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Medical knowledge is constantly changing. As new information becomes available, changes in treatment, procedures, equipment and the use of drugs become necessary. The authors, editors, contributors and the publisher have, as far as it is possible, taken care to ensure that the information given in this text is accurate and up-to-date. However, readers are strongly advised to con rm that the information, especially with regard to drug dose/usage, complies with current legislation and standards of practice. Please consult full prescribing information before issuing prescriptions for any product mentioned in the publication.
Note that the multiple choice questions presented in this book are prepared by memory based data received from various students who have appeared in such competitive examinations. Neither the Publisher nor the Author is in anyway associated to the boards conducting such examinations. The Author and the Publisher have tried to the best of their abilities to provide most recent and scienti cally accurate information. However, in view of the possibility of human and typographical errors or advancement in medical knowledge, readers are advised to con rm the information contained herein with other sources. It is the responsibility of the readers to rely on their experience and knowledge to determine the appropriate responses while attempting the examinations. Neither the Publisher nor the Authors assume any liability for any loss/injury and/or damage to persons or property arising from this publication..
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Dedication
Dedicated to my Parents and Grandparents
Foreword
Physical pharmacy is the foundation for learning and understanding the physicochemical properties of drug molecules, developing products and formulations and establishing stability and shelf life of medicines. Besides, its knowledge provides the basis of explaining physiological processes in human body including drug absorption, distribution, metabolism and elimination. One can also predict, on the basis of physical pharmacy, the therapeutic behaviour including interactions, adverse drug reactions and contraindications. Its knowledge is useful to understand A–Z of drug and product development.
Before the advent of physical pharmacy about 60 years ago, the drug products were empirically prepared without sound basis. Now the formulations have become more rational, reliable and reproducible with reduced side e ects.
Voluminous literature exists in the form of both text/reference books and research papers dealing with di erent aspects and facets of physical pharmacy. The authors of this textbook are experienced teachers at Hamdard University, New Delhi. Dr Gaurav Kumar Jain is a young, budding and enthusiastic Assistant Professor associated with teaching of the subject for about six years. He has a clear understanding of the requirement of the student and has very
discerningly provided the theoretical basis, practice exercises and objective questions with their answers. Another author, Dr Farhan Jalees Ahmad, Associate Professor of Pharmaceutics with about 13 years of teaching and 7 years of industrial experience, has given it a touch of necessary application aspect in product development. Prof. Roop Krishen Khar, the third author, is a renowned pharmacy teacher of over 30 years experience of teaching and research in pharmaceutics in general and physical pharmacy in particular. The present book has a avour of his in-depth knowledge.
The book Theory and Practice of Physical Pharmacy, being published by Elsevier, comprises 12 chapters on theoretical aspects, which ow in rational and systematic order embodying salient details. In practice section the authors have included relevant exercises to illustrate the theoretical problems. Finally, objective questions and answers have made a useful appendix from the students' point of view. The book is well written with necessary details. It should prove extremely useful to students pursuing the rst degree course in pharmacy.
S.N. Sharma Professor Emeritus Hamdard University, New Delhi
Preface
While sitting on the bench in the classroom during my graduation I found it di cult to understand the fundamentals of physical pharmacy. Even after a decade of my student years, I still nd the present-day students with a confounded expression on their face during physical pharmacy lectures.
The book Theory and Practice of Physical Pharmacy, by Elsevier, has had a long period of gestation. The concepts espoused in this book are a result of the rst-hand experience that I have garnered while delivering undergraduate and postgraduate lectures at Hamdard University.
The fundamentals of physical pharmacy are utilized in nearly all aspects of the professional pharmacy curriculum. All unit operation procedures, from distillation and evaporation processes to more advanced drug nano-sizing methodologies, require knowledge of states of matter (Chapter 1). The basics for developing solid oral formulations rely on powder micromeritics (Chapter 2) whereas those of liquid formulations rely on principles of rheology (Chapter 3). Many promising drug candidates fail to make it through human drug development owing to poor biopharmaceutical properties. Biopharmaceutical properties of such drug candidates can be improved by applying the concepts of surface tension (Chapter 4)
or by pH modulation using bu er systems (Chapter 5) or by formation of a stable complex (Chapter 6). Further, study of protein binding of drug is an essential component of understanding its pharmacokinetics and pharmacological action. Another way out to improve bioavailability of drugs with poor aqueous solubility is to formulate them as colloidal or coarse dispersions and therefore study of properties, fundamental concepts, formulation aspects and stability of these dispersions (Chapters 7, 8 and 9) are of utmost importance. Drug release from a dosage form is a key prerequisite for the drug to be systemically e ective. Therefore understanding the mechanism of drug release is of prime importance in the product development strategy (Chapter 10). The release studies also help to develop novel strategies for spatial and temporal delivery. Assessment of product quality through dissolution testing methodologies is an essential component to form robust and reliable drug products. The dissolution test not only guides formulation development but also helps predict in vivo performance of the dosage form (Chapter 11). Finally, a drug product that remains stable until it is consumed by the patient requires the knowhow of degradation kinetics and methods to prevent and assess degradation (Chapter 12).
