Neutral drug substance

Composite Assay Method for a Neutral Drug Substance... 

Figure 8.9. HPLC chromatogram of an isocratic composite method for a neutral drug substance.

Tables 7.12-7.14 list the pH 7.4 permeability and retention values of the probe series of drug substances, grouped as bases, acids, and neutral molecules. Figures 7.31a-c are graphs of the effective permeabilities with and without sink as a function of increasing soy content, beginning with 2% DOPC for a benchmark. Figures 7.32a-c are plots of the corresponding membrane retentions.

Information on chemical structure, molecular weight, nature of the drug substance (acid, base, amphoteric, or neutral), and dissociation constants (pKa(s))... 

Clopidogrel bisulfate has been reported to be freely soluble in methanol, sparingly soluble in methylene chloride, and practically insoluble in ethyl ether and in water at neutral pH. At pH 1, the compound is freely soluble in water [3], which is one of the reasons why the hydrogen sulfate salt is the preferred form of the drug substance. 

Issa et al. [9] used various metal ions for the volumetric determination of mefenamic acid. Mefenamic acid was precipitated from its neutral alcoholic solution by a standard solution of either silver nitrate, mercurous acetate, or potassium aluminum sulfate. In the argentimetric procedure, residual Ag(I) was titrated with standard NH4SCN. With Hg(OAc)2 or potash alum, the residual metal was determined by adding EDTA and conducting back titration of excess of EDTA with standard Pb(N03)2 using xylenol orange indicator. The applied methods were used for the determination in bulk drug substance, and in its formulations. 

Dual cyclodextrin systems can be developed to provide impressive selectivity of separation [30—32], A typical recipe uses 0.5-1 mM of a charged CD and 5-10 mM of a neutral CD. The development of a dual-CD system chiral separation of secondary amine drug substances is illustrated in Figure 4 using various blends of CDs. A complete separation is only found in run (d), where the buffer contained 5 mM of a neutral and 1 mM of a charged CD. 

The separation selectivity of a mixture of acidic, basic, and neutral compounds can be altered with the addition of chaotropic mobile-phase additives (Figure 4-62). The retention of the basic compounds can be increased by addition of chaotropic counterions in the mobile phase, while the retention of neutral and acidic compounds is generally unaffected. This is particularly useful during the development of impurity profile methods in the pharmaceutical industry where the retention of a polar protonated basic impurity may be adjusted such that adequate separation selectivity is obtained when union-izable, acidic, or basic (in neutral form) impurities in the drug substance are present. In Figure 4-62 the retention of protonated basic compounds, metoprolol and labetalol, increase while the retention of phenol (in its neutral state) remains constant. 

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. 

The dissolution rate of a drug substance is related to its aqueous solubility. For neutral drugs there is a direct correlation between the solubility and dissolution rate as demonstrated by the Noyes and Whimey equation (37.11). However, depending on the pH of the dissolution medium... 

A large proportion of drug substances, whether neutral molecules, free adds, free bases or salts, are capable of exhibiting polymorphism or pseudopolymorphism (hydrate or solvate formation). It has been reported that 70% of barbiturates, 60% of sulfonamides and 23% of steroids exhibit polymorphism." Polymorphism often influences a range of physicochemical properties such as solubility, dissolution rate, stability and powder properties as well as bioavailability. Usually, it is possible to determine the most stable polymorph and discover recrystallization solvents that uniquely produce this form and improve the physicochemical and physicome-chanical properties and chemical stability of the drug. 

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