Biopharmaceutics. Группа авторов

which could then be used to risk assess future lead compounds.

      An overview of the findings is presented as this can also support key biopharmaceutics properties:

      3.6.1 Molecular Weight

      A higher molecular weight results in a larger molecule that will have poorer permeability due to its size/volume. Larger compounds can also display poorer solubility due to the large number of solvent molecules required to solvate them. Thus, the target molecular weight was <500.

      3.6.2 Lipophilicity

      The ratio of solubility of a drug in octanol:aqueous phase is reported as its log P value. This is also known was the partition coefficient between octanol and water. This value captures the relative hydrophilic to lipophilic property of a particular compound, in biopharmaceutics this is the API. Following oral ingestion of a drug product, the solubility is measured within an aqueous system which drives absorption, yet the membrane permeability favours an unionised and lipophilic compound thus a balance of hydrophilic and lipophilic property is desirable for a drug. A log P value of <5 was reported as preferred.

      It should be noted that human physiology is not as simple as a ratio between octanol and water. The aqueous phase within the gastrointestinal tract for example can vary from an acidic gastric media to a neutral pH within the small intestine. Therefore it is often more relevant to consider the partition coefficient between an aqueous buffer of the appropriate pH and octanol. Particular pH values of interest include the following: pH 7.4 (the pH of blood/serum); pH 6.5–6.8 (the pH within the small intestine) and pH 1–2 (the pH within the stomach).

Drug compounds that are not ionisable will show the same value of partition ratio across a full pH range. Many drugs are ionisable and thus the partition between octanol and an aqueous phase will differ according to their ionisation status. Ionised compounds are more polar and will thus favour the aqueous phase. This is shown schematically in Figure 3.2.

      The distribution coefficient (D) (usually expressed as log D) is the effective lipophilicity of a compound at a given pH and is a function of both the lipophilicity of the unionised compound and the degree of ionisation.

Consider a weak acid; this compound will be unionised at low pH and thus will partition into octanol to a greater extent at lower pH values. An example of this is shown in Figure 3.3 for indomethacin which has a pK_a value of 4.5. Note that the log P value is the partition coefficient when the compounds under test are fully unionised. A log D value should always be reported with a pH value.

Figure 3.2 Schematic diagram to demonstrate the impact of ionisation on the partition of a compound between octanol and an aqueous phase.

Figure 3.3 Impact of log D vs pH for a compound with a pKa value of 4.5.

      3.6.3 Hydrogen Bond Donors/Acceptors

      A high number of hydrogen bond donors can impair membrane permeability due to the polarity of the compound. Compounds with fewer than five hydrogen bond donor groups were preferred. Similarly, hydrogen bond acceptors indicate polarity and fewer than 10 were correlated to better absorption characteristics.

References

      1 [1] IUPAC (1997). Compendium of Chemical Terminology (the “Gold Book”), 2e. Compiled by A. D. McNaught and A. Wilkinson. Oxford: Blackwell Scientific Publications. ISBN: 0‐9678550‐9‐8. https://doi.org/10.1351/goldbook. Online version (2019) created by S.J. Chalk (online version created 2019).

      2 [2] Lipinski, C.A., Beryl, F.L., Dominy, W., and Feeney, P.J. (1997). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews 23 (1): 3–25.

      3 [3] Camenisch, G., Alsenz, J., van de Waterbeemd, H., and Folkers, G. (1998). Estimation of permeability by passive diffusion through Caco‐2 cell monolayers using the drugs' lipophilicity and molecular weight. European Journal of Pharmaceutical Sciences 6 (4): 313–319.

      4 [4] Adson, A., Raub, T.J., Burton, P.S. et al. (1994). Quantitative approaches to delineate paracellular diffusion in cultured epithelial cell monolayers. Journal of Pharmaceutical Sciences 83 (11): 1529–1536.

4 Solubility

       Hannah Batchelor

       Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom

4.1 Definition of Solubility

      Solubility is a measurement of the amount of a substance that can stay in a solvent without precipitation. Solubility may be expressed in units of concentration, molality, mole fraction, mole ratio and other units. For the purposes of biopharmaceutics, the substance of interest is usually the API and the solvent will vary depending upon the physiological region of interest; for example the stomach, small intestine or pulmonary fluid.

      A drug's structure determines its solubility as the chemical structure will also determine lipophilicity, hydrogen bonding, molecular volume, crystal energy and ionisability. Thus during lead compound optimisation, there is scope to balance potency with solubility [1].

      The solubility of a substance can change when pressure, temperature and/or the composition of the solvent changes thus it is important to accurately detail solubility data to provide sufficient information.

4.2 The Importance of Solubility in Biopharmaceutics

Poor aqueous solubility of a drug can lead to issues during the preclinical phase of drug development and beyond. Insufficient solubility within the gastrointestinal lumen can limit absorption and subsequent exposure to the drug in question. Thus, the solubility of a drug candidate will impact upon decisions and risk assessments undertaken during development.

      There has been an increase in the proportion of poorly water‐soluble drugs with estimates of up to 75% of candidates in development being classified as low aqueous solubility [2]. This trend towards increasing proportions of low aqueous solubility drugs is linked to the drive towards potent and selective drugs where candidate optimisation often adds lipophilic groups to enhance binding, yet the lipophilicity of the resulting molecule increases. However, poorly water‐soluble candidate drugs are associated with higher rates of attrition as well as higher costs during drug development [3]. Furthermore, poorly water‐soluble drugs are associated with greater inter‐individual pharmacokinetic variability as well as being susceptible to food effects [3].

      Solubility data will determine the need for an enabling formulations (e.g., wetting agents, micronisation, solubilising agents, solid solutions, emulsions and nanoparticles).

      The importance of solubility is recognised within the biopharmaceutics classification system, where further details are provided in