Solubility in Pharmaceutical Chemistry

Christoph Saal, Anita Nair, Christoph Saal, Anita Nair

• Publisher: De Gruyter
• Year: 2020
• eBook ISBN: 9783110558883
• Edition: 1
• Topic: Medicine
• Subtopic: Pharmacology

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.

1 Solubility – 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 chemical–potential gradient between the solid (µ^s) and solid–liquid interface (µ^l). Then, the hydrated or solvated molecules diffuse from the “solid–liquid interface into the solution bulk phase” [3]. Similarly, the thermodynamic driving force for this latter process is defined by the concentration gradient and resulting chemical–potential gradient between the solid–liquid interface (µ^l) and the solution phase (µ^sol).

Solubility can be simplistically defined as the “amount of a substance that will dissolve in a given amount of another substance” [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 “the analytical composition of a saturated solution expressed as a proportion of a designated solute in a designated solvent”. The term “designated” implies no change in solid-state form, but this isn’t 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].

Table 1.1:Definitions of differing types of solubility.

Type of solubility measurement	Definition^1
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.

Table 1.2:USP definitions of solubility [6].

Descriptive term	Solubility (g/mL)
Very soluble	<1 part solvent needed to dissolve 1 part solute
Freely soluble	1–10 parts solvent needed to dissolve 1 part solute
Soluble	10–30 parts solvent needed to dissolve 1 part solute
Sparingly soluble	30–100 parts solvent needed to dissolve 1 part solute
Slightly soluble	100–1,000 parts solvent needed to dissolve 1 part solute
Very slightly soluble	1,000–10,000 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 “hit” 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 company’s 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...

Table of contents

• Title Page
• Copyright
• Contents
• 1 Solubility – definition and basic physicochemical considerations
• 2 Solubility and supersaturation
• 3 In Silico methods to predict solubility
• 4 How solubility influences bioavailability
• 5 Estimation of intraluminal drug solubility
• 6 Biorelevant media
• 7 The role of solubility to optimize drug substances – a medicinal chemistry perspective
• 8 The role of solubility in optimizing drug products – a pharmaceutical development perspective
• 9 The relevance of solid-state forms for solubility
• 10 Solubility and phase behaviour from a drug substance manufacturing perspective
• 11 Biowaivers
• List of Abbreviations
• Index