Solubility-pH Profiles

Chowhan, Z. T. pH-solubility profiles of organic carboxylic acids and their salts. 

Molecular structure and weight Melting point Thermal profile Particle size and shape Hygroscopicity potential Ionization constant Light stability Optical activity pH solubility profile pH stability profile Polymorphism potential Solvate formation... 

Todd, D. Winnike, R. A., A rapid method for generating pH-solubility profiles for new chemical entities, Abstr. 9th Ann. Mtng., Amer. Assoc. Pharm. Sci., San Diego, 1994. 

Chowhan, Z. T., pH-solubility profiles of organic carboxylic acids and their salts, J. Pharm. Sci. 67, 1257-1260 (1978). 

Streng, W. H. Tan, H. G. H., General treatment of pH solubility profiles of weak acids and bases, n. Evaluation of thermodynamic parameters from the temperature dependence of solubility profiles apphed to a zwitterionic compound, Int. J. Pharm. 25, 135-145 (1985). 

Ledwidge, M. T. Corrigan, O. I., Effects of surface active characteristics and solid state forms on the pH solubility profiles of drug-salt systems, Int. J. Pharm. 174, 187-200 (1998). 

The pH-solubility profile has been studied by these workers and also by Takasugi and coworkers. (13)... 

Drug dissociation constants are experimentally determined by manual or automated potentiometric titration or by spectrophotometric methods.40 Current methods allow determination of pXa values with drug concentrations as low as 10 to 100 pM. For highly insoluble compounds (concentration <1 to 10 pM), the Yesuda-Shedlovsky method41 is commonly used where organic cosolvents (i.e., methanol) are employed to improve solubility. The method takes three or more titrations at different cosolvent concentrations, and the result is then extrapolated to pure aqueous system. The dissociation constant can also be determined with less accuracy from the pH-solubility profile using the following modification of Henderson-Hasselbach equation ... 

When restrictions are not placed on the amount of time or the amount of material, different solvents or different quantities of acid or base are usually used as variables. It is not only important to know the solubility of the compounds in aqueous solutions but also in other solvents to which the compound might be exposed during synthesis and formulation. The solvents usually have a wide range of dielectric constants and the experimental results provide a solubility profile which can be utilized in the selection of appropriate solvents to use during the development of the compound. Since the compounds almost always selected for development are either weak acids or weak bases, the solubilities of the compounds will be pH-dependent. The use of different amounts of acid or base with an excess amount of compound permits the determination of a pH-solubility profile. 

A quick means to identify whether or not a drug may be more suitable for solution or suspension is to overlap the pH-stability profile with the pH-solubility profile. This overlap creates a window, which may suggest which dosage form might be most desirable and subsequently the type of excipients needed. The overlapped figures below demonstrate for aspirin (which is a weak acid) that the pH of greatest stability is also the pH at which there is low solubility (Fig. 1). 

FIGURE 1.16 pH-Solubility profile of atorvastatin calcium, as predicted using the advanced chemistry development program. 

Avdeef introduced an alternative approach. Aliquots of DMSO stock solutions are pipetted robotically into incubation well plate containing an aqueous buffer. The concentration of the test compound should be between 50-150 iM in order to keep the DMSO content below 0.5 %. After a time of incubation, the plate is filtered and the solved compound is quantified with an UV plate reader. The method is fast, robust and reported to be reliable (Kerns). 200-300 compounds can be measured per day. Additionally, pH solubility profiles can be set up easily (Kibbey). 

The pKa is dissociation constant for a given media. It is a parameter which indicates the ionization state at a given pH and describes the acidity of a compound in a special medium. In drug discovery it is a valuable parameter for S ARs but also helps in the interpretation of pH-solubility profiles. For an acid ... 

Drugs may also have more than two pKa values, such as polyprotic or polybasic compounds (e.g., minocycline), and such drugs exhibit a complex pH solubility profile. It is essential to know per se pH of the drug solution during preformulation studies. The pH is measured or theoretically calculated if the pKa and drug concentration C are known. The pH of a weak acid or the salt of a weak base and a strong acid can be calculated using the equation... 

Figure 3 Theoretical pH-solubility profile in titration regime for a weak base with pK =9.6 (thick line). It represents changes in solubility when a saturated solution of the base at pH=14 is slowly titrated with a strong acid HX to pH =0 (titration regime), saturation maintained at all times. The profile is a minimal combination of two curves represented by Equation (6) (free-base region) and Equation (8) (salt region), respectively. A sharp decrease in solubility at pH

In the early stage of preformulation, characterization of the drug molecule involves ionization constants and partition coefficient determinations, aqueous and nonaqueous kinetic and equilibrium solubility determination, pH solubility profile, chemical stability assessment, and salt and polymorph screening. Assessment of biopharmaceutics and toxicological screening are also essential... 

An objective of preformulation scientist is to determine the equilibrium solubility of a drug substance under physiological pH to identify the BCS class of drug candidate for further development. For BCS classification the test conditions are strictly defined by the FDA. The pH solubility profile of the test drug substance should be determined at 37°C in aqueous media with a pH in the range of 1-7.5. Standard buffer solutions described in the USP are considered to be appropriate for use in these studies. A number of pH conditions are used bracketing the pKa value for the respective test substance. For example, for a drug with a Ka of 5, solubility should be determined at... 

The pH-solubility profiles are very similar to the pH-log D profiles however, it is more difficult to estimate the solubility of the charged form of molecules. The reason for this is that the counter-ions in the aqueous solutions influence the solubility of the charged species so while we can estimate the partition for the charged species into octanol, we cannot make definitive predictions or estimations of the solubility of the charged species in the presence of various counter-ions in the aqueous buffer solution. 

Although a cocrystal involves different neutral molecules, if one or both components of the cocrystal is ionizable, the solubility of the cocrystal will be dependent on the solution pH. For the sake of simplicity, we shall restrict our discussion to the pH-solubility profile... 

Alternatively, Eq. (33) can be used to predict the pH-solubility profile for a cocrystal when the K p and Ka values are known for the cocrystal and the ligand respectively. Rearranging Eq. (33) yields... 

Fig. 17 shows the pH-solubility profile for cocrystal plotted according to Eq. (34) with cocrystal K p values of 1 X 10 and 1 x 10 and acidic ligand pKa = 5. The pH-solubility profile of a cocrystal with one component that is a weak acid is similar to that of a weak acid. At pH < pKa, the cocrystal solubility is at its lowest intrinsic solubility value, given by K pf-. At pH = pKa, the cocrystal solubility is 1.4 times higher, and at pH > pKa, the solubility increases exponentially. Also, increasing the K p value increases the intrinsic solubility of cocrystal as observed in Fig. 17. The K p value is characteristic of the cocrystal of an API with a specific ligand. Therefore, if multiple cocrystals exist for the same API, determination and comparison of the K p and values enables one to select the cocrystal with the desired solubility pH dependence.

The techniques for predicting the chemical stability of homogeneous drug systems are well defined. " The formulation chemist should consider both the pH-solubility profile and the pH-stability profile when selecting the optimum pH for formulation of the liquid oral dosage form. For example. Figs. 3 and 4 show the... 

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