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Developing Solid Oral Dosage Forms Pharmaceutical
Theory and Practice 1st Edition Yihong Qiu Digital
Instant Download
Author(s): Yihong Qiu, Yisheng Chen, Geoff G.Z. Zhang, Lirong Liu, William
Porter
ISBN(s): 9780444532428, 0444532420
Edition: 1
File Details: PDF, 12.09 MB
Year: 2009
Language: english
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This work is dedicated to Drs R.D. Schoenwald, J. Keith Guillory, L.E. Matheson, E.L. Parrott, D.R. Flanagan,
D.E. Wurster, P. Veng-Pedersen and the late D.J.W. Grant.
By generously sharing their experience, time and wisdom, what they’ve taught us is well beyond
what we learned in school.
We are also forever indebted to our families for their love, unwwderstanding, and sacrifice.
 Foreword

Physical pharmacy, the application of physico- and by extensive study. It is in the areas of prefor-
chemical principles to the solution of problems related mulation, the development of new and sophisticated
to dosage forms is, as a discipline, rapidly disappear- drug delivery systems, and the day-to-day work of
ing from curricula in colleges of pharmacy. It is being optimizing the effects of new drug entities that this
replaced by an emphasis on communication skills and knowledge is most needed. There are, of course, many
pharmacotherapeutics. Biopharmaceutics and pharma- textbooks that deal with specific subjects important
cokinetics, sciences that arose from the efforts of such to the industrial pharmacist, focusing on tablets, cap-
early physical pharmacists as Sidney Riegelman, Milo sules, disperse systems, parenterals, etc. However,
Gibaldi, Gary Levy, John Wagner and Edward Garrett, there is a critical need for a comprehensive treatment
are still considered essential, at least for the present. In of the science underlying each of these special areas,
graduate programs in pharmaceutics, physical phar- together with practical applications of the science that
macy has taken a back seat to such fashionable and results in quality dosage forms. Questions related to
fundable areas as genetics and tissue scaffolding. Yet, solubility, dissolution, chemical and physical stabil-
the demand for the skills of the physical pharmacist ity, interfacial phenomena, and the absorption and
remains strong in the pharmaceutical industry. That is distribution of drug molecules are common to all.
why this textbook fills an important need. Consequently, a single textbook that brings together
Scientists entering the pharmaceutical industry experts in all of these subjects can be an invaluable
today often lack the fundamental knowledge that is asset to the novice industrial scientist. Each chapter in
reflected in the chapters contained in this book. Many this book contains a useful bibliography of references
of the researchers entering industry have backgrounds that can provide for ready access to current research
in chemical engineering or organic chemistry. Their in the field. We should be grateful that these authors
exposure to the principles of physical pharmacy is a have taken time from their busy schedules to share
deficit that must be overcome by on-the-job training their knowledge and experience with all of us.

J. Keith Guillory, Ph.D.

Professor Emeritus
University of Iowa

04_N53242_FOR.indd xxxi 11/17/2008 7:39:03 PM

 List of Contributors
Gregory E. Amidon (Chapter 8) Min Jiang (Chapter 35)
Pfizer Inc. Abbott Laboratories

Thomas Baxter (Chapter 28) Wenlei Jiang (Chapter 38)

Jenike & Johanson Inc. US Food and Drug Administration

James Brady (Chapter 9) David Jones (Chapter 34)

Aqualon Division, a Business Unit of
OWI-Consulting Inc
Hercules Incorporated.
David LeBlond (Chapter 23)
Geoff Carr (Chapter 22)
Global Pharmaceutical Nonclinical Statistics
Patheon Inc.
Michael Levin (Chapters 29 & 32)
Wei Chen (Chapters 25 & 26)
Metropolitan Computing Corporation
Eli Lilly and Company
Ping Li (Chapter 40)
Yisheng Chen (Chapters 7, 14, 24 & 37) Novartis Pharmaceuticals Corporation
Novast Laboratories (China) Ltd
Lirong Liu (Chapters 29, 31, 32 & 33)
Tom Durig (Chapter 9)
Pfizer Inc.
Aqualon Division, a Business Unit of Hercules
Incorporated Zhongqiu Liu (Chapter 11)
Walter Dziki (Chapter 35) Southern Medical University, Guangzhou, China
Abbott Laboratories
Michelle Long (Chapter 14)
Abbott Laboratories
Xingchun (Frank) Fang (Chapter 22)
Novast Laboratories (China) Ltd Sean Mackey (Chapter 35)
Abbott Laboratories
Douglas R. Flanagan (Chapters 7 & 13)
University of Iowa Walt Morozowich (Chapter 19)
Prodrug and Formulation Consultant, Kalamazoo,
Ronald C. Freeze (Chapter 22)
MI, USA
Abbott Laboratories

Joseph Fuchs (Chapter 39) Deanna Mouro (Chapter 8)

Rockey, Depke & Lyons, LLC Pfizer Inc.

Ping Gao (Chapter 19) Eric Munson (Chapter 3)

Abbott Laboratories, Chicago, IL, USA University of Kansas

Xiaorong He (Chapter 18) Ajit S. Narang (Chapter 6)

Asymchem Laboratories Bristol-Myers Squibb Co.

Steven F. Hoff (Chapter 37) Dale Natoli (Chapter 32)

Abbott Laboratories Natoli Engineering Company

Ming Hu (Chapter 11) Brian Pack (Chapter 25)

University of Houston Eli Lilly and Company

Richard Hwang (Chapters 25 & 26) Stuart Porter (Chapter 33)

Pfizer Inc. ISP

xxxiii
xxxiv LIST OF CONTRIBUTORS

William R. Porter (Chapters 5 & 10) Wei-Qin (Tony) Tong (Chapters 4 & 40)
Abbott Laboratories Teva Pharmaceuticals USA

James Prescott (Chapter 28) Lev Tsygan (Chapter 32)

Jenike & Johanson Inc. Metropolitan Computing Corporation

Yihong Qiu (Chapters 17, 20 & 21) Lynn Van Kampen (Chapter 36)
Abbott Laboratories University of Wisconsin

Krishnaswamy S. Raghavan (Chapter 6) Jianzhou (Jake) Wang (Chapter 13)

Bristol-Myers Squibb Co. Gorbec Pharmaceutical Services

Venkatramana M. Rao (Chapters 1 & 6) Stephen Wang (Chapter 11)

