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Salt Selection in Drug Development
An estimated 50% of all drug molecules used in medicinal therapy are administered as salts. This fact indicates that the salification, or salt formation, of a drug substance is a critical step in drug development (1, 2). A drug substance often has certain suboptimal physicochemical or biopharmaceutical properties that can be overcome by pairing a basic or acidic drug molecule with a counterion to create a salt version of the drug (3). The process is a simple way to modify the properties of a drug with ionizable functional groups to overcome undesirable features of the parent drug (4). This fact underlines the importance of salt formation for drugs that are designed, developed, and marketed after a rigorous research and development program (1).
Basic concepts in salt formation
The importance of salt formation
The stage of 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 foolproof (25). Ideally, the salt form should be chosen before long-term toxicology studies are performed (i.e., at the start of Phase I clinical trials) (24). This timing is an important factor 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 cost (26). A new salt form introduced at a late stage must also be evaluated for potential impurity changes, and its bioequivalence (bio-bridge), pharmacokinetic equivalence (PK-bridge), and toxicity equivalence (tox-bridge) to the previous salt form must be proven.
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 development. The following four
parameters are often considered primary or essential criteria for the selection of a particular form:
A serious deficiency in any of these characteristics should exclude that form from further development. In addition to these
essential criteria, the following desirable criteria also influence salt-form selection:
A single salt form generally cannot satisfy all the requirements for developing drug-substance 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 possible (9). 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. Gould says that "the balance required in assessing the correct salt from to progress into drug development makes it a difficult semiempirical exercise" (8). This statement emphasizes the need to prioritize the salt-selection process so that various development issues are addressed as early as possible.
Potential candidate for salt formation. The decision about whether salt or free acid or base should be developed depends on these forms' relative pharmaceutical and commercial merits. If the active compound is a liquid, a solid dosage form is usually preferred because oil is difficult to purify, characterize, and maintain in its effective form. Oil is also difficult to transport, sensitive to oxygen, and susceptible to batch-to-batch variations. If the free acid or base is a water-soluble solid with a high melting point, preparing a salt form is generally unnecessary. Alternatively, several useful properties of salt forms may be explored (6).
In spite of the numerous advantages associated with salt forms, developing them is not always feasible. The preparation of a stable salt may not be possible for some drugs. The salt may have certain undesirable properties compared with the free acid or base, and it would thus be appropriate to develop the free acid or base (28). In a salt-screening study of RPR111423, a pyridine base, hydrochloride and mesylate salts were formed. The hydrochloride salt showed a loss of hydrogen chloride at high temperatures (110–120 °C) and precipitation at an acidic pH because of the common-ion effect. The mesylate salt also showed precipitation at acidic pH. The two salts were polymorphic and hygroscopic in comparison with free base, which was nonpolymorphic and nonhygroscopic. These results proved the free base to be a better candidate than the salt forms (29).
Pharmacological indications also help determine whether the salt form or the free acid or base should be pursued. For example, when a slow onset or a constant plasma level is required, a highly ionized salt form may be inappropriate if the free acid or base provides a sufficient plasma level. Tolbutamide sodium, an antihyperglycemic agent, causes a rapid fall in blood glucose levels because it is highly ionized. This characteristic causes hypoglycemia in patients with normal insulinomas. Therefore, tolbutamide sodium's corresponding free acid was preferred for oral administration. The salt form's only application is the diagnosis of pancreatic adenomas (30).
Ionic considerations. The degree of ionization is a critical parameter for the physiological performance of the drug and for its formulation development (25). The pK a of the drug and counterion is important for successful salt formation as well. For the preparation of salt forms of basic drugs, the pK a of the counterion should be at least 2 pH lower than the pK a of the drug (34). Similarly, for the preparation of salt forms of acidic drugs, the pK a of the counterion should be at least 2 pH higher than the pK a of the drug. These specifications are required because the counterion must bring the solution's pH to a level lower than the pHmax (see Figure 2) to reach the salt plateau, at which the solubility of salt prevails over the solubility of free acid or base (5). The generalized rule of difference in pK a units of the ionizable group in the active pharmaceutical ingredient (API) and in the acid or base is meant to make the proton transfer energetically favorable. When the pK a of the API and counterion are not significantly different, a solid complex may form but may rapidly disproportionate (i.e., break down into the individual entities of drug and counterion) in an aqueous environment (35).
