The Impact of Different Salt Forms of the Same API in Pharmaceutical Formulations
A Brief Discussion on Potential Issues in the Consistency Evaluation of Drugs with Different Salt Forms of the Same API
Source: China Food and Drug Administration, 2019 Issue No. 1
Authors: He Ruirui, Yang Jinbo Center for Drug Evaluation, National Medical Products Administration
Author Profiles: He Ruirui Master of Pharmacy, Department of Statistics and Clinical Pharmacology, Center for Drug Evaluation, National Medical Products Administration; Clinical Pharmacology Reviewer, Assistant Researcher; Primarily engaged in review work related to clinical pharmacology research.
Yang Jinbo Doctor of Medicine, Department of Statistics and Clinical Pharmacology, Center for Drug Evaluation, National Medical Products Administration; Minister, Chief Pharmacist; Primarily engaged in clinical pharmacology review and consistency evaluation of quality and efficacy for generic drugs.
Abstract The consistency evaluation of generic drug quality and efficacy involves evaluating the consistency in quality and efficacy of marketed drugs against the originator product. In China, many early approved products exist due to special purposes such as circumventing originator patents or facilitating tender procurement, resulting in a large number of salt form modifications. An important task in consistency evaluation is to re-evaluate the consistency in quality and efficacy between salt-modified products and the originator product.
API vs. Salt Forms The appropriate salt form for most APIs should be determined early in chemical molecule development to facilitate formulation optimization. It is estimated that half of therapeutic drugs are administered in salt form, making the determination of salt forms for candidate drugs a basic step in drug development. The interchangeability of "pharmaceutical alternatives" has long been a controversial topic, particularly in considering the substitutability between generics, posing a challenge to regulatory authorities [1]. The term "pharmaceutical alternative" is used in EU guidelines [2] to define interchangeability in situations where drugs have the same active ingredient but differ in chemical form (e.g., esters, salts), dosage form, or strength. The FDA Orange Book also has a similar definition for therapeutic equivalence [3]. The difference lies in the FDA's emphasis that only therapeutic equivalence allows drugs to be considered substitutable. In contrast, the EMA considers that as long as the excipients in the formulation do not affect the safety and efficacy of the dosage form, both pharmaceutically equivalent and pharmaceutical alternative products can be regarded as therapeutically equivalent. Pharmaceutical equivalence as defined in the FDA Orange Book refers to drugs containing the same active ingredient, same dosage form, same route of administration, and same strength or concentration. The EMA stipulates that to conclude therapeutic equivalence between one product and another, evidence of the clinical safety and efficacy of the test product must first be available; thus, bioequivalence between two products containing different salt forms may not suffice to support substitutability [2]. It is generally believed that even if the active ingredient content is the same, different dosage forms may exhibit significant differences in the absorption rate (Cmax) and extent (AUC) of the active moiety, i.e., bioavailability. The FDA [4] requires that products must have both pharmaceutical equivalence and bioequivalence to achieve interchangeability in prescriptions. The EMA is relatively more open, considering bioequivalent drugs as therapeutically equivalent without mandating pharmaceutical equivalence, meaning non-pharmaceutically equivalent products are substitutable. Therefore, establishing pharmaceutical alternatives and therapeutic equivalence requires considering several factors, such as different salt forms, different dosage forms and strengths, and different routes of administration. It is well known that most drugs are generally in the form of weak organic acid or base salts. The same drug active ingredient (API) can exist in many different salt forms. Although they share the same active ingredient, each salt form should still be regarded as a distinct chemical entity with unique chemical and biological properties, potentially leading to differences in therapeutic efficacy and safety. Converting an API to a specific salt form is a method to appropriately modify and optimize specific physicochemical properties. However, changing the salt form may also alter the biological properties of the drug and have significant effects on safety and toxicity [5]. The appropriate salt form for most APIs should be determined early in chemical molecule development to facilitate formulation optimization. It is estimated that half of therapeutic drugs are administered in salt form, making the determination of salt forms for candidate drugs a basic step in drug development [6]. For the same API, different salt forms may have different physicochemical properties, especially solubility, hygroscopicity, stability, flowability, etc. Additionally, the presence of specific impurities related to the salt molecule, either from the synthesis route of that particular salt or from instability and degradation products, may produce toxicity and/or adverse biological activity, differing greatly from the expected clinical use of the drug [7]. Therefore, drugs using different salt forms may lead to different therapeutic effects and bring negative impacts on safety and/or quality. Currently, there is no reliable method to predict the impact of a specific salt form on the in vivo behavior of the parent compound. This article discusses potential issues with salt-modified products from the perspectives of laws and regulations, formulation characteristics, and biological activity.