Schering-Plough
Bristol-Myers Squibb Co.
Martin Warman (Chapter 35)
Lisa Ray (Chapter 25) Martin Warman Consultancy Ltd, Swalecliffe,
Eli Lilly and Company
Kent, UK
Gary Sackett (Chapters 31 & 33)
Vector Corporation Ken Yamamoto (Chapter 30)
Pfizer Inc.
Ritesh Sanghvi (Chapter 1)
Forest Laboratories Inc. Yongsheng Yang (Chapter 12)
US Food and Drug Administration
Pamela J. Secreast (Chapter 8)
Pfizer Inc. Lawrence X. Yu (Chapters 12 & 38)
US Food and Drug Administration
Kathleen Seitz (Chapters 15 & 16)
Centocor Research & Development, Inc. Erika A. Zannou (Chapter 40)
Novartis Pharmaceuticals Corporation
Nancy E. Sever (Chapter 35)
Abbott Laboratories Geoff G. Z. Zhang (Chapters 2 & 5)
Abbott Laboratories
Sherwin Shang (Chapter 9)
Abbott Laboratories Guohua Zhang (Chapter 21)
Novast Laboratories
Z. Jesse Shao (Chapter 30)
Arena Pharmaceuticals, Inc. Jack Y. Zheng (Chapters 25 & 26)
Eli Lilly and Company
Paul Sheskey (Chapter 31)
The Dow Chemical Company Deliang Zhou (Chapters 2 & 5)
Abbott Laboratories
Timothy J. Smith (Chapter 31) Honghui Zhou (Chapters 15 & 16)
Vector Corporation
Centocor Research & Development, Inc.

Suchinda Stithit (Chapters 25 & 26) Haijian (Jim) Zhu (Chapter 1)

Century Pharmaceuticals Forest Laboratories Inc.

John Strong (Chapter 27) Hao Zhu (Chapter 15)

Abbott Laboratories Centocor Research & Development, Inc.
 P A R T I

THEORIES AND TECHNIQUES IN THE

CHARACTERIZATION OF DRUG
SUBSTANCES AND EXCIPIENTS
 C H A P T E R

1
Solubility of Pharmaceutical Solids
Venkatramana M. Rao, Ritesh Sanghvi and Haijian (Jim) Zhu

1.1 INTRODUCTION solubility enhancement has been a regular feature

of pharmaceutical research for several decades. The
1.1.1 Implication of Solubility in Dosage need for such approaches has been on a rise following
the introduction of combinatorial chemistry and high
Form Development
throughput screening techniques to the drug discov-
The solubility of a drug is one of its most impor- ery arena. The advent of these techniques, resulting
tant physico-chemical properties. The determination in a rapid development of libraries of pharmaceuti-
of drug solubility and ways to alter it, if necessary, cally active compounds, has led to a greater number
are essential components of pharmaceutical devel- of highly active compounds. At the same time, it has
opment programs. The bioavailability of an orally resulted in generation of a far higher percentage of
administered drug depends primarily on its solubil- extremely lipophilic and poorly water-soluble com-
ity in the gastrointestinal tract and its permeability pounds adding more challenges to formulation devel-
across cell membranes. This forms the basis for the opment. It has been reported2 that more than a third
biopharmaceutical classification system (BCS).1 Drug of the compounds registered by Pfizer in the late 1990s
molecules are required to be present in a dissolved had solubilities that were lower than 5 μg/ml.
form, in order for them to be transported across bio- While solubility enhancement remains one of the
logical membranes. Therefore, low aqueous solubility primary areas of focus during the drug development
can either delay or limit drug absorption. Knowledge phase, there are several situations that may require
of the solubility of a drug is also important when solubility reduction. Development of sustained release
direct administration into the blood stream is desired. products, taste masking, and enhancement of chemi-
Injectable formulations usually require a drug to be cal stability are examples of such situations.
in solution for administration. In addition, a drug Knowledge of solubility also finds application in
solution is preferred for conducting pharmacologi- developing analytical methods for drugs. Reverse
cal, toxicological, and pharmacokinetic studies dur- phase liquid chromatography is one of the most widely
ing the drug development stage. Thus, poor aqueous used techniques for pharmaceutical separation and
solubility not only limits a drug’s biological applica- analysis. Separation is based on the differential affinity
tion, but also challenges its pharmaceutical develop- of the solute towards the mobile phase and the station-
ment. As a result, investigation into approaches for ary phase, which is a direct outcome of its solubility in

Developing Solid Oral Dosage Forms: Pharmaceutical Theory and Practice 3 © 2009, Elsevier Inc.
4 1. SOLUBILITY OF PHARMACEUTICAL SOLIDS

these phases. The analysis of concentration using UV molecules, the redeposition process starts to accel-
spectroscopy is also performed on drug solutions. erate. Once sufficient solute molecules have popu-
Based on the above discussion, it should be clear lated the solvent bulk, the rate of molecules leaving
that solubility plays an important role in several becomes equal to the rate of redeposition (dynamic
avenues of pharmaceutical research. As a conse- equilibrium). The concentration of the solute in the
quence, the determination of solubility remains one solvent at which this equilibrium is reached is defined
of the most commonly conducted experiments for any as the thermodynamic solubility. The rate at which the
new compounds. While solubility experiments are equilibrium is achieved is the dissolution rate. Thus,
sometimes perceived as trivial, accurate determina- solubility is an equilibrium concept, while dissolution
tion of solubility is a challenging exercise. A number is a kinetic phenomenon. Both are dependent on the
of experimental variables may affect the solubility experimental conditions, including temperature. The
results, inducing high degrees of scatter in the data.3 dissolution rate of a solute in a solvent is directly pro-
This builds a strong case for the applicability of tools portional to its solubility, as described by the Noyes–
for estimation of solubility based on theoretical calcu- Whitney equation:4,5
lations. While most of these calculation approaches
are useful with respect to providing reasonable esti- dM DA
Dissolution rate   (Cs  Ct ) (1.1)
mation and time saving, they can never completely dt h
replace the experimentally determined values.
This chapter is written with the intent of develop- where:
ing a thorough understanding of the concepts of solu- dM/dt is the rate of mass transfer
bility. The various physico-chemical forces and factors D is the diffusion coefficient (cm2/sec)
that determine the solubility of a solute in a solvent A is the surface area of the drug (cm2)
will be discussed in detail. The thermodynamics of h is the static boundary layer (cm)
solubilization and various theoretical models for its Cs is the saturation solubility of the drug
estimation have also been included. Considerable Ct is the concentration of the drug at time (t).
emphasis has been laid on the techniques used for sol- Solubility is expressed in units of concentration
ubility enhancement along with practically relevant including percentage on a weight or volume basis,
examples. In addition, the various aspects of solubil- mole fraction, molarity, molality, parts, etc. The US
ity determination experiments including challenges Pharmacopeia and National Formulary describe solu-
and strategies to overcome them are discussed. bility as the number of milliliters of solvent required
to dissolve 1 gram of the solute.
It follows from the previous discussion that the
1.1.2 Basic Concepts of Solubility equilibrium solubility of a solute will depend on
and Dissolution its relative affinities towards solvent molecules and
fellow solute molecules. Thus, the strength of molecu-
A true solution is a homogenous mixture of two or lar interactions, both inter and intra, affect solubility.
more components on a molecular level. Any sample While a detailed description of these interactions can
collected from such a mixture will be representative be found in any physical chemistry book, they are dis-
of the entire bulk. In a two-component system, the cussed here briefly.
component present in larger proportion is generally
referred as the solvent, and the other as the solute.
When a solute is placed in contact with a solvent, Ionic Interactions
mixing occurs due to the propensity of all molecules Pure ionic interactions occur between two oppo-
towards randomization, resulting in an increase in sitely charged ions. Such interactions are relevant to
overall entropy of the system. The solute molecules pharmaceutical salts and ion pairs. An ion can also
start to break away from the surface and pass into interact with a polar molecule (ion–dipole) or induce
the solvent system. The detached solute molecules a dipolar character to a non-polar molecule (ion-
are free to move randomly throughout the solvent induced dipole). When sodium chloride is dissolved
bulk forming a uniform solution. Some of these solute in water, the free sodium and chloride ions interact
molecules strike the bulk solute surface and redeposit with polar water molecules such that the positive
on it. Initially, when the concentration of solute mol- head of water molecules interact with the chloride
ecules is low in the solution, the number of molecules ions, while the negative head of water molecules
leaving the bulk solute surface is much higher. As the interact with the sodium ions. By virtue of these inter-
solvent bulk starts becoming saturated with the solute actions, pharmaceutical salts generally have a higher