This book presents, in a mechanistic, quantitative manner, many of the necessary fundamentals and their real practical applications. The text utilizes the expertise of renowned pharmacy teachers and
my guides, Dr Farhan J. Ahmad and Prof. Roop K. Khar. The book is divided into three major parts, as mentioned below:
Part A (Theory) includes theoretical principles written and explained in a logical and easy-to-understand language to guide professional students and pharmaceutical scientists engaged in drug product development. Highlights present within the chapters illustrate important concepts. Each chapter contains solved examples to allow students to apply concepts in problem-solving exercises.
Part B (Practicals) includes exercises where a student could apply his or her theoretical concepts to real practical situations. Practicals included in the textbook are indeed useful for application-based understanding and learning.
Part C (Multiple Choice Questions) consists of multiple choice questions along with their answers useful for GPAT aspirants.
Gaurav K. Jain
Farhan J. Ahmad Roop K. Khar
Acknowledgements
We are immensely grateful to all the contributing authors who have shared their research and industrial knowledge with us. We are also thankful to Mr Mayank Singhal, Ms Neha Mallick, Ms Ayesha Anjum Baig and Ms Vaidehi Garg for their assistance in typing of several chapters, linguistic corrections and feedback on the chapters.
We hope that the book will be useful not only for the students of pharmaceutical sciences but also for the students of cognate disciplines interested in pharmaceutical formulation development.
Gaurav K. Jain
Farhan J. Ahmad
Roop K. Khar
Contributors
Nitin Jain Research Associate
Nanomedicine Laboratory, Faculty of Pharmacy, Hamdard University, New Delhi, India
Musarrat H. Warsi Research Fellow
Department of Pharmaceutics, Faculty of Pharmacy, Hamdard University, New Delhi, India
Jayabalan Nirmal Post Doctoral Research Fellow
Urology Research, Oakland University William, Beaumont School of Medicine, Royal Oak, Michigan, USA
Shadab A. Pathan Assistant Manager
New Product Development, GlaxoSmithKline Consumer, Healthcare Ltd., Gurgaon, India
Part A Theory
States of Matter
Matter is de ned as anything that has mass and occupies space. It exists in several di erent states such as gaseous, liquid, solid, plasma and Bose–Einstein condensates. Each state of matter has unique physical properties. Gases and liquids take the shape of the containers in which they are placed, whereas solids have their own particular shapes. Gases are easily compressed, but liquids and solids do not. Apart from the above-mentioned states, certain molecules lie between the liquid and crystalline states so called mesophase or liquid crystals. Supercritical uids are also considered as mesophase having properties intermediate between those of liquids and gases. Generally, as the temperature or pressure increases matter moves to a more active state and one can observe a physical change.
Highlights
Temperature and pressure are the two important factors that determine whether a substance exists in gaseous, liquid or solid state.
Gaseous State
A gas is a compressible uid and has no de nite shape or volume, but occupies the entire container. The kinetic energy of a gas is so high that the e ect of intermolecular forces is nil, and thus the intermolecular distances are very large. A gas, at temperatures below its critical temperature, is called a vapour, and can be lique ed without cooling by compression alone.
Ideal Gas Law
Several laws that are signi cantly used to describe the behaviour of gases are as follows:
Boyle's Law
This law de nes the relationship between the volume of a gas (V) and pressure (P) if the temperature and amount of gas are held constant. According to Boyle's law, at constant temperature, the volume of a gas is inversely proportional to pressure. The law is expressed mathematically as:
(1.1)
Charles' Law
This law de nes the relationship between volume of a gas and temperature (T) and states that at constant pressure, the volume of a
gas is directly proportional to the temperature.
Gay-Lussac's Law
This law characterizes the relationship between pressure of the gas and temperature when volume of gas is held constant. According to this law, at constant volume, the pressure of a gas is directly proportional to temperature. The law is expressed mathematically as:
Avogadro's Law
Unlike temperature and pressure, volume is an extensive property, which is dependent on the amount of substance present in the system. Avogadro law states that at constant temperature and pressure, the volume of a gas is directly proportional to the number of moles of the gas (n).
