Drug substances equilibrium solubility

The other main approach to solubility is to measure the concentration of the drug substance after an equilibrium has been reached with the solvent in question. This work is also conducted very early during the development process, normally at the stage of preformulation characterization [7]. A full discussion of the various aspects of solution theory is beyond the scope of the present chapter, but it is available [68]. Only a few salient points will be addressed in the following paragraphs. 

In an ideal solution, the maximum solubility of a drug substance is a function of the solid phase in equilibrium with a speciLed solvent system at a given temperature and pressure. Solubility is an equilibrium constant for the dissolution of the solid into the solvent, and thus depends on the strengths of solute solvent interactions and solute solute interactions. Alteration of the solid phase of the drug substance can inLuence its solubility and dissolution properties by affecting the solute solutc molecular interactions. 

Most drug substances and substances of interest to health and environmental risk assessors enter cells by passive permeation (diffusion). In this process, a substance dissolves in the membrane lipid bilayer, permeates through the membrane, and enters into the cytoplasm of the cell. The substance thus must be soluble in lipids. The process is passive because the rate and extent to which a substance will enter a cell by this means depends on its concentration outside and inside the cell. The net movement is from the region of higher concentration to that of lower concentration. Unlike the cell membrane, which is chiefly lipid, the extracellular and intracellular spaces separated by the membrane are aqueous. The higher the concentration of substance outside of the cell, and the more soluble the substance in the membrane lipid bilayer, the greater will be the tendency for the substance to diffuse across the membrane and enter the cytoplasm. The rate and extent of diffusion will decrease as the concentration of the substance inside the cell increases until, eventually, equilibrium is reached. 

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... 

As discussed in detail above, the intestinal absorption of Class II drug substances may be limited by dissolution rate or solubility rate. In the latter case, when the absorption is limited by the drug equilibrium solubility, an IVIVC is not likely to be obtained. The GI tract drug concentrations in this case will be close to the saturation concentration, and since standard dissolution tests are carried out under sink conditions, they can predict only processes occurring well below the saturation concentration [85], Hence, at this point, Class II solubility rate limited drugs are probably poor candidates for BA/BE waiver. 

According to the Noyes-Whitney equation (48), the dissolution rate of a drug substance is directly proportional to its equilibrium solubility. However, the nature of the dissolving solid and the dissolution medium also exert strong... 

Solubility determination is an important step in pharmaceutical preformulation. Although the experiment seems simple and well known, depending on the properties of the drug substance, special care must be taken to ensure the reliability of the results. Establishment of equilibrium and identifying what solid material is in equilibrium are two of the most important considerations in any solubility experiment. 

For ascertaining the process conditions of RESS and PGSS, it is essential to have knowledge of the equilibrium solubility of the solute in dense gas (SCF phase) and vice versa, and also the P-T trace for the solid-liquid-vapor (S-L-V) phase transition of the drug substance. If all three phases coexist, there is only a single degree of freedom for a binary system, and a P-T trace of the S-L-V equilibrium is sufficient to determine the phase equilibrium compositions. 

The properties of solubility and dissolution rate are key to the form selection process. Solubility in this discussion refers to equilibrium solubility, which is important to both process development and formulation activities. The rate of dissolution of drug substance in physiological media often correlates to the rate of attainment of therapeutic blood levels after administration of solid drug product. In such cases the appropriate choice of form is critical to product efficacy. 

Equilibrium solubility is most easily determined by agitating a mixture of solid drug substance and solvent until equilibrium is reached, and then measuring... 

Fig. 43 Equilibrium solubility curves for stable form 1 (lower), metastable form 2 (middle), and the supersaturation curve (upper) for a drug substance in water. Either form could be reproducibly obtained by adding the appropriate seeds to a solution of 50 mg/ mL of drug substance in water at the appropriate temperature, 70°C for form 1 and 50°C for form 2. Dissolution rates for these same forms are shown in Fig. 44.

Fig. 44 Dissolution rate curves for stable form 1 and metastable form 2 for a drug substance in water at approximately 25°C. Equilibrium solubilities for these same forms are shown in Fig. 43.

To prepare solid samples for analysis, information about the solubility of the analyte must be collected. The solubility of a solute is the concentration of the solute when it is at equilibrium with the solid substance, that is, the solution is saturated. For the preparation of a solid drug substance or product, the final drug concentration should be considerably less than the drug s solubility, to assure reliable recovery from day to day. 

The dissolution rate and solubility in a solvent medium are two of the most important characteristics of a drug substance, because these quantities determine the bioavailability of the drug for its intended therapeutic use. Solubility is defined as the equilibrium concentration of the dissolved solid (the solute) in the solvent medium and is ordinarily a function of temperature and pressure. 

On a more practical note, it is generally understood that alternate crystal forms will exhibit sufficiently different solid-state properties so that one could anticipate encountering measurable differences in properties of pharmaceutical importance. For example, it has been reported that polymorphs of some drug substances exhibit different equilibrium solubilities and dissolution rates, and these differences have... 

The pH should also be measured for each solution after a thermodynamic equilibrium has been established. If the pH of the solution is different from the pH of the initial buffer, this will indicate that the ionized drug substance has overcome the buffering capacity of the buffer solution and has changed the solution pH, which can lead to incorrect assumptions about solubility at a given pH." ... 

Solubility measurement at a single pH [37-39] under equilibrium conditions is largely a labor-intensive procedure, requiring long equilibration times (12h-7 days). It s a simple procedure. The drug is added to a standard buffer solution (in a flask) until saturation occurs, indicated by undissolved excess dmg. The thermostated saturated solution is shaken as equilibration between the two phases is established. After microfiltration or centrifugation, the concentration of the substance in the supernatant solution is then determined using HPLC, usually with UV detection. If a solubility-pH profile is required, then the measurement needs to be performed in parallel in several different pH buffers. 

In physicochemical terms, about two-thirds of all existing drug entities belong to the class of weak electrolytes, i.e. substances which in aqueous solution are at least partly present as ions. They are formed by releasing protons (acids) into, or by accepting protons (bases) from, an aqueous environment. Ionized species are easily hydrated and hence are generally more soluble in an aqueous phase than their nonionized source. The aqueous solubility of weak electrolytes is influenced and can be controlled by adjusting the pH of the solution via the equilibrium between the nonionized and the ionized species. 

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