattice. Obviously this process is facilitated as the interaction between water molecules and the crystal surface becomes stronger. Therefore pharmaceutical salts exhibiting polar crystal surfaces in many cases show superior dissolution behavior compared to the respective free base or free acid.
Further Physical Chemical Parameters to be Optimized
Beyond the optimization of solubility, further physical chemical parameters must be borne in mind when selecting the salt. However, in many cases these parameters do not have to be improved to an extent as great as possible, but instead merely have to be tuned to become acceptable. As an example we consider the melting point of a drug. The melting point of a drug – either as a free base, acid or salt form – should be higher than a certain threshold to allow processing steps such as drying or tabletting. Nevertheless, it is not necessary to obtain a drug exhibiting as high a melting point as possible.
Further physical chemical parameters that have to be considered during salt selection include:
• melting point
• thermal behavior
• hygroscopicity
• crystal habit
• particle size
• polymorphic behavior
• stability
• purity
Most of these parameters are not independent of each other, but instead are linked in certain ways. An increase in melting point, for example, is frequently accompanied by a decrease in solubility.
Quite obviously thermal behavior includes melting point. Beyond the melting point, the assessment of thermal behavior – which is typically done by thermogravimetry (TG) and differential scanning calorimetry (DSC) – also includes solid-solid phase transitions. These may be either enantiotropic or monotropic and can be related to the conversion of one polymorph to another or one pseudo-polymorph to another pseudo-polymorph - e.g. a lower solvate or hydrate – or a true polymorph. In the case of pharmaceutical salts in particular, solid-solid transitions may also include transitions from the salt form to the free base or acid upon thermal treatment. Thermomicroscopy (TM) represents a further powerful tool to learn about crystal habit and to complete the picture obtained from DSC and TG.
Hygroscopicity plays a key role in the evaluation of solid-state forms, as this property is highly relevant for many process steps such as drying, storage, blending, granulation, to name but a few. Hygroscopicity can be easily investigated by dynamic vapor sorption (DVS). Basically this technique not only yields information on the amount of moisture that is taken up by the drug at a certain relative humidity level, but also allows to distinguish between physisorption and chemisorption, the formation of hydrates. In many cases, drugs showing only low levels of physisorption are preferred. However, as solubility and hygroscopicity are both based on the interaction of the drug with water molecules, solid-state forms that exhibit better solubility also frequently show more pronounced watervapor sorption. As regards salt forms, in a quite common situation the free base or acid would not be hygroscopic and would exhibit a slow intrinsic dissolution, whereas salt forms dissolve faster but also show more pronounced hygroscopicity. If a solid-state form proves to be hygroscopic, the formation of well-defined hydrates - e.g. monohydrates, dihydrates - that are stable over the relevant temperature and humidity range is given preference. A good review on this topic can be found in the literature [6].
Discussing thermal behavior and hygroscopicity represents the link to another parameter that has to be considered in salt selection: a manageable polymorphic behavior is required for a salt form to continue in pharmaceutical development. Therefore, at least a brief assessment of polymorphism is typically carried out in a salt-selection procedure. In this sense, a manageable polymorphic behavior is not equivalent to the existence of only one or two polymorphic forms, but rather to render a situation where the conversion of polymorphic or pseudo-polymorphic forms that are not equivalent – e.g. in terms of ICH [7] – is excluded or closely controlled. One has to be especially careful in the case of pharmaceutical salts of weak bases and weak acids, as these salts might exhibit hydrolysis upon exposition to elevated moisture levels as may be the case e.g. in wet granulation, coating of tablets or granules and even during stability studies. In this case, hydrolysis yields the conjugated free bases and acids. This typically will not only change dissolution profiles but will also lead to a situation where the drug product no longer contains the active pharmaceutical ingredient, but its degradation product instead.
The last physical chemical parameter discussed in this short summary is crystal habit. How crystal habit can be influenced by salt selection is shown in Figure 2. In this sense, optimization in many cases means moving away a drug in the form of needle-shaped crystals towards e.g. platelets or even cubic crystals exhibiting better flowability.