Generation of salt forms. Salts can be prepared on a small scale using various methods. Forming salts from free acid or base is the most common method. The free acid or base of the drug substance is combined with the counterion base or acid in specific molar ratios in a suitable solvent system. The salt form is then isolated, and the solid precipitate is recrystallized. A less common method is to form salts through salt exchange. In this method, a counterion salt is treated with a free acid or base in a specific molar concentration in a suitable solvent. The solid is then isolated and recrystallized. The sulfate salt of methyl pyridinium-2-aldoxime was prepared using silver sulfate as a counterion. The unwanted silver ions were removed as insoluble iodide salt, and the desired sulfate salt was precipitated by adding antisolvent (36). A wide range of salts are generally prepared for each new substance. Their properties are compared during a preformulation program that improves the chances of selecting the optimal salt form (29). However, a balanced approach should be adopted because limited resources are available at this early stage of drug development. Commonly used salts such as hydrochlorides and sodium have advantages over other salt-forming moieties. For example, they have low molecular weight and low toxicity. However, other salt forms such as mesylate may sometimes offer advantages such as higher solubility and bioavailability (37).
Salt-form selection. The generated salt forms are compared for the desired physico-chemical and biopharmaceutical properties, which guide the final selection of an optimal salt form.
Salt-selection studies. Morris et al. adopted a multitiered approach to screen salts for their optimal physical forms (39). In this approach, physicochemical tests are conducted in several tiers, and a go–no-go decision is made after each tier. Only appropriate salts, free acids, or bases are tested further, thus avoiding the generation of extensive data about each salt form generated. The studies can be planned so that the least time-consuming experiments that could still prompt a go–no-go decision are conducted in the first tier. Experiments that are more time consuming and labor intensive can be conducted at later tiers. In this way, many salt forms can be screened with a minimum of experimental effort. If the tiered approach eliminates all the candidates, additional salts must be considered before reevaluating any salt rejected in an earlier tier.
Stages of salt selection. Salt screening starts with the characterization of free acid or base, followed by the identification of possible counterions. The acid or base characterization provides information for potential counterion selection and for planning relevant crystallization experiments. This stage is followed by a screening of crystallization conditions for the desired salts, salt formation and its confirmation, and finally the preformulation characterization of generated salts (20).
During salt-form selection, the determination of pK a and corresponding ionizable groups gives an idea of the feasibility of salt formation. This information is the basis for selecting suitable counterions and a preliminary synthesis of salt forms, preferably at the microlevel, coupled with characterization for salt formation. After the confirmation of salt formation, the prepared salts are screened for various biopharmaceutical properties with a view to selecting the optimal salt form.
Assessment of crystallinity is the first stage of salt selection. The salt form should preferably be crystalline so that its properties remain constant during pharmaceutical handling, transportation, and use. However, the amorphous form may have advantages (e.g., solubility) that can be harnessed by proper formulation development. On the other hand, stabilizing the amorphous form for devitrification to crystalline form may lead to the loss of these advantages. Atorvastatin calcium was originally developed in an amorphous form. During Phase III clinical trials, it reverted to crystalline form, and the final product was developed using a crystalline form (43).
After crystallinity assessment, the salt form's hygroscopicity profile is assessed to find a salt form that retains its properties in the varying humidity conditions of pharmaceutical operations. This assessment can be performed using methods such as traditional saturated salt solutions in a desiccator or more advanced dynamic vapor sorption methods. The salt forms with acceptable hygroscopicity profiles are then evaluated for their solubility. The salts with adequate solubility are tested for their physicochemical stability, including polymorphic stability and excipient compatibility. These tests are especially relevant in combination formulations such as aspirin–propoxyphene. Aspirin–propoxyphene hydrochloride is unstable, but aspirin–propoxyphene napsylate is stable (8).
