Drug salts

Ledwidge, M. T. Corrigan, O. I., Effects of surface active characteristics and solid state forms on the pH solubility profiles of drug-salt systems, Int. J. Pharm. 174, 187-200 (1998). 

Altria, K. D., Wood, T, Kitscha, R., and Roberts-Mcintosh, A. (1995). Validation of a capillary electrophoresis method for the determination of potassium counter-ion levels, in an acidic drug salt. /. Pharm. Biomed. Anal. 13(1), 33 — 38. 

Noteworthy are the articles from Altria et al. and Assi et al. describing the robustness and validation of the determination of potassium as a counterion. An intercompany cross-validation of the determination of sodium in an acidic drug salt was also published. 

Inter-company cross-validation of sodium in acidic drug salt... 

In conclusion, the remarkable influence on DAP activity exerted by the low-viscosity PGA vehicles is an issue deserving further attention, in view of the possible implication of a muco-adhesive mechanism. A closer study of the potential interactive properties of polyuronic acids and of their drug salts with the precorneal mucin might lead to a better understanding of the bioadhesive properties of these and other similar anionic polymeric materials, and of their influence on ocular drug bioavailability. 

Source Data from Agharkar, S., S. Lindenbaum, and T. Higuchi. (1976). Enhancement of solubility of drug salts by hydrophilic counterions Properties of organic salts of an antimalarial driJgPharm. Sci. 65 747-749. Copyright 1976 American Pharmaceutical Association, and reprinted with permission of Wiley-Liss, Inc., a subsidiary of John Wiley Sons, Inc. 

TABLE 7 Various Counterions Used to Form Drug Salts... 

The properties of the drug (salt form, crystalline structure, formation of solvates, and solubility). 

The formulations of an IDDS are the ingredients in the drug and counter reservoirs, which typically consist of a solvent, a drug salt or a biocompatible salt, and a matrix-forming material. A formulation may also include additives such as buffers, antimicrobial agents, antioxidants and additional electrolyte salts or permeation enhancers. All of these can interact in a complex fashion to affect rate of delivery, biocompatibility, and product shelf life. 

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 A-cyclohexylsulfamic acid (cyclamate) as the counterion can render bitter drugs such as dextromethorphan and chlorpheniramine palatable. ... 

A wide range of potential counterions exists with potential for drug salt formation. However, the actual choice is restricted because of the known or uninvestigated toxicity of many potential counterions. Therefore, consideration must be given to any likely pharmacological and toxicological actions of the counterion. Examples of counterions in use, which have pharmacological actions and potential for toxicity, are lithium, copper, aluminum, calcium, and ammonia. The bromide ion, which has inherent sedative actions also has a 12-day half-life, may accumulate in the body and cause bromism, while iodide can produce iodism. 

Table 3 Examples of pharmacological/toxicological issues relating to drug salt forms...

Dissociation of HCl or HBr from drug salts may occur, resulting in the release of the hydrohalide gas.f 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. 

Cracking of tablets, because of conversion on high humidity storage of the anhydrous HCl drug salt to a hydrate form has been reported. ... 

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 impact on processability, dissolution rate, and bioavailability, without... 

Cj (solubility in diffusion layer) That of weak electrolytes altered by change in pH, by use of appropriate drug salt or buffer ingredient (-)(+)... 

EXAMPLE 3.8 Calculation of the pH of drug salts Calculate the pH of the following solutions... 

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