I. THEORIES AND TECHNIQUES IN THE CHARACTERIZATION OF DRUG SUBSTANCES AND EXCIPIENTS

 1.2 THERMODYNAMICS OF SOLUTIONS 5

solubility than their free form. The strength of ionic hydrogen bonding. The aqueous solubility of a drug
interactions depends on the electrostatic charge den- is directly related to its hydrogen bonding capability.
sity on the interacting ions, as well as the media prop- The higher water solubility of phenol, as compared to
erties, including dielectric constant and temperature. benzene and toluene, can be attributed to the former’s
hydrogen bonding nature. The evolving field of
cocrystals is based on the hydrogen bond interactions
van der Waals Interactions between molecules of drug and the cocrystal former.
Two molecules with permanent dipole moments The strength of hydrogen bond interactions depends
can interact, when placed in sufficiently close proxim- upon the electronegativity of the participating atoms,
ity (dipole–dipole or Keesom interaction). The mol- as well as the temperature of the media. Since the
ecules will try to arrange in a manner to minimize requirement of ideal positioning is highest for hydro-
the energy associated with them. Thus, the positive gen bonding interactions, they are more sensitive to
head of one molecule will position close to the nega- temperature than other interactions.
tive head of the other molecule. The positioning,
however, may not be ideal due to geometric con-
straints and random thermal motion of the participat- 1.2 THERMODYNAMICS OF SOLUTIONS
ing molecules (entropic influence). As a consequence
a situation arises where the participating molecules, In order to grasp the concepts of solubility, it is
on average, spend more time in an aligned position. essential to understand the basic thermodynamics
Strongly polar molecules can induce polar attributes of mixing. This section covers the various thermody-
to non-polar molecules to result in dipole-induced namic aspects that dictate the process of mixing.
dipole (Debye) interactions. The strength of van der
Waals interactions is a direct outcome of the dipole
moment and polarizability of the participating mol-
ecules, and is also affected by the media properties 1.2.1 Volume of Mixing
such as temperature. The volume of mixing, ΔVmix, is the difference
between the physical volume occupied by the mixture
(Vuv) and the sum of physical volumes occupied by
Dispersion Interactions
the solute (Vu) and solvent (Vv):
Also known as London forces, dispersion inter-
actions occur between any adjacent pair of atoms or ΔVmix  Vuv  (Vu  Vv ) (1.2)
molecules when they are present in sufficiently close
A negative volume of mixing is indicative of strong
proximity. These interactions account for the attrac-
inter-molecular interactions between the solute and
tive forces between non-ionic and non-polar organic
solvent molecules. Aqueous solutions of strong electro-
molecules, such as paraffin and many pharmaceutical
lytes have significantly large negative volumes of mix-
drugs. The origin of these forces remains unclear, but
ing, due to strong hydration of ions in the solution.3 In
it is believed that at any given instance molecules are
the case of most pharmaceutically active compounds
present in a variety of distinct positions due to ther-
the volume of mixing is small and can be ignored.
mal oscillations. These positions give rise to a tempo-
rary molecular dissymmetry resulting in a dipole-type
characteristic. This instantaneous dipole then induces
polar character to the neighboring molecules and
1.2.2 Enthalpy of Mixing
starts interacting with them. The enthalpy of mixing, (ΔHmix), is the difference
between the sum of enthalpies of the solute (Hu), the
solvent (Hv), and of the mixture, (Huv):
Hydrogen Bonding
ΔH mix  H uv  ( Hu  Hv ) (1.3)
These interactions occur between hydrogen bond
donating groups and strong electronegative atoms From a strictly enthalpic standpoint, mixing is
such as halogens, oxygen, and nitrogen. Hydrogen favored if ΔHmix is negative. The excess enthalpy is
atoms become associated with electronegative atoms liberated in the form of heat (exothermic process).
by virtue of electrostatics, and result in the formation The energy of mixing (ΔEmix) is related to the
of hydrogen bridges. These interactions are prevalent enthalpy of mixing as:
in aqueous and alcoholic systems. A large number of
drugs are involved in either inter- or intra-molecular ΔEmix  ΔH mix  P ⋅ ΔVmix (1.4)

