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It is important to report the method used to assess solubility when reporting the solubility value. A range of methods are available, yet the most common method used for biopharmaceutics is the shake‐flask method that is recommended by the regulatory agencies (FDA and EMA). In the shake‐flask method excess drug is added to the solvent to form a saturated solution which is noted by the observation of undissolved material within the flask. The total content of the flask is then transferred to a shaker and agitated for a predetermined time to reach equilibrium solubility at a fixed temperature (usually 37 °C).

However, during the drug development process often high throughput or in silico methods are used during lead optimisation and candidate selection. In silico methods to predict solubility use structural parameters including the use of 2D and 3D chemical structures, log P and melting point models [4]. Within high throughput methods, solubility is measured based on a small amount of drug that was dissolved in DMSO; then precipitated prior to dissolution in buffers at pH 6.5 or 7.4. However, these high throughput methods have been demonstrated to overestimate solubility, most likely due to residual DMSO present within the solvent.

A second common method is the intrinsic dissolution rate (IDR) which is defined as the dissolution rate of the drug substance from a constant surface area and stirring speed in a solvent with defined pH and ionic strength. The IDR is calculated as the mass rate transferred from the solid surface to the solvent phase. The major differences between IDR and the shake‐flask are that the shake‐flask method provides an equilibrium solubility measurement whereas the IDR is a rate measurement. The notation of dissolution can cause confusion in this context. However, the intrinsic dissolution rate relates to the drug substance and how rapidly the drug substance achieves saturated solubility. Dissolution in the context of biopharmaceutics relates to the rate of solvation of the drug substance from the formulated drug product, dissolution is discussed in detail in Chapter 6.

It is important that solubility is assessed by the most suitable method at the appropriate stage during development, particularly as it is known that the crystalline form will affect the solubility recorded.