Why are drugs formulated as salts

Ionic considerations. The degree of ionization is a critical parameter for the physiological performance of the drug and for its formulation development The p K a of the drug and counterion is important for successful salt formation as well. For the preparation of salt forms of basic drugs, the p K a of the counterion should be at least 2 pH lower than the p K a of the drug Similarly, for the preparation of salt forms of acidic drugs, the p K a of the counterion should be at least 2 pH higher than the p K a of the drug.

These specifications are required because the counterion must bring the solution's pH to a level lower than the pH max 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 p K 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 p K a of the API and counterion are not significantly different, a solid complex may form but may rapidly disproportionate i. 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 pyridiniumaldoxime 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 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 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 High-throughput synthesis has gained greater importance in the salt-selection process. This technique allows many counterions and crystallization solvents to be evaluated using as little as 50 mg of drug substance.

After the optimum drug-substance form is selected at the microlevel, the synthesis of the compound can be scaled up to several hundred grams to test for other stages of preformulation In situ salt screening also offers a viable alternative to traditional salt screening This method has a special relevance for poorly soluble compounds because it can rapidly rank compounds based on their solubility, effectively screening out insoluble compounds immediately During in situ salt screening, a known concentration of drug is added to a concentrated counterion solution sufficient to obtain the pH max see Figure 2 for successful salt formation that may be subjected to solubility screening.

Tong applied in situ salt screening to GW, an alpha 1A adrenergic receptor antagonist, and short-listed four salts—the phosphate, succinate, mesylate, and hydrochloride—for further development. These salts were found to be crystalline with adequate solubility comparable with the authentic salts later prepared by the traditional method and were selected for further evaluation Figure 2: The pH-solubility profile for a compound with a single, basic pKa value of 5.

The four regions of pH-dependent solubility are: salt plateau, pHmax, ionized compound, and unionized compound. In spite of the abundance of available counterions, few are used frequently.

The preference for pharmaceutical counter-ions is explained by studying the distribution of different counterions of medicinal compounds in USP 38 see Table III. The table shows that salt forms of drugs Hydrochloride and sodium remain the favorite counterions for the salt formation of medicinal compounds. However, the availability of many pharmaceutically acceptable counterions makes the salt-selection process difficult and cumbersome.

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.

Techniques for the characterization of salts. After synthesis, the formation of the salt forms must be confirmed. Next, their pharmaceutical properties must be assessed. Several characterization techniques provide valuable information for salt screening see Table IV. Salt-selection studies. Morris et al. 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. For a rational approach to salt screening, the tiered approach should be combined with a goal-oriented approach in which the main problems associated with the free acid or base are handled first, followed by secondary problems.

However, the hydrochloride salt of ranitidine has better absorption properties compared with the free base and is one of the most successful drugs ever marketed. In a multitiered approach, the hydrochloride salt would have been rejected after hygroscopicity testing, in spite of its better absorption profile High hygroscopicity could be mitigated by developing proper packaging.

Similarly, the hydrochloride form of sertaline i. This fact underlines the importance of a goal-oriented approach that addresses the most critical problems first. Less critical problems could be overcome by a proper development strategy. The final salt form selected should have a fine balance of the optimal physicochemical and biopharmaceutical properties. Each stage of salt selection see Figure 3 is relevant and contributes to the selection of the optimal salt form.

However, salt selection can be a difficult task because each salt imparts unique properties to the parent compound. 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 During salt-form selection, the determination of p K 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. 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 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 The selected salt form may then be subjected to extensive long-term toxicology studies in Phase I clinical trials of drug development.

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. 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. These salts, in corresponding formulations, were particularly suitable for topical applications.

Patenting new salts, therefore secures an exclusive position in the market Selecting an appropriate salt form of an API may also play a role in blocking the development of generic drug products. 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 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, 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 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 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. Wermuth and P. Stahl and C. Wermuth, Eds. Berge, L. Bighley, and D. Monkhouse, "Pharmaceutical Salts," J. Anderson and R. Bhattachar, L. Deschenes, and J.

Bighley, S. Berge, and D. Swarbrick and J. Boylan, Eds. Marcel Dekker, New York, , pp. Florence and D. You need to be a member to print this page. Find out more about our membership benefits. You need to be a member to download PDF's. Toggle navigation. This website is intended for UK healthcare professionals only Log in Register. You can access this article without logging in. But don't miss out on the many Benefits of our Membership.

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