I. THEORIES AND TECHNIQUES IN THE CHARACTERIZATION OF DRUG SUBSTANCES AND EXCIPIENTS

6 1. SOLUBILITY OF PHARMACEUTICAL SOLIDS

As previously mentioned, ΔVmix is small, and It follows from Equation 1.10 that the slope will
therefore the values of ΔEmix and ΔHmix are close to be highest in dilute solutions (when either Xu or Xv is
one another. small). Thus, the manifestation of entropy is highest in
dilute solution, which explains why thermodynami-
cally there is some miscibility between all systems.
1.2.3 Entropy of Mixing
The entropy of a pure system is a measure of the 1.2.4 Free Energy of Mixing
randomness of its molecules. Mathematically:
The free energy of mixing, ΔGmix, determines the
S  R ln Ω (1.5) possibility and extent of two compounds mixing to
form a solution. It combines the effects of enthalpy
where: and entropy on mixing and is mathematically
Ω is the number of ways molecules can be present described as:
in the system.
ΔGmix  ΔH mix  T ⋅ ΔSmix (1.11)
Since Ω is always equal to or greater than unity,
entropy is either zero or positive. The entropy of a where:
mixture, (ΔSmix), is related to the number of ways the T is the temperature in Kelvin.
solute and solvent molecules can exist in pure forms, Like any thermodynamic process, mixing will occur
and in mixture: if the free energy of mixing is negative. On the other
⎛ Ωmix ⎞⎟ hand, if the free energy of mixing is greater than zero
ΔSmix  R ln⎜⎜⎜ ⎟ (1.6)
⎜⎝ Ωu  Ωv ⎟⎟⎠
there will be phase-separation. As mentioned in the
previous section, solubility depends on the tempera-
ture of the system. It follows from Equation 1.11 that
Generally, the molecules have more freedom to
an increase in temperature will increase the effect of
move around in a mixture, i.e., Ωmix is greater than
entropy, thus making mixing more favored. In addi-
Ωu  Ωv. As a consequence ΔSmix is usually positive.
tion, temperature may also affect ΔHmix, particularly
However, in rare situations where the molecules have
for hydrogen-bonded solvents such as water. It is well
less freedom in the mixture (solute molecules under-
known that the strength of hydrogen bonding inter-
going complexation-like interactions with solvent
actions is very sensitive to temperature. An increase
molecules),6,7 ΔSmix can be negative.
in temperature makes the self-associated structure of
The entropy of mixing is related to the composition
water weaker. Since the self-associated structure of
of the solution as:
water is primarily responsible for poor aqueous solu-
ΔSmix  R(Xu ln Xu  Xv ln Xv ) (1.7) bility of non-polar solutes, including drugs, increasing
the temperature thereby facilitates their solubility.
where:
Xu and Xv are the mole fractions of the solute and
solvent, respectively, in the mixture.
1.3 THEORETICAL ESTIMATION OF
In a two component system Xv  1  Xu; ΔSmix can
be written as:
SOLUBILITY

ΔSmix  R ⎡⎣ Xu ln Xu  (1  Xu ) ln(1  Xu ) ⎤⎦ (1.8) While solutions of all states of matter (gas, liquid,
and solid) exist in practice, the focus of this chapter
ΔSmix   R ⎡⎣ Xv ln Xv  (1  Xv ) ln(1  Xv ) ⎤⎦ (1.9) will be on solutions comprising of liquid solvent, since
these systems are most commonly encountered and
It follows from Equation 1.7 that ΔSmix will be high- have highest relevance in the pharmaceutical field.
est for solutions containing equimolar amounts of sol- The backbone of the concepts discussed here may be
ute and solvent molecules. applied to other systems, with some modifications.
The slope of entropy of mixing as a function of
solution composition is given by:
∂ΔSmix 1.3.1 Ideal Solutions
 R ln Xu  R ln(1  Xu )
∂Xu In an ideal solution the strength and density of
 R ln Xv  R ln(1  Xv ) (1.10) interactions between the solute molecules and the

I. THEORIES AND TECHNIQUES IN THE CHARACTERIZATION OF DRUG SUBSTANCES AND EXCIPIENTS

 1.3 THEORETICAL ESTIMATION OF SOLUBILITY 7

solvent molecules are equal to that in the solution. In The effect of crystallinity of a solid on its solubility
other words, the solute–solvent interactions are equal is described by the Clausius–Clapyron equation:
in magnitude to the solute–solute interactions and T ( at T )
ΔH m
solvent–solvent interactions. Thus, the solute and sol-
vent molecules have no preference in terms of inter-
Rln Xuideal  ∫ T2
dT (1.15)
Tm
acting with other molecules present in the solutions.
This results in the enthalpy (ΔH mix ideal ) and volume of Xuideal represents the ideal solubility of the crystal and
mixing (ΔVmix ideal ) being 0. Such solutions rarely exist the effect of crystallinity on the solubility.
in practicality, but understanding the concept of ideal According to Kirchoff’s law, the energy of an irre-
mixing provides a good platform to understand more versible process is equal to the energy of a series of
complex systems. A solution comprising of solute and reversible processes between the same end points.
solvent bearing very close structural resemblance (in Therefore, the irreversible enthalpy of melting at any
temperature T(ΔH m T ) can be described as the sum of
terms of functionality and size) may make nearly ideal
solutions. A solution of water in heavy water nearly the enthalpies for the following three reversible proc-
fits the description of an ideal solution. esses: heating the solid to its melting point, Tm (quan-
The entropy of mixing of an ideal solution (ΔSmix ideal ) tified by the heat capacity of the solid); melting the
is given by Equation 1.7. The partial molar entropy of solid at its melting point (enthalpy of fusion); and
mixing of the solute in a dilute solution is given by: cooling the liquid back down to T (quantified by the
heat capacity of the liquid). The heat of melting at T,
can thus be related to its value at the melting point as:
ΔSmix
ideal (u)  R ln X
u (1.12)
ΔH m
T  ΔH Tm  C C (T  T )  C L (T  T )
m p m p m (1.16)
Since Xu is always less than 1, ΔSmix
ideal
is positive.
The free energy of mixing for an ideal solution CpC and CpL are the heat capacities of the crystal and
ideal ), which is the difference between the enthalpy
(ΔGmix liquid form, respectively.
and entropy of mixing, will therefore always be nega- Combining Equations 1.15 and 1.16, the effect of
tive. Thus, in ideal solutions, a liquid solute will be crystallinity can be calculated to be:
miscible with the solvent in all proportions. (Tm  T )
Rln Xuideal  ΔH m
Tm T
ΔGmix
ideal (u)  TR ln X
u (1.13) ⎡ Tm  T T ⎤
 ΔCpm ⎢  ln m ⎥ (1.17)
⎣⎢ T T ⎥⎦
where:
1.3.2 Effect of Crystallinity ΔCpm is the heat capacity of melting.
According to the van’t Hoff expression, the heat
In the case of an ideal solution of a crystalline sol-
capacity of melting is close to zero. The Hildebrand8
ute, more considerations are required. As discussed
expression states that the heat capacity of melting
above, the solute molecules have no preference in
is equal to the entropy of melting (ΔHm/Tm). This
terms of interacting with other molecules in the solu-
expression has been used by several workers includ-
tion. However, if the solute exists as a crystalline solid,
ing Prausnitz et al.,9 Grant et al.,10 and Mishra.11 Later,
the enthalpic component related to the crystallinity of
Mishra and Yalkowsky12 compared the mathematical
the solute also warrants consideration. In other words,
significance of the two expressions and concluded that
the liquid solute molecules are free to move around
the results using either expression are close for solids
in the solution while the crystalline solute molecules
melting below 600K. Thus, Equation 1.17 can be sim-
have to be removed from the crystal lattice before they
plified to the following form:
can start moving around. Mathematically, this can be
(Tm  T )
stated as: log10 ( Xuideal )  ΔH m (1.18)
2.303 RTm T
ideal (u)  X ideal (u)  Effect of Crystallinity
X solid (1.14)
liquid Equation 1.18 may be further simplified by apply-
ing Walden’s rule for entropy of melting. Walden13
The process is conceptually similar to melting of a showed that the entropy of melting of coal tar deriv-
solid, which is followed by dissolution of the liquid atives, which can be assumed to represent organic
solute molecules, and is governed by the same inter- solids like drugs, is constant at approximately 6.9R.
actions as melting. Martin et al.,14 Dannenfelser et al.,15 and Jain et al.16

