Salt selection

For ionic drugs the salt form can be considered as an alternative to increase the solubility. Drug substance usually is more soluble in aqueous media in its ionic form. Low solubility of the neutral form of the drug substance suggests the necessity to formulate it in the form of salt. The reader is referred to reference 46 for more information about the properties, selection, and use of salt forms for future drug development. Examples of commonly used salt counterions are shown in Table 12-6. 

Salt form selection is mainly covered by solid-state charactezation methods, and HPLC is only used to determine the solubility and solid/solution stability of different salt forms. The requirements for HPLC method development is the same as for solubility/stability determination described previously, and the same HPLC method may be applied. 

Measurement of the key physiochemical properties of solid forms of lead candidates is essential during the early discovery process, not only from manufacturing and regulatory perspectives, but from a formulation viewpoint as well, where dosage form, processability, and compatibility with other excipients are the key issues. Some of the key physical, chemical, and biologically relevant properties that should be evaluated comprehensively prior to making a hnal decision on salts for further development are listed in Table 24.2. 

TABLE 24.1 Classification of Commonly Accepted Pharmaceutical Salts 

Inorganic acids Hydrochloride, hydrobromide, sulfate, hydrogen sulfate, nitrate, phosphate 

Sulfonic acids Mesylate, esylate, tosylate, napsylate, besylate 

Carboxylic acids Acetate, propionate, maleate, benzoate, salicylate, fumarate 

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Finally, none of the ionic liquids were found to be hydrogen bond acids [5], although this may well be a consequence of the salts selected, none of which had a cation that would be expected to act as a hydrogen bond donor. Earlier qualitative measurements on ionic liquid stationary phases of mono-, di-, and trialkylammo-nium salts suggest that hydrogen bond donation can be important where a potentially acidic proton is available [7-9]. More recent work, with [BMIM] salts, also indicates that these ionic liquids should be considered to be hydrogen bond donor solvents [10]. However, this has yet to be quantified. 

Triarylpyrylium salts react with hydrazine to give 4//-l,2-diazepines 472-1°s,ioo vja g unstable intermediates 3.110 The reaction fails with pyrylium salts containing alkyl groups in positions 2 and 6, with the exception of 2,4,6-tri-tert-butylpyrylium perchlorate. In some cases it is advantageous to use a thiapyrylium salt in place of the pyrylium salt. Selected examples are given. 

With electron-deficient aromatic substrates (Entries 4 and 5), high yields and selectivities were observed, but enantioselectivities were variable and solvent-de-pendent (compare Entry 6 with 7 and see Section 1.2.1.3 for further discussion). With a,P-unsaturated tosylhydrazone salts, selectivities and yields were lower. The scope of this process has been extensively mapped out, enabling the optimum disconnection for epoxidation to be chosen [10]. 

Scaleup of drug substance (e.g., 2 g) Salt selection and physical properties Formulation development... 

Salt selection may help to improve various properties of a drug substance such as bioavailability, stability, and manufacturability. 

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

Morris et al. (1994) pointed out that this selection approach could be improved if the salt-selection process involved a decision, in the case of each salt form under consideration, to pursue... 

Bowker, M. J. 2002. A procedure for salt selection and optimizatioridindbook of Pharmaceutical Salts ... 

Gould, P. L. 1986. Salt selection of basic drulgtf. J. Pharm.33 201-217. 

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. 

Serajuddin, A. T. M. and M. Pudipeddi. 2002. Salt-selection strategiefelahidbook of Pharmaceutical... 

Pitman, I. H. 1976. Three chemical approaches towards the solubilisation of drugs control of enantiomer composition, salt selection, and pro-drug formatiAnstr. J. Pharm. ScNS5 17-19. 

Equation (4.9) shows that concentration polarization increases exponentially as the total volume flow Jv through the membrane increases. This is one of the reasons why modem spiral-wound reverse osmosis membrane modules are operated at low pressures. Modem membranes have two to five times the water permeability, at equivalent salt selectivities, of the first-generation cellulose acetate reverse osmosis membranes. If membrane modules containing these new membranes were operated at the same pressures as early cellulose acetate modules, two to five times the desalted water throughput could be achieved with the same... 

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