Salt form selection based

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. 

Urns-Epoxides. This unstable ylide (1), when generated as formulated above, reacts with an aliphatic aldehyde at —78° to give a fram-epoxide with almost complete stereoselectivity. The stereochemical selectivity is markedly dependent on the base and also on the counterion of the arsonium salt. Optimum selectivity for the trans-epoxide is obtained with conditions similar to those that induce cis-olefination in Wittig reactions.2 Stereoselection is not so high with aromatic aldehydes. The reagent also reacts with ketones to form trisubstituted epoxides. 

Stage II Selection of acid/base/salt form (3-25)... 

Oral dmg product formulation and manufacturing process development can use a hierarchical approach to meeting three conditions based on, in order of importance, bioavailability, stability, and manufacturability. The bioavailability of a drug product is the most critical condition and must meet established criteria or the product is not viable. Dmg substance properties such as salt form, solubility, and particle size can significantly affect pharmacokinetic and pharmacodynamic performance of a product. The dosage form platform, formulation design, and manufacturing process can also affect the PK/PD profile of a product. Therefore, all selections must maintain the required pharmacokinetic/pharmacodynamic outcome and work within these confines to achieve a stable and robust product/process. 

The stability, both chemical and physical, of a drug may be enhanced or retarded by salt formation. For example, solid dosage forms of diclofenac contain salt forms rather than the less stable free acid. Although salt formation may result in improved dissolution rate and bioavailability of a poorly water-soluble compound, the preparation of stable salt forms for some drugs may not be feasible and the free acid or base forms may be preferred. For example, the base form of a-pentyl-3-(2-quinolinylmethoxy)benzenemethanol was selected for dosage form design because of the physical instability of its hydrochloride salt. ... 

Because a balance between different salt properties needs to be taken into consideration in assessing the correct salt form to progress into drug development, some decision-making models have been developed to aid in the selection of an appropriate salt form. Gould described a salt selection process based on melting point, solubility, stability, wettability, etc. of various salt forms. However, in the absence of clear go/no go decisions at any particular stage of the salt selection process, this approach would lead to the... 

To illustrate the ARS form selection process, two pharmaceutical examples of ARS form selection are provided. Indinavir sulfate is the API for Crixivan , a specific and potent inhibitor of the HIV-1 protease used in the treatment of AIDS. Indinavir sulfate is produced as a crystalline ethanolate sulfate salt. If the material is stored in double polyethylene liners within fiber containers or repeatedly exposed to ambient conditions changes occur in both crystallinity and solvation. Using XRPD, KF, and RP-HPLC, conversion of the crystalline ethanolate to amorphous material or to a hydrate crystal form has been detected and degradation is observed. However, the material is stable if stored in a tightly sealed container impermeable to ethanol/moisture transport under an inert nitrogen atmosphere at a controlled room temperature.82,83 These storage conditions are not practical for a routinely used ARS. Therefore, the free base monohydrate form of indinavir sulfate was evaluated and selected as the ARS. This form of the API was demonstrated to be extremely stable under ambient conditions needed for routine analysis. 

Chao and Cheng [76CHA/CHE] studied the determination of a number of anions, single or in mixtures, by a stepwise potentiometric titration with silver nitrate at pH = II. The silver ion activity was measured with a silver ion selective electrode based on silver sulphide. The data were also used to estimate the solubility products of the silver salts formed during a titration. The method is only sketched in the paper but appears to have proceeded along the following course. The potential of incipient precipitation ( prec) was estimated graphically from the shape of the titration curve. p,ec would thus be a measure of the silver ion activity at the nominal and known concentration of the anion in the presence of its silver salt. 

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. 

Determine the acid-base character of the functional groups in the two molecules drawn above as well as the salt form of codeine phosphate. As originally drawn above, which of these two agents is more water soluble Provide a rationale for your selection that includes appropriate structural properties. Is the salt form of codeine phosphate more or less water soluble than the free base form of the drug Provide a rationale for your answer based on the structural properties of the salt form of codeine phosphate. What is the chemical consequence of mixing aqueous solutions of each drug in the same IV bag Provide a rationale that includes an acid-base assessment. 

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