I. THEORIES AND TECHNIQUES IN THE CHARACTERIZATION OF DRUG SUBSTANCES AND EXCIPIENTS

8 1. SOLUBILITY OF PHARMACEUTICAL SOLIDS

have successfully verified and extended the applicabil- deviation from ideality that is related to the activity
ity of Walden’s rule to several organic nonelectrolytes. coefficient of the solute. The activity of a solute in a
Applying this approximation the effect of crystallinity solution is equal to the product of its concentration
on the solubility of crystalline solute at 25°C can be and activity coefficient as:
calculated by:
αu  Xu ⋅ γ u (1.20)
(crystalline
log10 Xu ) ≈ 0.01( MP  25) (1.19) where:
γu is the activity coefficient of the solute.
where:
MP is the melting point of the solute expressed The mole fraction solubility of a crystalline solute
in °C. in a non-ideal solution can be calculated by combin-
ing Equations 1.19 and 1.20:
The obvious interpretation of Equation 1.19 is
that the effect of crystallinity will be greater for high log10 ( Xureal )  0.01( MP  25)  log γ u (1.21)
melting solutes. It is intuitive that a high melting
crystalline solid will offer greater resistance towards In the case of ideal solutions, γu is 1 and the solubil-
solubilization. It also follows that an increase in tem- ity is ideal.
perature will diminish the effect of crystallinity and The mathematical meaning of γu is derived using
therefore, result in increased solubility. various theories depending upon the type of solute
For liquid solutes, where there is a complete and solvent molecules. Two of the most commonly
absence of crystallinity, Equation 1.19 should be accepted theories are regular solution theory and
omitted while calculating the solubility. The effect of aqueous solution theory.
crystallinity on solubility can be easily followed by
referring to Figure 1.1.
1.3.4 Regular Solution Theory
1.3.3 Non-ideal Solutions This theory is applicable largely to non-hydrogen
bonding systems. According to the theory, γu is a func-
Nearly all solutions encountered in the pharma- tion of following three steps in which mixing occurs:
ceutical arena are not ideal. Non-ideal solutions or
real solutions are formed when the affinity of solute 1. Removal of a solute molecule from the solute
molecules for each other is different than that towards surface. This involves breaking of solute–solute
the solvent molecules or vice versa. In either case, bonds, and the work required to accomplish this is
the enthalpy of mixing is not ideal. This results in a given by Wuu.

Crystal at MP Liquid at MP

ΔHf
Melting

Cp(s)ΔT Heating Cooling Cp(liq)ΔT

Crystal at RT Liquid at RT

 Solvent

Solution
FIGURE 1.1 Role of crystallinity in solubility of solids. Modified from a presentation by Dr Kenneth Morris (Short Course on Solubility
and Solubilization of Drugs, 2007)

I. THEORIES AND TECHNIQUES IN THE CHARACTERIZATION OF DRUG SUBSTANCES AND EXCIPIENTS

 1.3 THEORETICAL ESTIMATION OF SOLUBILITY 9

2. Removal of a solvent molecule from bulk to create Fedor19 has proposed a scheme to estimate solu-
a cavity in which the solute molecule can fit. This bility parameters of liquid organic compounds based
involves breaking of solvent–solvent bonds and on a group contribution approach. Similarly, Sanghvi
the work required for this is given by Wvv. and Yalkowsky20 have proposed a group contribution
3. Insertion of the free solute molecule in the created scheme to estimate the enthalpy of vaporization of
cavity. This results in gain of work, which is given organic compounds.
by Wuv. The cavity filling involves surfaces of both Equations 1.21 and 1.27 can be combined to calcu-
solute and solvent molecules, and that is why the late the solubility of a crystalline solute according to
total work gained is 2Wuv. the regular solution theory:
The total work is therefore equal to (Wuu  Wvv 
2Wuv). The activity coefficient of a solute is related to
(
log 10 Xu
regular
)  0.01( MP  25)
this work by the following relationship: Vu Φv2
 (δu  δv) 2 ⋅ (1.27)
2.303 RT
Vu Φv2
log10 (γ u )  (Wuu  Wvv  2Wuv ) ⋅ (1.22)
2.303 RT It follows from Equation 1.27 that the solubility
of a solute is a function of the difference in the cohe-
where: sive energy densities of the solute and solvent. Thus,
Vu is the molar volume of the solute a liquid solute (no crystal term) with a molar volume
Φv is the volume fraction of the solvent. of 100 ml will be completely miscible in a solvent
It is assumed that Wuv is the geometric mean of Wuu if their solubility parameter difference is less than
and Wvv. Upon applying this assumption, Equation 7(J/cm3)0.5.
1.22 transforms to: The regular solution theory has been applied by
several groups to successfully estimate the solubil-
Vu Φv2
log10 (γ u )  (Wuu  Wvv  2 Wuu ⋅ Wvv ) ⋅ ity of organic compounds in non-polar solvents. It
2.303 RT appears that the geometric mean assumption does
(1.23) not seem to hold well for strongly hydrogen-bonded
Equation 1.23 may be rewritten in the following systems, limiting the applicability of the regular solu-
form: tion theory mainly to organic media. Martin et al.21
proposed a correction factor to cater for the hydrogen-
Vu Φv2
log10 (γ u)  ( Wuu  Wvv ) ⋅
2
(1.24) bonding interactions of the solvent. Similarly, the
2.303 RT extended Hildebrand solubility approach22 utilized
The terms Wuu and Wvv are known as the sol- an extra activity coefficient term to account for strong
ubility parameters of the solute (δu) and solvent (δv), forces, including hydrogen bonding.
respectively. Thus, Equation 1.24 becomes:
Vu Φv2
log10 (γ u )  (δu  δv )2 ⋅ (1.25) 1.3.5 Aqueous Solution Theory
2.303 RT
The solubility parameter is a measure of the cohe- As discussed in the previous section, the regu-
sive energy density (also referred as internal pressure) lar solution theory is not applicable to hydrogen-
of a compound: bonding systems like water, since the geometric mean
assumption is not valid in such systems. Yalkowsky
ΔEv et al.,23,24,25 and later Amidon and Yalkowsky,26 pro-
δ (1.26)
Vm posed that instead of using pressure–volume work to
account for enthalpy of mixing, surface tension–area
ΔEv and Vm are the enthalpy of vaporization and work should be considered. This theory is based on
molar volume, respectively. the concept that only the surface of the solute mole-
The solubility parameter is a measure of intermo- cule is capable of interacting with solvent molecules.
lecular interactions of a compound and can be used as Thus, using surface area instead of volume work is
a measure of polarity. Hildebrand and Scott17 compiled more meaningful. The following equation was pro-
solubility parameters for a number of compounds, posed to calculate the energy requirement for solubili-
and so did Hansen and Beerbower.18 Hansen further zation in an aqueous system:
extended the concept by ascribing contributions of the
 (γ w  γu  γuw )Au
aqueous aqueous
non-polar, polar, and hydrogen-bonding components ΔEu  ΔHu
of a molecule to the total solubility parameter.  ∑ γuw Au (1.28)