1 Laws and Regulations Selecting the appropriate salt form for an API is not only crucial in early new drug development but also a key factor in generic drug development. An example is the calcium channel blocker amlodipine, where Pfizer's product is amlodipine besylate tablets, trade name Norvasc. Its original patent expired in 2003, but to compensate for FDA review delays, the patent protection was extended to 2007 [8]. The original patent granted to Pfizer protected the chemical structure of amlodipine besylate and a series of other amlodipine salts. Subsequently, Dr. Reddy's Laboratories in India developed amlodipine maleate and demonstrated its bioequivalence to Norvasc [9]. Dr. Reddy's claimed that Pfizer's patent did not cover amlodipine maleate. However, on February 27, 2004, the U.S. Court of Appeals for the Federal Circuit overturned the U.S. District Court for the District of New Jersey's dismissal of Pfizer's patent infringement lawsuit against Dr. Reddy's generic version of Norvasc, effectively blocking amlodipine generics from entering the U.S. market [10]. For consistency evaluation targets—most marketed drugs—the patent concerns are fewer. But for APIs still under patent protection, patents must be considered when developing generic new drugs.
2 Formulation Characteristics In addition to patent issues, the same API with different salt forms may have different physicochemical properties, especially solubility, hygroscopicity, stability, flowability, polymorphism, etc. Therefore, when developing generics using alternative salt forms, other issues such as solubility, dissolution, bioavailability, toxicity, polymorphism, formulation, and manufacturing processes must also be addressed. Solubility and polymorphism may directly affect the bioavailability of the drug, thereby altering its in vivo behavior.
2.1 Solubility After the active ingredient is released from its formulation, the dissolution rate in gastrointestinal fluids is primarily a function of the API's water solubility. Thus, solid dosage forms of the same active ingredient with different salt bases can exhibit different in vivo dissolution characteristics. According to the basic principles of the Biopharmaceutics Classification System (BCS) [11], for highly permeable drugs, the in vivo dissolution rate is the rate-limiting step and, in some cases, determines the extent of absorption. If a drug has low permeability and relatively good water solubility, in vivo dissolution is not the rate-limiting step in absorption, so differences in water solubility and dissolution are not significant determinants of bioavailability. Numerous literature reports indicate that the same API with different salt bases can significantly alter the aqueous solubility of the API, and the solubility of different salt bases can vary greatly. For example, the antidepressant trazodone is currently available on the market in hydrochloride salt form. To prepare trazodone with lower water solubility than the hydrochloride, various salt forms were once prepared [12]. Among the selected salt bases for evaluation, p-toluenesulfonate and phosphate showed lower water solubility than sulfate and hydrochloride, and p-toluenesulfonate exhibited an interesting solubility profile from 3 mg/ml at pH 1.0 to 0.2 mg/ml at pH 12.0. The low water solubility of mesylate makes it suitable for developing extended-release oral formulations for the elderly, thereby improving compliance in these patients. Compared to hydrochloride, the significantly reduced solubility of mesylate (8-10 times lower in the pH 1-5 range) may lead to absorption of trazodone limited by dissolution rate after oral mesylate [12]. The vast difference in solubility makes it unlikely that these two salts are bioequivalent in vivo. Further elucidation of the impact of specific salt water solubility differences on the therapeutic activity and duration of action of APIs was provided by evaluating the solubility of dextropropoxyphene hydrochloride and naphthoate [13]. Dextropropoxyphene hydrochloride is highly soluble (0.3 parts water per part drug), while the naphthoate is practically insoluble (10,000 parts water per part drug) [13]. Compared to naphthoate, dextropropoxyphene hydrochloride has broader analgesic activity and longer duration of action, partly due to differences in solubility between the two salts [14]. Additionally, compared to the naphthoate drug, oral administration of hydrochloride resulted in higher acute toxicity of dextropropoxyphene in mice, possibly due to the faster absorption rate from the gastrointestinal tract [15].
