Preformulation salt selection

Gu, L. and R. G. Strickley. 1987. Preformulation salt selection. Physical property comparisons of the tris(hydroxymethyl)aminomethane (THAM) salts of four analgesic/antiin ammatory agents with the sodium salts and the free acid iarm. Res4 255-257. 

In preformulation studies, the stability and potential formulation issues must be considered before the Lnal salt selection is made. 

The formulation, manufacturing process, analytical development, and long-term toxicology studies in animals are parallel to the clinical investigation (Table 1.1). Clinical trial materials should be developed, manufactured, tested, and released before conducting a phase I clinical trial. Process chemists may redesign the synthetic route for the dmg candidate to meet the requirements of large-scale production in a pilot plant. Preformulation scientists complete the activities of salt selection,... 

The pH rate profile is an important parameter that is studied in the solution state. In early preformulation studies, an approximate pH rate profile is generated, usually including the pH encountered in salt selection and in vivo [55], The studies are later followed with a detailed pH profile in the whole pH range of 1-10. A typical pH rate profile is shown in Figure 18, which is useful to extract useful information on... 

Michael J. Bowker studied chemistry and received his doctorate in Organic Chemistry from the University of Leeds, UK. After 5 years working for a multinational polymer company, he moved to May Baker Ltd., a UK subsidiary of Rhone-Poulenc Sante (now Sanoli-Aventis). He was a Director of Analytical Chemistry for about 15 years and, more recently. Director of Preformulation at Aventis Pharma Ltd. He has been intimately involved in preformulation and solid-state activities, on a worldwide basis for more than 15 years. He has published several research papers and one chapter for a book on pharmaceutical salts and is currently a Director of M. J. Bowker Consulting Limited, a small company undertaking consultancy in salt selection, polymorph selection and pharmaceutical preformulation. 

One way in which the transport of zwitterionic drugs through skin has been enhanced is by salt formation. This was demonstrated by Mazzenga et al. (1992) who showed that the rank order of epidermal flux of the salts of phenylalanine across the epidermis was hydrobromide > hydrochloride > hydrofluoride > phenylalanine. Thus, like most other delivery routes, it is worth considering salt selection issues at the preformulation stage to optimize the delivery of the compound via the skin. 

Hence it is important to study this effect during preformulation by testing the solubility of the salt in the presence and absence of sodium chloride. Although salts do not alter the pharmacological activity of the drug, safety is an important consideration in the selection of salts. From this perspective, salts are treated as a new molecule by the FDA. The safety of the salt is evaluated with respect to its route of administration and dose of the drug [37],... 

After the preformulation studies have been performed and appropriate pharmacokinetic parameters considered, the most suitable salt form can be proposed and decided upon. Subsequently, when more material is available, a more comprehensive range of preformulation studies can be carried out on the selected salt to assist in formulation development. 

To assist in the selection of the salts for the final drug substance for IND and subsequent NDA, a number of salts based on available information must be prepared and tested in the preformulation program with the following properties taken into account ... 

Additional preformulation and physicochemical characterization of the candidate compound are performed and stress stability studies may be initiated. Ideally, the optimal solid state (polymorphic) and chemical (salt) form of the molecule are identified as part of clinical candidate selection. Selection of the most stable and bioavailable form will expedite subsequent development. The methods for testing the drug substance are refined and additional methods may be developed. 

Solid-state characterization is one of the most important functions of the preformulation group, which is assigned the responsibility of making recommendations for further formulation work on a lead compound. Physical properties have a direct bearing on both physical and chemical stabilities of the lead compound. Much of the later work on formulation will depend on how well the solid state is characterized from the decisions to compress the drug into tablets to the selection of appropriate salt forms. The studies reported in this section, of course, apply to those drugs that are available in solid form, crystalline or amorphous, pure or amalgamated. 

L Gu, O Huynh, A Beccker, S Peters, H Nguyen, N Chu. Preformulation selection of a proper salt for a weak acid-base (RS-82856)—A new positive inotropic agent. Drug Dev Ind Pharm 13(3) 437, 1987. 

The key information that will be obtained from a solid-state technique will describe the crystal form of the API. Once a salt form is selected, the crystalline nature of the API will be fully characterized. Any potential polymorphic forms, hydrates, or cocrystals will be identified. The drug substance itself should not convert from the initial crystalline habit, into any different form dm-ing storage at normal storage condition, or ideally, during accelerated stability. This is critical preformulation information that must be established before drug product development. 

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