I. THEORIES AND TECHNIQUES IN THE CHARACTERIZATION OF DRUG SUBSTANCES AND EXCIPIENTS

10 1. SOLUBILITY OF PHARMACEUTICAL SOLIDS

where: The octanol–water partition coefficient is the ratio

γu and γw are the surface tensions of the pure solute of the activities of the solute in octanol (ao) and that
and water, respectively in water (aw). For dilute solutions where the activity
γuw is the solute–solvent interfacial tension coefficient is close to unity, Kow can be approximated as:
Au is the surface area of the solute.
So
K ow  (1.35)
The entropy of mixing of aqueous systems is also Sw
non-ideal. The water molecules cluster around an
organic solute to form a so-called “iceberg-like” struc- So and Sw are the solubilities of the liquid solute in
ture. The aqueous solution theory accounts for this octanol and water, respectively.
deviation by introducing a correction factor in the
log10 (Sw )  log10 (So)  log10 (K ow ) (1.36)
entropy term:
aqueous Jain and Yalkowsky32 proposed that log10So can be
ΔSu  ΔSuideal  ∑ hi Au (1.29)
replaced by 0.5 for solutes that are completely misci-
hi is the contribution of the entropy of mixing per ble with octanol. The explanation they provided is as
unit area due to “iceberg” formation at the molecular follows.
surface. The concentration of pure octanol is 6.3 molar.
The free energy of mixing of aqueous solution is The saturated solution of a completely miscible sol-
calculated using Equations 1.28 and 1.29: ute of similar molar volume as octanol will contain
3.15 moles of the solute. Since the logarithm of 3.15
 ∑ γuw Au  T ( ∑ hi Au  ΔSuideal ) (1.30)
aqueous
ΔGu is about 0.5, Equation 1.36 can be modified in the fol-
lowing form to give the molar aqueous solubility of a
This can be written as:
liquid solute:
 ∑ γuw Au  T ∑ hi Au
aqueous
ΔGu log10 (Sw )  0.5  log10 (K ow ) (1.37)
 T (RXu ln Xu  Xv ln Xv ) (1.31)
It has been discussed previously that, according
or: to the regular solution theory, the miscibility of a sol-
ΔGu
aqueous
 ∑ gu Au  T (RXu ln Xu  Xv ln Xv ) (1.32) ute with a solvent depends on the difference in their
solubility parameters and molar volumes. Sepassi
gu  γiw Ai  T(hi Ai) is the group contribution to the and Yalkowsky33 have shown that in the case of octa-
activity coefficient which caters to both the enthalpic nol (solubility parameter of 21.1 (J/cm3)0.5 and molar
and the entropic deviations to ideality. volume of 158 cm3), a liquid solute of molar volume
The solubility of a crystalline solute in a hydrogen- 200 cm3 will be completely miscible if its solubility
bonding solvent can be calculated by combining parameter is between 15.2 and 27 (J/cm3)0.5. Since the
Equations 1.21 and 1.32: solubility parameters of most drugs are in this range,
their liquid forms are expected to be completely mis-
(
log10 Xu
aqueous
)  0.01( MP  25)  ∑ gu Au (1.33) cible in octanol.
Consistent with previous discussions, solute crys-
Myrdal et al.27,28,29,30 have developed a robust group tallinity should be to be taken into consideration while
contribution scheme, called the AQUAFAC approach, calculating the solubility of a crystalline solute. Thus,
for estimation of the aqueous activity coefficient of the solubility of a crystalline solute can be estimated
organic compounds. Their work successfully demon- using GSE by combining Equations 1.19 and 1.37:
strates the applicability of aqueous solution theory.
log10 (Sw )  0.5  log 10 (K ow )  0.01( MP  0.5) (1.38)

1.3.6 The General Solubility Equation (GSE) The GSE provides a very simple means of estimat-
ing aqueous solubility. Unlike the regular solution
The general solubility equation utilizes the rela- theory and aqueous solution theories, which require
tion between the octanol–water partition coefficient a number of empirically generated coefficients, GSE
of a solute and its water solubility, first proposed by requires only two input parameters (melting point
Hansch et al.:31 and octanol–water partition coefficient). The measure-
log10 (Sw ) = A log10 (K ow )  B (1.34) ment of both the parameters is a routine part of the
API characterization process. The value of log10Kow
Kow is the octanol–water partition coefficient of a liq- can also be estimated from the chemical structure by
uid solute, while A and B are solute specific constants. using one of several commercially available software

I. THEORIES AND TECHNIQUES IN THE CHARACTERIZATION OF DRUG SUBSTANCES AND EXCIPIENTS

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Title: The Flying Inn

Author: G. K. Chesterton

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*** START OF THE PROJECT GUTENBERG EBOOK THE FLYING INN

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 THE FLYING INN

GILBERT K. CHESTERTON
 BY THE SAME AUTHOR

MANALIVE
HERETICS
ORTHODOXY
GEORGE BERNARD SHAW
ALL THINGS CONSIDERED
THE BALL AND THE CROSS
THE NAPOLEON OF NOTTING HILL
THE INNOCENCE OF FATHER
BROWN
 THE
FLYING INN
BY
GILBERT K. CHESTERTON
AUTHOR OF
“Manalive,” “The Innocence of
Father Brown,” ETC.

