Salt form selection

Engel GL, Earid NA, Eaul MM, Richardson LA, Winneroski LL. (2000) Salt form selection and characterization of LY333531 mesylate monohydrate. Int J Pharm 198 239-247. 

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. 

The importance of identifying the mode of delivery to the lung (i.e., nebulizer, MDI, DPI) as early as possible cannot be overemphasized. A drug salt form selected assuming development of a propellant-based MDI suspension formulation may be wholly unsuited for application in an aqueous-based nebulizer suspension on the basis of solubility and crystal growth potential. Physicochemical properties and stability issues considered to be of importance in the development of inhalation formulations are discussed later, as they relate to the individual dosage forms. 

Salt forms of a strong base anion exchangerare used to remove other anions for which the resin has greater selectivity. 

Weak base resins when in the free base (hydroxyl) form are not capable of splitting neutral salts such as sodium chloride. Salt forms of weak base resins release anions to the Hquid phase if other ions for which the resin has a greater selectivity are present. 

Nitroso compounds are formed selectively via the oxidation of a primary aromatic amine with Caro s acid [7722-86-3] (H2SO ) or Oxone (Du Pont trademark) monopersulfate compound (2KHSO KHSO K SO aniline black [13007-86-8] is obtained if the oxidation is carried out with salts of persulfiiric acid (31). Oxidation of aromatic amines to nitro compounds can be carried out with peroxytrifluoroacetic acid (32). Hydrogen peroxide with acetonitrile converts aniline in a methanol solution to azoxybenzene [495-48-7] (33), perborate in glacial acetic acid yields azobenzene [103-33-3] (34). 

Trichloro- and dichloromethane, ether, dioxane, benzene, toluene, chlorobenzene, acetonitrile, or even pyridine itself has been employed to carry out the one-pot syntheses. Tliese solvents allow straightforward preparation of the salts. The temperature range between 0° and 20°C is usually employed and the salts formed are sufficiently soluble. In the case of slow reactions, selection of a solvent with a higher boiling point is prohtable since thermal instability of the A -(l-haloalkyl)heteroarylium halides has not been reported. Addition of water or an aqueous solution of sodium acetate does not cause a rapid decomposition of the salts so that this constitutes a useful step in the optimization of some procedures. 

When sulfates, carbonates, and other dissolved BW salts exceed their individual maximum solubility limits, they form sludges, scales, and deposits. This situation may arise either from a general overconcentration of the BW TDS (high COC) or from the deliberate precipitation of salts of selective ions, as occurs when using phosphate precipitation programs. 

Selective or preferential extraction of diastereomeric salts formed from sulfoxide carboxylic acids and alkaloids in water relative to the reciprocal diastereomeric salts has been studied33. 

Anions of weak acids can be problematic for detection in suppressed IEC because weak ionization results in low conductivity and poor sensitivity. Converting such acids back to the sodium salt form may overcome this limitation. Caliamanis et al. have described the use of a second micromembrane suppressor to do this, and have applied the approach to the boric acid/sodium borate system, using sodium salt solutions of EDTA.88 Varying the pH and EDTA concentration allowed optimal detection. Another approach for analysis of weak acids is indirect suppressed conductivity IEC, which chemically separates high- and low-conductance analytes. This technique has potential for detection of weak mono- and dianions as well as amino acids.89 As an alternative to conductivity detection, ultraviolet and fluorescence derivatization reagents have been explored 90 this approach offers a means of enhancing sensitivity (typically into the low femtomoles range) as well as selectivity. 

If a reference "teaches away" from some research activity (e.g., selecting a particular chemotype for modification, modifying a chemo-type in a specific fashion, or making a particular salt form), note this in the laboratory notebook and in the invention disclosure form. 

The results of the polymorph screening step in combination with bioavailability studies, provide the information required by the clinical research team to nominate the desired crystal form of the API for long term manufacture and formulation. This form will usually be the most stable polymorph, where a number of forms have been identified, or a salt form if bioavailability is low or when there are formulation concerns regarding polymorph stability. In some cases it may be necessary to select an amorphous form or metastable polymorph because of crystallization difficulties, time constraints or bioavailability requirement. The nomination of a hydrate or solvate is generally avoided because of their relative instability and compositional variability such constraints are less of a concern for the earlier synthetic intermediates. 

Alkylation of P-dicarbonyl compounds and p-keto esters occurs preferentially on the carbon atom, whereas acylation produces the 0-acyl derivatives (see Chapter 3). There are indications that C- and 0-alkylated products are produced with simple haloalkanes and benzyl halides, but only C-alkylated derivatives are formed with propargyl and allyl halides [e.g. 90]. Di-C-alkylation frequently occurs and it has been reported that the use of tetra-alkylammonium 2-oxopyrrolidinyl salts are more effective catalysts (in place of aqueous sodium hydroxide and quaternary ammonium salt) for selective (-90%) mono-C-alkylation of p-dicarbonyl compounds [91]. 

The resin-bound 1,3-oxazinium salt 116, obtained by oxidation of 4//-l,3-oxazines 115 with 2,3-dicyano-5,6-dichloro-p-benzoquinone (DDQ), behaved as /3-diketone equivalents and formed pyrazoles 117 through a functionalizing release process on treatment with hydrazines (Scheme 18). When the hydrazines were substituted (R = Me, Ph), the oxazinium salts reacted selectively to afford one regioisomer 117 <2004JC0846>. 

In a related study (78CC934,79HCA2763) Lehn and coworkers incorporated guanidinium groups into macrocycles (e.g. 29). The resulting polyguanidium salts form stable complexes in water with phosphate and carboxylate anions. Unlike polyammonium anion receptors, these species remain protonated over a wide pH range and hold considerable potential in the development of anion-selective electrodes. 

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