Candidate drug salt selection

Furthermore, pharmacokinetic administration, distribution, metabolism and excretion (ADME) factors affect drug bioavailability, efficacy and safety, and, thus, are a vital consideration in the selection process of oral drug candidates in development pipelines. Since solubility, permeability, and the fraction of dose absorbed are fundamental BCS parameters that affect ADME, these BCS parameters should prove useful in drug discovery and development. In particular, the classification can used to make the development process more efficient.For example, in the case of a drug placed in BCS Class II where dissolution is the rate-limiting step to absorption, formulation principles such as polymorph selection, salt selection, complex formation, and particle size reduction (i.e., nanoparticles) could be applied earlier in development to improve bioavailability. 

Salt formation may be key for the efficient purification of ionizable compounds. Various salts can display different solubilities and tendencies to crystallize and might possess physicochemical differences that can be exploited for convenient processing on scale. Salt forms of drug candidates are selected for desired stability, bioavailability, and formulation characteristics (Chapter 12). A few trends for salt selection are shown in Table 11.4. 

So far, no definitive decision mechanisms covering the choice of salt formers have been developed, so the final evaluation and selection process remains essentially empirical to a large extent. In addition to the reasons mentioned earlier that in the major pharmaceutical companies the search for crystalline salts occurs very early along the development timeline, there is further reason. Preclinical investigations are necessarily initiated at a time when the candidate drug substance is usually impure (often around 95% pure) and material is at a premium. Here the formation... 

KR Morris, MG Fakes, AB Thakur, AW Newman, AK Singh, JJ Venit, CJ Spag-nuolo, ATM Serajuddin. An integrated approach to the salt selection of optimal salt form for a new drug candidate. Int J Pharm 105 209, 1994. 

Classical QSAR will continue to play its part in the optimization and selection of drug candidates. A fundamental difficulty with classical (property-based) QSAR is an over-reliance on the relevance of hydrophobicity, electrostatic and simple bulk steric effects as determinants of relative potency. We know that conformation is crucially important, but this is ignored in the classical approaches. The need for a structure-based QSAR method which also incorporates conformational flexibility might be met by development of a neural network (Livingstone and Salt, 1992 So and Richards, 1992) or machine learning program (King et al., 1992). 

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. 

A variety of factors need to be considered when selecting the optimum chemical form of a new drug candidate. These include all physicochemical properties which would influence physical and chemical stability, processability under manufacturing conditions, dissolution rate, and bioavailability. Such selection of chemical form must be done at the initial stages of development, when material and time are limited. Often the medicinal and process chemists select salt forms based on a practical basis, such as previous experience with the salt type, ease of synthesis, reaction yield, etc. Pharmaceutical considerations such as stability, handleability, hygroscopicity, and suitability for a specific dosage form may be secondary considerations. 

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