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Solubility in Pharmaceutical Chemistry
Christoph Saal, Anita Nair, Christoph Saal, Anita Nair
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eBook - ePub
Solubility in Pharmaceutical Chemistry
Christoph Saal, Anita Nair, Christoph Saal, Anita Nair
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This book describes the physicochemical fundamentals and biomedical principles of drug solubility. Methods to study and predict solubility in silico and in vitro are described and the role of solubility in a medicinal chemistry and pharmaceutical industry context are discussed. Approaches to modify and control solubility of a drug during the manufacturing process and of the pharmaceutical product are essential practical aspects of this book.
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Informations
1 Solubility â definition and basic physicochemical considerations
David Elder
Hertford, Hertfordshire, SG14 2DE, UK
1.1 Introduction
Solubility is often regarded as one of the most important attributes of a drug substance [1]. However, solubility of a solid active pharmaceutical ingredient (API) in a solvent (or mixed solvent) is a complicated phenomenon, and it is generally considered to be a dynamic equilibrium between the opposing forces of dissolution and reprecipitation. Under certain scenarios the equilibrium solubility may be exceeded to produce a supersaturated solution, which is metastable in nature [2]. The first stage in the process leading to a solution in an aqueous or organic solvent is disintegration of the crystal lattice and hydration or solvation of the API molecules. The thermodynamic driving force for this process is defined by the concentration gradient and resulting chemicalâpotential gradient between the solid (”s) and solidâliquid interface (”l). Then, the hydrated or solvated molecules diffuse from the âsolidâliquid interface into the solution bulk phaseâ [3]. Similarly, the thermodynamic driving force for this latter process is defined by the concentration gradient and resulting chemicalâpotential gradient between the solidâliquid interface (”l) and the solution phase (”sol).
Solubility can be simplistically defined as the âamount of a substance that will dissolve in a given amount of another substanceâ [4]. This is often further refined as the amount of a solute that will dissolve in a given amount of solvent at a specified temperature and pressure. The latter caveats of temperature and pressure are important as most solutes become more soluble as the temperature increases, but the exact relationship is usually not simple [3].
However, these definitions omit an important factor, which is the nature of the solid-state form of the API. Dependent on the type of solubility measurement selected, this can change, as is typically seen with kinetic solubility or usually remain the same, that is, equilibrium solubility (see Table 1.1). IUPAC [5] tries to address this deficiency by defining solubility as âthe analytical composition of a saturated solution expressed as a proportion of a designated solute in a designated solventâ. The term âdesignatedâ implies no change in solid-state form, but this isnât implicitly stated. Solubility may be expressed in units of concentration, mole ratio, mole fraction, percentage, that is, 1% w/v, molality, or indeed other units [5].
Type of solubility measurement | Definition1 |
---|---|
Kinetic | The concentration of a solute in solution when an induced precipitation first appears; this precipitate is often a thermodynamically metastable solid-state form. |
Thermodynamic or equilibrium | A saturated solution in equilibrium with the thermodynamically stable solid-state form. No phase change occurs during the experiment if the thermodynamically stable solid-state form is introduced into the assay. |
Intrinsic | The thermodynamic solubility at pH where API is in its neutral form (S0). |
Apparent | The solubility measured under given assay conditions. |
Biorelevant (see Chapter 6) | The solubility measured using biorelevant media, for example, SGF, SIF, but more typically using FeSSGF, FaSSGF, FeSSIF, or FaSSIF media. Measurements are often performed at controlled body temperature, that is, 37 °C ± 1 °C |
Performed at controlled room temperature, that is, 25 °C ± 1 °C, unless specified otherwise.
SGF, simulated gastric fluid; SIF, simulated intestinal fluid; FeSSGF fed state simulated gastric fluid; FaSSGF, fasted state simulated gastric fluid; FaSSGF fed state simulated intestinal fluid; FaSSIF, fasted state simulated intestinal fluid.
Interestingly, changes in temperature play slightly different roles in the initial dissolution process depending on the intrinsic solubility of the API. For highly soluble compounds, it affects the diffusion rate constant and an increase in the intrinsic thermodynamic driving force. In contrast, for poorly soluble APIs, it affects the surface reaction rate constant as well as the intrinsic thermodynamic driving force [3].
The pharmacopoeias such as the USP (United States Pharmacopoeia) [6] tend to describe solubility using much broader based terminology, for example, very soluble, freely soluble and soluble (see Table 1.2), which are based on the amount of solvent (in mL) needed to dissolve a specified amount of solute (1 g). The same terminology and definitions that are used in the USP are equally applicable in other pharmacopoeias, for example, European Pharmacopoeia and British Pharmacopoeia. Although all the pharmacopoeias provide information on the solubility of majority of the test articles in specified solvents (typically water and certain stated organic solvents), the broad-based nature of these definitions renders this information to be less than useful for more than just a characterization of the respective substance.
Descriptive term | Solubility (g/mL) |
---|---|
Very soluble | <1 part solvent needed to dissolve 1 part solute |
Freely soluble | 1â10 parts solvent needed to dissolve 1 part solute |
Soluble | 10â30 parts solvent needed to dissolve 1 part solute |
Sparingly soluble | 30â100 parts solvent needed to dissolve 1 part solute |
Slightly soluble | 100â1,000 parts solvent needed to dissolve 1 part solute |
Very slightly soluble | 1,000â10,000 parts solvent needed to dissolve 1 part solute |
Practically insoluble | >10,000 parts solvent needed to dissolve 1 part solute |
1.2 Why is solubility important?
Generally, solubility plays a major role within pharmaceutical research and development with regard to different areas:
- Discovery, that is, utility in assay formats, for example, high-throughput screening (HTS)
- API manufacturing
- Formulation development for preclinical, clinical, and commercial formulations
- Drug bioavailability for per-oral drugs
1.2.1 Drug discovery
During âhitâ identification and lead discovery phases of drug discovery, it is necessary to start to develop compound screening assays. This typically involves either (i) HTS of the companyâs entire compound library using biochemical or cell-based assays to screen for activity against the drug target and other proteins to get an understanding of selectivity of research compounds, (ii) fragment-based screening using small molecular weight (MW) compound libraries, or (iii) a tissue-based screening approach [7]. In all cases, compound solubility in DMSO (dimethyl sulfoxide) or, to a lesser extent, ethanol is required. These solvents are typically used because of their near universal solubilizing power and water miscibility [8]. Handling research compounds that are dissolved in such solvent...