Salt forms having adequate stability are assessed for variability in their properties resulting from polymorphism. Compounds with a limited number of polymorphs are preferred because their performance during pharmaceutical operations and performance is predictable. The salt forms that qualify the stage of polymorphism are tested for process control, economic feasibility, and processability (including parameters such as corrosiveness, taste, wettability, and flowability). These criteria are generally evaluated at a small scale by a medicinal chemist, who narrows the choice to a particular salt form. However, after a particular salt form is selected, these parameters are evaluated at a larger scale so that the selected salt form has properties that are easily controlled batchwise and over time.
The selected salt form is subjected to pharmacological testing for drug release as per the requirements of onset and the duration of activity. Pharmacological safety studies are also performed. For example, epinephrine borate causes occasional mild stinging in the eye, compared with hydrochloride and bitartrate salt, which cause moderate to severe stinging (44). The selected salt form may then be subjected to extensive long-term toxicology studies in Phase I clinical trials of drug development.
Patent aspects of salt forms
Salt-selection studies provide a viable extension of a drug's patent because salts with superior properties can be patent-protected. New salt forms often have novel physical properties related to processability (e.g., crystallization, morphology, and filtration) and formulation (e.g., stability) (45). They may also result in the detection of new polymorphs (1).
A new salt form may have a profile that makes it suitable for a new route of administration. For example, diclofenac sodium salt (Ciba-Geigy) was marketed as Voltaren. Before the Voltaren patent expired, other salts (e.g., diclofenac diethylamine) with substantially better skin-penetration properties were discovered and patented. These salts, in corresponding formulations, were particularly suitable for topical applications. Patenting new salts, therefore secures an exclusive position in the market (20).
Selecting an appropriate salt form of an API may also play a role in blocking the development of generic drug products. Dr. Reddy's Laboratories tried to obtain marketing authorization for amlodipine maleate, a different salt version of amlodipine besylate. However, the US Court of Appeals for the Federal Circuit concluded that the basic patent for amlodipine covers other salt forms of the drug, including its maleate salt. The verdict against Dr. Reddy's Laboratories effectively prevented the generic version from entering the market (19).
Regulatory aspects of salt forms
Salt-selection studies should consider the regulatory aspects of introducing a new salt form. A new salt form of an approved drug substance is considered a new chemical entity, thus requiring a full dossier to be submitted for marketing approval (1). For regulatory purposes, a new salt form is designated a "pharmaceutical alternative" to the original form (46, 47). However, the approval process for a new salt may use some of the details already known about the active entity of a related, previously accepted salt (1). Therefore, when scientists change the active moiety of a salt that is already marketed, they may usually submit an abbreviated application, popularly known as the 505 b(2) filings (or the hybrid NDA), if they can prove that the new salt form's active moiety has the same pharmacokinetics, pharmacodynamic, and toxicity characteristics as the original (19). A generic version of a drug based on an alternative salt form may also be approved in a similar way. However, the benefits expected from the introduction of a new salt form must be weighed against the cost and time involved in the studies required for regulatory approval.
Selecting an optimal salt form for development is a critical step in ensuring the efficient and successful development of a robust product. Salt selection requires a well designed screening strategy that fulfills the essential and desirable criteria that set the standard for salt screening. In addition, salt selection procedures must also assess the regulatory, intellectual, and marketing considerations to balance the drug's physicochemical and biopharmaceutical properties against commercial considerations.
Lokesh Kumar is a student, Aeshna Amin is a student, and Arvind K. Bansal* is an associate professor at the National Institute of Pharmaceutical Education and Research, Sector-67, Phase-X, S.A.S.
Nagar, Punjab 160062, India, tel +91 0 172 2214682 87, fax +91 0 172 2214692,
*To whom all correspondence should be addressed.
Submitted: Apr. 2, 2007. Accepted: Apr. 5, 2007.
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