2.2 Bioavailability Human bioequivalence studies of different salt form drugs reported show that although water solubility differs between different salt bases, no significant differences in bioavailability have been reported. For example, different salt forms of the basic antihypertensive agent have significantly different intrinsic dissolution rates, with no reported improvement in bioavailability. Literature reports no difference in bioavailability between nafimidone oxalate and citrate [16], and in healthy volunteers, after oral quinine hydrochloride, sulfate, and ethyl carbonate, there were no significant differences in quinine's Cmax, Tmax, or AUC [17]. To demonstrate therapeutic equivalence between drugs with the same active ingredient but different salt bases, in vivo bioequivalence studies are required. In special cases, biowaivers can be considered, such as when both salts are highly soluble and highly permeable, i.e., both belong to BCS Class I compounds. In such cases, if the oral immediate-release formulation dissolves rapidly in vitro and meets some additional conditions, a BCS-based biowaiver for in vivo BE studies can be requested [18].
2.3 Polymorphism Polymorphism is often a key factor in determining salt bases. Polymorphism refers to the ability of a drug to exist in two or more crystalline forms, where crystalline form refers to different molecular structures and/or conformations in the crystal lattice [9]. Polymorphism is a common phenomenon in all APIs, and the most critical issue related to API polymorphism is equilibrium solubility, which is an important determinant of dissolution rate, and equilibrium solubility in turn affects the bioavailability of the active drug [19]. Many examples show differences in oral bioavailability of active ingredients in solid dosage forms related to polymorphism, including chloramphenicol palmitate and camazepam base [20,21]. Therefore, to overcome solubility and other challenges in producing drugs with different salt forms, studying polymorphism is crucial. Thorough research helps generate appropriate APIs, preparing for scale-up production and subsequent formulation manufacturing.
2.4 Solid-State Properties The solid-state properties of molecules and their properties in solution can be altered by different salt forms. Selecting the appropriate salt form for a specific route of administration or dosage form requires thorough investigation of all relevant solid-state characteristics of candidate salt bases before proceeding with product development.
3 Toxicity and Safety In addition to patent issues, several important concerns need attention: What studies are needed to ensure that API drugs in a specific salt form have comparable pharmacokinetic, pharmacologic, toxicologic, and safety profiles to approved drugs with the same API in a different salt base? Furthermore, for pharmaceutically equivalent drugs proven to be bioequivalent, how likely is it that they have different clinical safety and efficacy?
3.1 Safety Issues from Instability As mentioned earlier, different salt forms of the same API may exhibit changes in physicochemical characteristics, including but not limited to solubility and hygroscopicity. Even in dosage forms such as tablets, increased hygroscopicity may reduce API stability, especially when the API is prone to hydrolytic degradation, with more severe impacts. Additionally, for different salt forms of the same API, thermal stability and degradation pathways may differ, requiring appropriate toxicologic and/or other studies to assess new degradation products. Taking amlodipine as an example again, compared to besylate, the instability of maleate leads to the formation of degradation products with significant impacts on safety and toxicity. Unlike besylate, amlodipine maleate has inherent chemical instability, leading to the formation of N-(2-{[4-(2-chlorophenyl)-3-(ethoxycarbonyl)-5-(methoxycarbonyl)-6-methyl-1,4-dihydro-2-pyridyl]methoxy}ethyl)aspartic acid. This impurity is biologically active and formed by an intramolecular reaction of unsaturated maleic acid with the primary amine group of amlodipine. Evidence indicates that this aspartic acid derivative has biological properties distinctly different from amlodipine itself. Although low levels of impurities may not lead to serious clinical consequences, the instability of maleate suggests that higher impurity levels may manifest after formulation production and long-term storage. Therapeutic equivalence between the two drugs not only implies the same efficacy but also the same safety profile. The potential differences in toxicity and stability between the above amlodipine maleate and besylate indicate that, for salt-modified products, in addition to achieving in vivo bioequivalence with the marketed product, toxicologic evaluation of the salt-modified product may also be necessary to determine therapeutic equivalence.
