Biopharmaceutics. Группа авторов

similar polarity will mix whereas those with differences in polarity will not mix. Attractive forces are the result of the positive head of one molecule positioning itself close to the negative head of another molecule. However, it is also important to consider physical, geometric constraints which may limit the efficiency of mixing.

      4.6.2 Hydrogen Bonding

The hydrogen bonding capacity of a drug molecule can be calculated based on its chemical structure. Much of biopharmaceutics is related to aqueous media where hydrogen bonding is a significant factor in aqueous solubility. Thus hydrogen bonds are important for biopharmaceutics.

      4.6.3 Ionic Interactions

      Oppositely charged ions will interact. This is of relevance in biopharmaceutics as many drugs can be prepared as salt forms which will interact with aqueous media as it is polar. Pharmaceutical salts can often have a higher solubility compared to their free base form.

4.7 Solid‐State Properties and Solubility

      Chemicals that exist in more than one solid‐state form are termed polymorphs; the classic example is carbon that can exist as diamond or graphite. Alternative polymorphic forms of a drug substance will have different crystalline forms which can affect their hydration and the time‐frame to reach equilibrium solubility. A change in polymorph can affect oral bioavailability due to the change in solubility as well as dissolution from the drug product.

      The crystal structure determines the free energy within the solid and this can influence the rate of solvation. In early preclinical phases drug is often already in solution for evaluation of the potency and other key factors so polymorphism is irrelevant as this only affects solid materials. However, once the drug is produced and administered as a solid it is essential to understand the polymorphic form and relative stability of each form. Polymorphic screening is undertaken by dissolving the drug into a range of solvents and evaporating the solvents to characterise the crystalline or amorphous material formed.

      Drug substances are manufactured as solids; a polymorph screen will be undertaken to identify the polymorphs present. This screen is usually undertaken early during drug development to identify and characterise the range of polymorphs.

      It is important to not only recognise and characterise all polymorphs (for patenting purposes amongst others) but also to control the form of polymorph present upon manufacture and throughout the shelf‐life of the product. Solubility and dissolution can be used as surrogate measures of change in polymorph due to the measured difference in solubility and dissolution rate.

      This phenomenon was significant for ritonavir in 1998 where the continued supply of the HIV drug was threatened due to the change in polymorph to a more stable and less soluble crystalline form. The original formulation contained ritonavir as an oral liquid or within semi‐solid capsules such that the drug was solubilised in an ethanol/water mix. A solubilised drug does not have a crystal structure thus no polymorphic control was required. However, it was noted that several batches of the semi‐solid capsules failed dissolution and upon investigation a second polymorph was identified which had much reduced solubility and subsequently reduced bioavailability which would limit exposure. As a result, a reformulation was required for both products [5].

4.8 pH and Drug Solubility

Many drugs are ionisable compounds and can exist as weak acids or bases. The solubility of a weak acid/base is highly dependent upon the pH of the solvent. As the pH changes along the gastrointestinal tract from the acidic conditions within the stomach to the neutral environment within the small intestine the impact of the pH of the solvent on the drug solubility needs to be understood. This is of greatest importance for weakly basic drugs as their solubility reduces within the small intestine which is the major site for drug absorption. Figure 4.2 shows the impact of pH on the solubility of a weakly acidic and a weakly basic compound.

Figure 4.2 Impact of pH on solubility of a weakly acidic and a weakly basic drug.

      Very small changes in pH can have a major impact on the solubility of an ionisable drug. Solubility measurements are usually undertaken in buffered solutions to prevent small changes in pH affecting the measurement obtained.

      pH solubility measurements are usually performed early in the drug development process to understand risks and whether there are drug candidates with favourable pH solubility profiles (see Chapter 7).

      The pK_a of the drug is another useful drug characteristic to understand the impact of pH on solubility as this is linked via the Henderson–Hasselbach equation.

      As well as the influence of pK_a on solubility it is important to note that it is the undissociated form that more readily penetrates biological tissues to exert a therapeutic effect. As the equilibrium between the dissociated and undissociated fractions is constant, it can be assumed that the undissociated permeated material will be replenished to maintain equilibrium and thus absorption can occur for both weak acids and weak bases.

4.9 Solvents

      Drug solubility in a range of solvents is of interest for both the prediction of biopharmaceutics parameters and also to aid in the formulation strategy. Drug solubility in a range of organic solvents can facilitate polymorph identification and process optimisation. For compounds that show poor aqueous solubility, additional solubility screening is performed with a range of solubilising vehicles to guide the formulation design and associated risk assessment.

      4.9.1 Biorelevant Solubility

It has been demonstrated that replication of the composition of the gastrointestinal media improves the ability to predict in vivo performance of drug products. Therefore, much effort has been made to replicate in vivo gastrointestinal media to provide simulated fluids for solubility assessment. Four levels of simulation of luminal composition have been proposed ranging from simple to more complex [6]; these are outlined in Table 4.2.

      During the drug development process, the level of complexity will increase to ensure that the measurements are appropriate to the risk assessment of the product. Often biorelevant media are first used just before the human clinical phase of development.

      As well as the levels of media it is important to note that there are significant compositional changes from the stomach to small intestine to large intestine that also need to be addressed. Furthermore, the impact of food cannot be ignored thus several variations of simulated fluids are reported in the literature. Most data has come from matching composition to intestinal fluids taken from healthy adult volunteers. However, there is also a need to account for populations that may differ including those with diseases or at the extremes of age (see Chapter 13).

      There are several papers that describe the characterisation of human intestinal fluids and translate these findings into simulated fluids for the fasted state [7–11] and for the fed state [10, 11].

The composition of commonly used media is presented in Table 4.3.