NEW YORK
JOHN LANE COMPANY
MCMXIV
 Copyright, 1914, by
JOHN LANE COMPANY
 TO
HUGH RIVIÈRE
 CONTENTS

CHAPTER PAGE

I. A Sermon on Inns 11
II. The End of Olive Island 21
III. The Sign of “The Old Ship” 32
IV. The Inn Finds Wings 41
V. The Astonishment of the Agent 52
VI. The Hole in Heaven 63
VII. The Society of Simple Souls 75
VIII. Vox Populi Vox Dei 86
IX. The Higher Criticism and Mr. Hibbs 97
X. The Character of Quoodle 110
XI. Vegetarianism in the Drawing-Room 122
XII. Vegetarianism in the Forest 136
XIII. The Battle of the Tunnel 149
XIV. The Creature that Man Forgets 166
XV. The Songs of the Car Club 178
XVI. The Seven Moods of Dorian 191
XVII. The Poet in Parliament 205
XVIII. The Republic of Peaceways 221
XIX. The Hospitality of the Captain 235
XX. The Turk and the Futurists 247
XXI. The Road to Roundabout 260
XXII. The Chemistry of Mr. Crooke 276
XXIII. The March on Ivywood 290
XXIV. The Enigmas of Lady Joan 302
XXV. The Finding of the Superman 316
THE FLYING INN
THE FLYING INN
 CHAPTER I