3.2 Salt Toxicity API salt toxicity may be due to the conjugate anion or cation used for salt formation [5]. Reports show that maleic acid anion in maleate pralidoxime exhibits nephrotoxicity and causes renal tubular lesions in dogs [22]. The safety of salt formers largely depends on their physicochemical properties and biological characteristics. The necessity to study the toxicity of specific salt formers generally requires first understanding whether they have been used in other pharmaceutical products, foods, and beverages, as well as the relative proportions of the salt former and active substance. When the active substance salt form is prepared from a new salt former with little or no toxicity information, toxicity studies on all new salt forms of the active substance are required, and it is also necessary to study the toxicity of the salt former separately. Differences in toxicity profiles among multiple salt bases of APIs may arise from the formation of potentially toxic chemical impurities during the preparation of specific salt forms of APIs. Therefore, it is necessary to assess the potential toxicity of all impurities formed and isolated during the synthesis of specific salt form APIs. For example, methanesulfonic acid is used to prepare mesylate salts of active basic drug molecules such as peginterferon, nelfinavir, imatinib, and amlodipine. The potential health hazards of trace methanesulfonate esters in drugs, including methyl methanesulfonate, ethyl methanesulfonate, and isopropyl methanesulfonate, have attracted the attention of health authorities [23]. These impurities are formed during the manufacturing of active substance mesylates by the reaction of methanesulfonic acid with solvents such as methanol, ethanol, and isopropanol. Additionally, the use of alcohol solvents during formulation production may also generate these impurities, leading to potentially unsafe formulations. Methanesulfonates are known strong mutagens, carcinogens, and teratogens. Therefore, when production and preparation routes for different salt bases of the same API lead to different chemical byproducts, the potential toxicity of these impurities should be assessed through preclinical trials for each salt type in synthesis/preparation.
3.3 Tolerability In addition to safety and toxicity issues, the tolerability of an API under a specific route of administration may also be affected by the specific salt form of the drug. For example, for oral drugs, the potential for the API to cause gastrointestinal irritation and/or ulcers may be partly due to differences in water solubility and dissolution rates among different salt bases of the drug. For instance, in a porcine esophageal model, the effects of five different salt forms of apraclonidine and placebo on ulcer formation were compared [24]. Highly water-soluble hydrochloride and fumarate salts of apraclonidine resulted in the highest plasma API concentrations and induced severe esophageal lesions, while benzoate, maleate, and sebacate—the low water-solubility salts—had no irritating effects on the esophagus. Additionally, compared to intraduodenal administration of the same dose and salt form, intraesophageal injection of apraclonidine hydrochloride resulted in much higher plasma levels of apraclonidine, possibly due to avoidance of first-pass hepatic metabolism after esophageal absorption, leading to higher bioavailability.
In summary, for salt-modified products, achieving bioequivalence with the originator product is not sufficient; comprehensive evaluation of specific impurities, stability, polymorphic characteristics, and resulting safety, toxicity, and tolerability issues should be conducted based on the product's physicochemical properties and synthesis route. For newly developed products, when considering modification of salt forms, in addition to the above issues, legal and regulatory aspects such as patents should also be considered.
Declaration The content of this article is solely for academic scientific discussion and does not serve as a basis for registration applications.
