Further Reading
1 [1] Batchelor, H.K. and Marriott, J.F. (2015). Paediatric pharmacokinetics: key considerations. British Journal of Clinical Pharmacology 79 (3): 395–404.
2 [2] Jambhekar, S.S. and Breen, P.J. (2012). Basic Pharmacokinetics. Pharmaceutical Press. ISBN: ISBN: 978 0 85369 772 5.
3 [3] McConnell, E.L., Fadda, H.M., and Basit, A.W. (2008). Gut instincts: Explorations in intestinal physiology and drug delivery. International Journal of Pharmaceutics 364 (2): 213–226.
4 [4] Varum, F.J.O., Hatton, G.B., and Basit, A.W. (2013). Food, physiology and drug delivery. International Journal of Pharmaceutics 457 (2): 446–460.
5 [5] Varum, F.J.O., Merchant, H.A., and Basit, A.W. (2010). Oral modified‐release formulations in motion: The relationship between gastrointestinal transit and drug absorption. International Journal of Pharmaceutics 395 (1): 26–36.
6 [6] Madla, C.M., Gavins, F.K.H., Merchant, H., Orlu, M., Murdan, S., and Basit, A.W. (2021). Let’s Talk About Sex: Differences in Drug Therapy in Males and Females. Advanced Drug Delivery Reviews. https://doi.org/10.1016/j.addr.2021.05.014
7 [7] Winter, M.E. (2009). Basic Clinical Pharmacokinetics. Wolters Kluwer Health/Lippincott, Williams & Wilkins. ISBN: ISBN‐10: 0‐7817‐7903‐0.
3 Introduction to Biopharmaceutics Measures
Hannah Batchelor1 and Pavel Gershkovich2
1 Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom
2 School of Pharmacy, Centre for Biomolecular Sciences, The University of Nottingham, Nottingham, United Kingdom
3.1 Introduction
Biopharmaceutics is centred on certain key measurements; this chapter aims to define and distinguish the following terms:
Solubility
Permeability
Dissolution
The chapter will also explain why these three measures are important in biopharmaceutics assessment; further chapters will explore these concepts in additional detail in the context of the drug development process.
3.2 Solubility
The International Union of Pure and Applied Chemistry (IUPAC) definition of solubility is, ‘The analytical composition of a saturated solution, expressed in terms of the proportion of a designated solute in a designated solvent, is the solubility of that solute’ [1].
In terms of biopharmaceutics, it is the drug that is the solute of interest and the solvent differs depending on where the drug is during the process of absorption or disposition. Thus, solubility will affect absorption, distribution within the body as well as elimination. A drug needs to be in solution to undergo pharmacological processes in vitro (e.g., permeation, metabolism, bioassay target binding) and in vivo (e.g., intestinal absorption). The solubility of a drug at the site of absorption is especially important to its uptake.
Poor solubility has been linked to the following outcomes that are of interest in biopharmaceutics:
1 Insufficient aqueous solubility to formulate an intravenous product
2 Inability to achieve sufficiently high blood/plasma concentrations to attain a therapeutic effect due to saturation of intestinal solubility limiting exposureInability to generate data from an ascending dose study or toxicity study due to dose‐limited exposurePoor or variable bioavailability due to insufficient solubility within the GI environmentHigh variability in pharmacokinetic data due to erratic dissolution and potential for precipitationFlattened pharmacokinetic curves as the dissolution of the poorly soluble drug does not allow for a rapid Tmax or high Cmax to be achieved.
The solubility of a list of commercial drugs was reported by Lipinski et al. [2]. It was identified that 87% of drugs on the market had a solubility of ≥65 μg/mL thus this value has since been used as a target solubility for compounds during drug discovery and development.
The solubility of a solute in a solvent can be expressed using a wide range of terminologies and units. This can range from units of moles per litre; grams per litre; parts per million; a percentage weight per volume and a range of others.
Pharmacopeial sources (British Pharmacopoeia, European Pharmacopoeia and US Pharmacopoeia) use broad descriptive terms ranging from very soluble to practically insoluble as listed in Table 3.1.
Analytically the solubility is based on a saturated solution; saturation depends on an excess solute being present and there being sufficient agitation for the saturated concentration to be achieved; this is a situation where the soluble and insoluble fractions are in equilibrium within the solvent. However, the time to reach equilibrium can be long, up to days for some compounds. The equilibrium solubility value achieved will depend on the affinity of the solvent molecules to the solute. These interactions can be formed via ionic, van der Waals, dispersion and hydrogen bonds.
Table 3.1 Solubility criteria as listed in the BP and USP.
| Descriptive term | Parts of the solvent required per part of solute | Expressed as mass per volume (g/mL) |
|---|---|---|
| Very soluble | <1 | >1 |
| Freely soluble | From 1 to 10 | 0.1–1 |
| Soluble | From 10 to 30 | 0.033–0.1 |
| Sparingly soluble | From 30 to 100 | 0.01–0.033 |
| Slightly soluble | From 100 to 1 000 | 0.001–0.01 |
| Very slightly soluble | From 1 000 to 10 000 | 0.0001–0.001 |
| Practically insoluble | 10 000 and over | <0.0001 |
Chemical solubility uses well‐defined conditions that are maintained over the duration of the experiments. However, the process of drug absorption is dynamic with changes in the volume, composition and agitation of the solute in biological fluids during the time‐course of absorption. Therefore, it is of interest to measure the solubility of a drug in a range of relevant liquids and to consider the time spent within each fluid as well as the level of agitation present. When considering the solubility of a drug it is essential to understand the factors that are limiting solubility within the absorptive