A SERMON ON INNS

The sea was a pale elfin green and the afternoon had already felt the
fairy touch of evening as a young woman with dark hair, dressed in a
crinkly copper-coloured sort of dress of the artistic order, was
walking rather listlessly along the parade of Pebblewick-on-Sea,
trailing a parasol and looking out upon the sea’s horizon. She had a
reason for looking instinctively out at the sea-line; a reason that
many young women have had in the history of the world. But there
was no sail in sight.
On the beach below the parade were a succession of small
crowds, surrounding the usual orators of the seaside; whether
niggers or socialists, whether clowns or clergymen. Here would
stand a man doing something or other with paper boxes; and the
holiday makers would watch him for hours in the hope of some time
knowing what it was that he was doing with them. Next to him
would be a man in a top hat with a very big Bible and a very small
wife, who stood silently beside him, while he fought with his
clenched fist against the heresy of Milnian Sublapsarianism so wide-
spread in fashionable watering-places. It was not easy to follow him,
he was so very much excited; but every now and then the words
“our Sublapsarian friends” would recur with a kind of wailing sneer.
Next was a young man talking of nobody knew what (least of all
himself), but apparently relying for public favour mainly on having a
ring of carrots round his hat. He had more money lying in front of
him than the others. Next were niggers. Next was a children’s
service conducted by a man with a long neck who beat time with a
little wooden spade. Farther along there was an atheist, in a
towering rage, who pointed every now and then at the children’s
service and spoke of Nature’s fairest things being corrupted with the
secrets of the Spanish Inquisition—by the man with the little spade,
of course. The atheist (who wore a red rosette) was very withering
to his own audience as well. “Hypocrites!” he would say; and then
they would throw him money. “Dupes and dastards!” and then they
would throw him more money. But between the atheist and the
children’s service was a little owlish man in a red fez, weakly waving
a green gamp umbrella. His face was brown and wrinkled like a
walnut, his nose was of the sort we associate with Judæa, his beard
was the sort of black wedge we associate rather with Persia. The
young woman had never seen him before; he was a new exhibit in
the now familiar museum of cranks and quacks. The young woman
was one of those people in whom a real sense of humour is always
at issue with a certain temperamental tendency to boredom or
melancholia; and she lingered a moment, and leaned on the rail to
listen.
It was fully four minutes before she could understand a word the
man was saying; he spoke English with so extraordinary an accent
that she supposed at first that he was talking in his own oriental
tongue. All the noises of that articulation were odd; the most
marked was an extreme prolongation of the short “u” into “oo”; as in
“poo-oot” for “put.” Gradually the girl got used to the dialect, and
began to understand the words; though some time elapsed even
then before she could form any conjecture of their subject matter.
Eventually it appeared to her that he had some fad about English
civilisation having been founded by the Turks; or, perhaps by the
Saracens after their victory in the Crusades. He also seemed to think
that Englishmen would soon return to this way of thinking; and
seemed to be urging the spread of teetotalism as an evidence of it.
The girl was the only person listening to him.
“Loo-ook,” he said, wagging a curled brown finger, “loo-ook at
your own inns” (which he pronounced as “ince”). “Your inns of which
you write in your boo-ooks! Those inns were not poo-oot up in the
beginning to sell ze alcoholic Christian drink. They were put up to
sell ze non-alcoholic Islamic drinks. You can see this in the names of
your inns. They are eastern names, Asiatic names. You have a
famous public house to which your omnibuses go on the pilgrimage.
It is called the Elephant and Castle. That is not an English name. It
is an Asiatic name. You will say there are castles in England, and I
will agree with you. There is the Windsor Castle. But where,” he
cried sternly, shaking his green umbrella at the girl in an angry
oratorical triumph, “where is the Windsor Elephant? I have searched
all Windsor Park. No elephants.”
The girl with the dark hair smiled, and began to think that this
man was better than any of the others. In accordance with the
strange system of concurrent religious endowment which prevails at
watering-places, she dropped a two shilling piece into the round
copper tray beside him. With honourable and disinterested
eagerness, the old gentleman in the red fez took no notice of this,
but went on warmly, if obscurely, with his argument.
“Then you have a place of drink in this town which you call The
Bool!”
“We generally call it The Bull,” said the interested young lady, with
a very melodious voice.
“You have a place of drink, which you call The Bool,” he reiterated
in a sort of abstract fury, “and surely you see that this is all vary
ridiculous!”
“No, no!” said the girl, softly, and in deprecation.
“Why should there be a Bull?” he cried, prolonging the word in his
own way. “Why should there be a Bull in connection with a festive
locality? Who thinks about a Bull in gardens of delight? What need is
there of a Bull when we watch the tulip-tinted maidens dance or
pour the sparkling sherbert? You yourselves, my friends?” And he
looked around radiantly, as if addressing an enormous mob. “You
yourselves have a proverb, ‘It is not calculated to promote prosperity
to have a Bull in a china shop.’ Equally, my friends, it would not be
calculated to promote prosperity to have a Bull in a wine shop. All
this is clear.”
He stuck his umbrella upright in the sand and struck one finger
against another, like a man getting to business at last.
“It iss as clear as the sun at noon,” he said solemnly. “It iss as
clear as the sun at noon that this word Bull, which is devoid of
restful and pleasurable associations, is but the corruption of another
word, which possesses restful and pleasurable associations. The
word is not Bull; it is the Bul-Bul!” His voice rose suddenly like a
trumpet and he spread abroad his hands like the fans of a tropic
palm-tree.
After this great effect he was a little more subdued and leaned
gravely on his umbrella. “You will find the same trace of Asiatic
nomenclature in the names of all your English inns,” he went on.
“Nay, you will find it, I am almost certain, in all your terms in any
way connected with your revelries and your reposes. Why, my good
friends, the very name of that insidious spirit by which you make
strong your drinks is an Arabic word: alcohol. It is obvious, is it not,
that this is the Arabic article ‘Al,’ as in Alhambra, as in Algebra; and
we need not pause here to pursue its many appearances in
connection with your festive institutions, as in your Alsop’s beer, your
Ally Sloper, and your partly joyous institution of the Albert Memorial.
Above all, in your greatest feasting day—your Christmas day—which
you so erroneously suppose to be connected with your religion, what
do you say then? Do you say the names of the Christian Nations? Do
you say, ‘I will have a little France. I will have a little Ireland. I will
have a little Scotland. I will have a little Spain?’ No—o.” And the
noise of the negative seemed to waggle as does the bleating of a
sheep. “You say, ‘I will have a little Turkey,’ which is your name for
the Country of the Servant of the Prophet!”
And once more he stretched out his arms sublimely to the east
and west and appealed to earth and heaven. The young lady,
looking at the sea-green horizon with a smile, clapped her grey
gloved hands softly together as if at a peroration. But the little old
man with the fez was far from exhausted yet.
“In reply to this you will object—” he began.
“O no, no,” breathed the young lady in a sort of dreamy rapture. “I
don’t object. I don’t object the littlest bit!”
“In reply to this you will object—” proceeded her preceptor, “that
some inns are actually named after the symbols of your national
superstitions. You will hasten to point out to me that the Golden
Cross is situated opposite Charing Cross, and you will expatiate at
length on King’s Cross, Gerrard’s Cross and the many crosses that
are to be found in or near London. But you must not forget,” and
here he wagged his green umbrella roguishly at the girl, as if he was
going to poke her with it, “none of you, my friends, must forget
what a large number of Crescents there are in London! Denmark
Crescent; Mornington Crescent! St. Mark’s Crescent! St. George’s
Crescent! Grosvenor Crescent! Regent’s Park Crescent! Nay, Royal
Crescent! And why should we forget Pelham Crescent? Why, indeed?
Everywhere, I say, homage paid to the holy symbol of the religion of
the Prophet! Compare with this network and pattern of crescents,
this city almost consisting of crescents, the meagre array of crosses,
which remain to attest the ephemeral superstition to which you
were, for one weak moment, inclined.”
The crowds on the beach were rapidly thinning as tea-time drew
nearer. The west grew clearer and clearer with the evening, till the
sunshine seemed to have got behind the pale green sea and be
shining through, as through a wall of thin green glass. The very
transparency of sky and sea might have to this girl, for whom the
sea was the romance and the tragedy, the hint of a sort of radiant
hopelessness. The flood made of a million emeralds was ebbing as
slowly as the sun was sinking: but the river of human nonsense
flowed on for ever.
“I will not for one moment maintain,” said the old gentleman,
“that there are no difficulties in my case; or that all the examples are
as obviously true as those that I have just demonstrated. No-o. It is
obvious, let us say, that the ‘Saracen’s Head’ is a corruption of the
historic truth ‘The Saracen is Ahead’—I am far from saying it is
equally obvious that the ‘Green Dragon’ was originally ‘the Agreeing
Dragoman’; though I hope to prove in my book that it is so. I will
only say here that it is su-urely more probable that one poo-ooting
himself forward to attract the wayfarer in the desert, would compare
himself to a friendly and persuadable guide or courier, rather than to
a voracious monster. Sometimes the true origin is very hard to trace;
as in the inn that commemorates our great Moslem Warrior, Amir Ali
Ben Bhoze, whom you have so quaintly abbreviated into Admiral
Benbow. Sometimes it is even more difficult for the seeker after
truth. There is a place of drink near to here called ‘The Old Ship’—”
The eyes of the girl remained on the ring of the horizon as rigid as
the ring itself; but her whole face had coloured and altered. The
sands were almost emptied by now: the atheist was as non-existent
as his God; and those who had hoped to know what was being done
to the paper boxes had gone away to their tea without knowing it.
But the young woman still leaned on the railing. Her face was
suddenly alive; and it looked as if her body could not move.
“It shood be admitted—” bleated the old man with the green
umbrella, “that there is no literally self-evident trace of the Asiatic
nomenclature in the words ‘the old ship.’ But even here the see-
eeker after Truth can poot himself in touch with facts. I questioned
the proprietor of ‘The Old Ship’ who is, according to such notes as I
have kept, a Mr. Pumph.”
The girl’s lip trembled.
“Poor old Hump!” she said. “Why, I’d forgotten about him. He
must be very nearly as worried as I am! I hope this man won’t be
too silly about this! I’d rather it weren’t about this!”
“And Mr. Pumph to-old me the inn was named by a vary intimate
friend of his, an Irishman who had been a Captain in the Britannic
Royal Navy, but had resigned his po-ost in anger at the treatment of
Ireland. Though quitting the service, he retained joost enough of the
superstition of your western sailors, to wish his friend’s inn to be
named after his old ship. But as the name of the ship was ‘The
United Kingdom—’”
His female pupil, if she could not exactly be said to be sitting at
his feet, was undoubtedly leaning out very eagerly above his head.
Amid the solitude of the sands she called out in a loud and clear
voice, “Can you tell me the Captain’s name?”
The old gentleman jumped, blinked and stared like a startled owl.
Having been talking for hours as if he had an audience of thousands,
he seemed suddenly very much embarrassed to find that he had
even an audience of one. By this time they seemed to be almost the
only human creatures along the shore; almost the only living
creatures, except the seagulls. The sun, in dropping finally, seemed
to have broken as a blood orange might break; and lines of blood-
red light were spilt along the split, low, level skies. This abrupt and
belated brilliance took all the colour out of the man’s red cap and
green umbrella; but his dark figure, distinct against the sea and the
sunset, remained the same, save that it was more agitated than
before.
“The name,” he said, “the Captain’s name. I—I understood it was
Dalroy. But what I wish to indicate, what I wish to expound, is that
here again the seeker after truth can find the connection of his
ideas. It was explained to me by Mr. Pumph that he was rearranging
the place of festivity, in no inconsiderable proportion because of the
anticipated return of the Captain in question, who had, as it
appeared, taken service in some not very large Navy, but had left it
and was coming home. Now, mark all of you, my friends,” he said to
the seagulls “that even here the chain of logic holds.”
He said it to the seagulls because the young lady, after staring at
him with starry eyes for a moment and leaning heavily on the railing,
had turned her back and disappeared rapidly into the twilight. After
her hasty steps had fallen silent there was no other noise than the
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