Combining Eqs. (1.1) and (1.2) with Eq. (1.4) gives the ideal gas law. The ideal gas law is a state of a hypothetical ideal situation and relates temperature, pressure and volume of an ideal or a perfect gas.
According to ideal gas law:
(1.5)
where P is pressure, V volume, n the number of moles, T the temperature and R the gas constant or proportionality constant.
The gas constant is determined experimentally by plotting PV against P and extrapolating to zero pressure (see Fig. 1.1). As one mole of an ideal gas occupies 22.414 L at 1 atmospheric pressure and 0°C, therefore, R is calculated as:
Figure 1.1 Plot of product of pressure and volume of gas versus pressure.
Molecular Weight Determination
If the number of moles of gas (n) is replaced by its equivalent grams of gas (g) per molecular weight (M), then Eq. (1.5) is used to calculate the approximate molecular weight of a gas using equation:
Example 1.1 (Ideal Gas Law)
Calculate the volume occupied by 23.6 g of tri uorochloroethane at 55°C and 720 mmHg pressure.
Solution
According to Eq. (1.6)
Real Gases
As the temperature of a gas is lowered and/or its pressure is increased, the ideal gas law is not followed because the volume of the gas is not negligible and intermolecular forces do exist, van der Waals proposed the incorporation of two constant terms, a and b, to account for the deviations from ideal behaviour. The ideal gas law equation then becomes:
The constant a accounts for the cohesive forces between the gas molecules and constant b accounts for the incompressibility of the gas molecules known as the excluded volume occupied by the gas molecules. Due to the cohesive forces between the gas molecules the pressure of the real gas is less than that of an ideal gas. These forces are dependent on the intermolecular distances and related to the density of the gas. The term a/V2 in Eq. (1.7) is called as internal pressure per mole, whereas term (V b) represents the e ective volume of the gas molecules that expand freely. At low pressure conditions, the volume of the gas molecules is large and the contribution of the excluded volume is very small. Under these conditions the term b becomes negligible and Eq. (1.7) is reduced to the ideal gas law (Eq. 1.5).
Liquid State
The liquid state lies between the gaseous and the solid state since there is neither the complete disordered arrangement of constituents as in gases nor the ordered arrangement as in solids. By and large the properties of liquids resemble those of gases while some of the properties approach those of the solids. Like a gas, a liquid can assume the shape of a container and can evenly distribute the applied pressure to every surface in the container. However, unlike a gas, a liquid may not always ll every space in the container, may not compress signi cantly and will not always mix readily with another liquid. The density of liquid is close to that of solid but unlike a solid, the molecules in a liquid have a much greater freedom to move allowing a liquid to ow.
Properties of liquids can be explained on basis of their following characteristics:
1. Molecules of liquid are in state of random motion but the motion is appreciably smaller in comparison to gases. This explains the incompressibility and higher density of liquids in comparison to gases.
2. The kinetic energy of the molecules of liquid and thus the vapour pressure of the liquid, increases with increase in temperature of the liquid.
3. Force of attraction exists between the molecules of a liquid and is about 106 times as strong as in gases. These forces are not strong enough to hold the molecules of liquid in xed position but are strong enough to disallow them from separating
spontaneously. The properties of liquids such as (1) viscosity, (2) surface tension and (3) vapour pressure can be explained in terms of these attractive forces.
Viscosity
Viscosity of a liquid is de ned as resistance to ow of liquids. The resistance to ow is developed because of the shearing e ect when one layer of liquid moves past another. The detailed description of the viscosity, viscous ow, its measurement and applications has been discussed in Chapter 3.
Surface Tension
A molecule in the bulk of liquid is surrounded by other molecules and is attracted equally in all the directions. The net force on molecule at bulk is zero. However, the molecules on the surface of liquid are subjected to unbalanced forces and are in a higher energy state compared to the bulk phase molecules. The molecules at the surface experience net inward pull because of greater number of molecules per unit volume in the liquid than in the vapour (see Fig. 1.2).
Figure 1.2 Representation of attractive forces on molecules of liquid.
Because of this inward pull, the surface of the liquids tends to contract and attain minimum possible area and behave as if it were in a state of tension. The force that counter balances this inward pull is known as surface tension. The detailed description of the surface tension, its measurement and applications has been discussed in Chapter 4.
