Biopharmaceutics. Группа авторов

strategies that formulation scientists can apply to improve the solubility of a drug; there are also aspects that medicinal chemists can adapt to provide optimised drug candidates. However, there are also instances where the solubility needs to be limited; specifically in taste masking of drugs to limit the exposure with taste buds on the tongue or in modified release compounds where the rate of drug release is controlled. Further details are presented in Chapter 4.

3.3 Dissolution

      Dissolution is defined as the transfer rate of individual drug molecules from the solid particles (usually crystalline) into solution as individual free drug molecules. It is often the dissolution rate that is of greater interest than solubility due to the dynamic nature of the absorption process.

      Whilst solubility assessment is typically focussed on the drug substance; dissolution is a parameter more relevant for a formulated drug product (e.g. tablet or capsule). In fact, dissolution testing is commonly used as an analytical technique to measure the rate of drug release from a pharmaceutical product. Although it is the drug product under test during dissolution it is the rate of drug substance release that is measured within the test. For immediate release drug products, rapid and complete dissolution is the goal; whereas for extended release a slower and controlled rate is desirable. Further details on dissolution testing apparatus, including images, is presented in Chapter 6.

      Within pharmaceutical product development dissolution testing is used in two distinct ways:

       In a ‘quality’ environment dissolution testing is used to ensure reproducibility in products and to provide assurance on batch to batch variability. When used for quality control purposes the dissolution testing conditions are designed to evaluate the robustness of the formulation and manufacturing process. Thus the test must be sufficiently sensitive to discriminate between formulations that are different based on their content or process for manufacture. This level of discrimination will depend upon the therapeutic window of the product under test and is further explored in Chapter 8.

       The second application of dissolution is to mimic the physiological conditions at the site of absorption to provide a biorelevant environment. In this format, the equipment will be adapted to reflect the relevant composition, volume and agitation. There are also efforts to mimic the timeframe within each environment and reflect the dynamic conditions within the body. Correlations between dissolution testing and in vivo data are frequently sought so that dissolution testing could be used as a surrogate for some in vivo preclinical and clinical testing.

      There is growing evidence to combine these approaches to have a dissolution methods that are biorelevant and also provide information on the product robustness.

      The primary goal of a dissolution test is to develop a discriminating, robust and reproducible dissolution method that can highlight significant clinically relevant changes in product performance due to changes in the formulation or manufacturing process.

      The dissolution method(s) will change during the development of a new product. In the early stages, the dissolution is used to understand the factors that govern drug release and to ensure that there are no interactions within the dosage form that adversely affect drug release. The next phase of testing would seek to correlate the in vitro dissolution release to in vivo release, once this data is available. Further details are provided in Chapter 6.

3.4 Permeability

      For drug to pass from the exterior of the body to the interior it needs to permeate at least one membrane. Moreover, membrane permeability is also needed for drug distribution and elimination following absorption. Permeability of the drug across the relevant membrane is a key measurement within biopharmaceutics. Measurement of permeability will help understand the rate‐limiting processes associated with absorption and manage risks during the development process.

      Permeability is reported as the mass of drug that is transported across a unit area of membrane over a given time. In most cases, the drug needs to be solubilised at the membrane surface in order to permeate the membrane. Yet cellular membranes are formed of lipid bilayers where the core is lipophilic, which can be a barrier to very hydrophilic compounds. This lipid bilayer favours transport of unionised and non‐polar compounds. In permeability modelling the lipid bilayer can be considered to be a homogenous organic layer thus lipidic molecules are preferred.

Figure 3.1 provides an overview of the transport pathways across cells as an example for permeability.

Passive membrane permeation is a concentration gradient driven process that typically follows a first‐order kinetics. Passive transport can be further divided into passive transcellular where the drug is transported through the cell and passive paracellular where the drug permeates the tight junctions between epithelial cells. In passive transcellular permeability there is a correlation between a drug's log P value between log P of −2 to +4 and the rate of transport; where the higher the log P value the greater the permeability [3]. Whilst cationic small molecules are able to permeate the paracellular pathway larger anionic molecules cannot [4]. There is much data on the most suitable animal or cell‐based models to mimic the transcellular permeation observed in humans that is described in Chapter 5.

Figure 3.1 Image of transport pathways across a cellular membrane.

      Active transport (also termed carrier‐mediated transport) across a membrane is facilitated by transporters present at either side of the membrane; this can result in net uptake or net efflux of a compound depending on the affinity to the transporter and the relative density of transporters present at the site of absorption. Transporters can also be subject to competitive binding that can lead to drug–drug or drug–nutrient interactions.

3.5 Absorptive Flux

      The overall net absorption or absorptive flux can be determined using the following equation, Fick's Law.

      where P_e is the effective permeability across a membrane; SA is the total surface area available for absorption and ∆C is the concentration gradient. The absorptive flux is written as a negative value as it is measuring the concentration from the outside to the inside of a membrane thus the directionality means that the flux is negative (drug is lost from the original site due to the transfer across the membrane).

      Using the simple biopharmaceutics measures the permeability and likely concentration gradient (identified via the solubility) can be predicted thus the absorptive flux estimated. It is often used to consider relative values of absorptive flux to compare new drugs to existing and well characterised compounds.

3.6 Lipinsky's Rule of 5

      A key article published in 1997 reported the Lipinsky rule of 5 [2]; this paper reviewed commercial drugs to highlight key biopharmaceutics properties (specifically solubility and permeability) of compounds within the drug discovery setting. The purpose of this work was to identify a library of compounds that