Optimized Salt Forms – Beyond Physical Chemical Parameters
In addition to the physicochemical aspects discussed above, a number of further parameters define what constitutes an “optimized salt form.” These aspects include:
• impurity profile
• chemical stability of salt form
• processability
• toxicological properties of counterion
• toxicological properties of process solvents
• yield and cost of synthesis
• molar mass and dosage of drug product
As regards impurity profiles of drugs, salt selection can be a tool to improve these properties since pharmaceutical salts often exhibit crystal structures that are quite different from the structure of the corresponding free base or acid. This is due to the fact that in pharmaceutical salts ionic forces – which are not present in the free base or acid form - play a key role in holding together the crystal structure. Accordingly, pharmaceutical salts may be easier to crystallize, yielding compounds with reduced impurity levels. The chemical stability can also be improved. As one example, the oxidation of amines to N-oxides is more difficult in salt forms in which the respective amine function is protonated.
The toxicological potential of process solvents and counterions has been extensively discussed in guidelines [8] and the literature [4]. Particular attention has been paid to genotoxic threads from sulfonic acid alkyl esters. Such genotoxic impurities may be present as impurities in raw materials or may form during synthesis as a result of using specific combinations of acids and solvents, such as the formation of mesylates in alcohols [9].
Finally, for high dosage drugs one argument against using a salt form could be that the generation of a salt form in any case increases the molar mass of the compound and consequently leads to still higher dosages, e.g. still larger tablets.
Trends in Salt Selection
Based on this short summary on a diverse set of properties influencing salt selection, it becomes clear that salt selection is a process involving a multidisciplinary team involving medicinal chemistry, process development, pharmaceutical development, toxicology, analytics and regulatory affairs. Further, it becomes obvious that there is no universal answer to the question as to which salt form may be most useful for a specific drug. This becomes especially clear when trends in the usage of pharmaceutical salts today are compared to the situation in the 1980s [10], a period in which mostly hydrochlorides were used as pharmaceutical salts. Over the last decades there has been a decrease in usage of hydrochlorides. Hydrochlorides have not been replaced simply by another salt form. Instead a broad variety of salt forms are now being used. This reflects the increased need to optimize a broader variety of parameters relevant for a specific drug.
References
1. R. Hilfiker (Editor), “Polymorphism”, Wiley VCH, Weinheim 2006.
2. E.H. Kerns, L. Di, Chapter 7: “Solubility” in “Drug-like Properties: Concepts, Structure, Design and Methods”, Elsevier, 2008.
3. C. Lipinski “Drug Solubility in Water and Dimethylsulfoxide” in R. Mannhold (Editor) “Molecular Drug Properties”, Wiley VCH, Weinheim, 2008.
4. P.H. Stahl, C.G. Wermuth, “Handbook of Pharmaceutical Salts: Properties, Selection and Use”, Wiley VCH, 2002.
5. G.L. Amindon, H. Lennernäs, V.P. Shah, J.R. Crison, “A theoretical basis for a biopharmaceutical drug classification: The correlation of in vivo drug product dissolution and in vivo bioavailability”, Pharm. Res. 1995, 12, 413-420.
6. A.W. Newmann, S.M. Reutzel-Edens, G. Zografi, “Characterization of the Hygroscopic Properties of Active Pharmaceutical Ingredients”, J. Pharm. Sci. 2008, 97, 1047-1059.
7. ICH Harmonised Tripartite Guideline Q6A: “Specifications: Test Procedures and Acceptance Criteria for new Drug Substances and new Drug Products: Chemical Substances”, http://www.ich.org
8. ICH Harmonised Tripartite Guideline Q3C: “Impurities: Guideline for Residual Solvents”, http://www.ich.org
9. D.J. Snodin, “Residues of genotoxic alkyl mesylates in mesylate salt drug substances: Real or imaginary problems?” Reg. Tox. Pharm. 2006, 45, 79-90.
10. S. Paulekuhn, J. Dressmann, C. Saal, “Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database”, J. Med. Chem., 2007, 50, 6665-6672.
Christoph Saal studied chemistry at the Technical University of Darmstadt with a Ph. D. in Physical Chemistry. In 1999, he joined Merck KGaA where worked in Central Analytics and Medicinal Chemistry. Currently, Christoph Saal is heading a group focused on analytical and physico-chemical characterization of New Chemical Entities. This field of activity includes solid state characterization as physico-chemical charaterization of pharmaceutical salts and polymorphs. To correspond with author, please e-mail him directly at: [email protected]