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`

`
`Entered according to Act of Congress, in the year 1885 by Joseph P Remington,
`in the Office of the Librarian of Congress, at Washington DC
`
`Copyright 1889, 1894, 1905, 1907, 1917, by Joseph P Remington
`
`Copyright 1926, 1936, by Joseph P Remington Estate
`
`Copyright 1948, 1951, by The Philadelphia College of Pharmacy and Science
`
`Copyright © 1956, 1960, 1965, .1970, 1975, 1980, 1985, 1990, by The Philadelphia College of
`Pharmacy and Science
`'
`
`All Rights Reserved
`
`Library of Congress Catalog Card No. 60-53334
`ISBN 0-912734-O4-3
`
`The use of structural formulas from USAN and the USP Dictionary of Drug Names is by
`permission of The USP Convention. The Convention is not responsible for any inaccuracy
`contained herein.
`
`NOTICE—This text is not intended to represent, nor shall it be interpreted to be, the equivalent
`of or a substitute for the official United States Pharmacopeia (USP) and/or the National
`Formaiary (NF). In the event of any difference or discrepancy between the current official
`USP or NF standards of strength, quality, purity. packaging and labeling for drugs and
`representations of them herein, the context and effect of the official cornpendia shall
`prevail.
`
`Printed in the United States of America by the Mach Printing Company, Easton, Pennsylvania
`
`Astrazeneca Ex. 2081 p. 2
`
`

`
`Table of Contents
`
`Part 1
`
`Orientation
`
`.
`.
`.
`.
`. . . . . . .
`.
`.
`.
`.
`. .
`. . . . . .
`.
`. . . .
`. . . . .
`.
`.
`Scope .
`1
`.
`.
`.
`.
`. . . . . . . .
`.
`.
`.
`2 Evolution of Pharmacy .
`. . . . . .
`. . .
`.
`. . . . . . . .
`.
`.
`.
`3 Ethics
`.
`.
`.
`. . . . .
`. . . .
`.
`. . . . . . . .
`4 The Practice of Community Pharmacy . . . . . . . .
`. .
`5 Opportunities for Pharmacists in the Pharmaceuti-
`cal industry . . . . . . . .
`.
`. . . . . . .
`. . .
`.
`. . . . . . .
`. .
`. .
`6 Pharmacists in Government
`. . . .
`.
`. . . . . . . . . .
`.
`. .
`7 Druginformation...........................
`8 Research . . .
`. . . . .
`
`Part 2
`
`Pharmaceutics
`
`.
`. . .
`. . . . . . .
`.
`.
`.
`.
`9 Metrology and Calculation . . . .
`.
`.
`.
`.
`. . . . . .
`. .
`.
`.
`10 Statistics . . . . . . . . . .
`. . . . . . . . . .
`.
`.
`.
`.
`. . . . . . . .
`.
`.
`11 Computer Science . .
`.
`. . . . . . . . .
`. . .
`. . . . . . . . . ..
`12 Calculus . .
`. . . . . . .
`13 Molecular Structure. Properties and States of
`. .
`.
`.
`Matter
`. .
`. . . . . . . . . .
`.
`. . . . . . .
`. .
`.
`.
`. . . . . . .
`. ..
`.
`14 Complex Formation .
`. .
`. . . . .
`.
`.
`. . .
`.
`15 Thermodynamics...........................
`16 Solutions and Phase Equilibria .
`.
`. .
`.
`. . . . . . . . .
`. .
`17
`Ionic Solutions and Electrolytic Equilibria . . . . . .
`. .
`13 Reaction Kinetics .
`.
`.
`.
`. . . . . . . .
`.
`.
`.
`. . . . . . . . . .
`. .
`19 Dlsperse Systems . . .
`. . . .
`. . . . . . .
`.
`. . . . . . . . .
`.
`. .
`20 Rheology . . . . . .
`. . . .
`. .
`. . . . . .
`.
`.
`. . .
`. . . . . .
`.
`.
`. .
`
`Part 3
`
`Pharmaceutical Chemistry
`
`. . . . .
`inorganic Pharmaceutical Chemistry . . .
`21
`. . . . .
`22 Organic Pharmaceutical Chemistry . . . .
`23 Natural Products
`. . .
`.
`. . . .
`. . . . . . .
`.
`. . . . . . . .
`24 Drug Nomenc|ature—United States Adopted
`Names . .
`. . . . . . . . . .
`.
`.
`. . . . . . . . . .
`. . . . . . . . . . .
`25 Structure-Activity Relationship and Drug
`Design . .
`. . .
`. . . . . . .
`.
`. . . . . . . . . .
`.
`. . . . . . . .
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`
`. .
`
`Part 4
`
`Testing“ and Analysis
`
`.
`. .
`
`.
`.
`
`26 Analysis of Medicinais
`27 Biological Testing . . .
`23 Ci|nicaiAnalysis
`.
`29 Chromatography . . .
`.
`30 instrumental Methods of Analysis
`31 Dissolution . . . .
`. . . .
`.
`. . . . . . . .
`. . .
`
`. . . . . . .
`. . .
`.
`.
`
`. . . .
`. . .
`.
`. . . . . .
`
`. .
`. .
`
`. . . .
`. .
`. .
`
`.
`.
`
`. . . . . . . .
`. . . . . . . .
`
`.
`.
`
`. .
`.
`.
`
`3
`8
`20
`28
`
`33
`38
`49
`60
`
`69
`104
`138
`145
`
`153
`162
`197
`207
`226
`247
`257
`310
`
`329
`356
`380
`
`412
`
`422
`
`435
`434
`495
`529
`555'
`589
`
`Part 5
`
`Iladioisotopes in Pharmacy and Medicine
`
`.
`32 Fundamentals of Raciioisotopes . . . . . . . . . . . .
`33 Medical Applications of Radiolsoiopes
`. . . . . . .
`
`. .
`. .
`
`605
`624
`
`Pharmaceutical and Medicinal Agents
`Part 6
`34 Diseases: Manifestations and Patho-
`physiology 655
`35 Drug Absorption. Action and Disposition . . . .
`.
`.
`.
`.
`697
`36 Basic Pharmacokinetics . . . . .
`. .
`.
`. . . . . . . . . .
`. . .
`.
`725
`37 Clinical Pharmacol-rlnetics . . . . .
`.
`. . .
`. . . . .
`. . . .
`.
`.
`746
`36 Topical Drugs . . . . .
`. .
`. .
`. . . . . .
`.
`. . .
`. . . . .
`. . . . . .
`757
`:39 Gastrointestinal Drugs . . . . . . . . .
`.
`.
`. . . . . . . . . . .
`.
`774
`40 Blood, Fluids. Electrolytes and Hematologic
`.
`.
`Drugs
`. . .
`. . . . . . . . . .
`.
`.
`. . . . . . . . .
`.
`. . . . . . . . .
`‘41
`Cardiovascular Drugs
`. .
`. .. . . . .
`.
`.
`.
`.
`. . . . .
`. . . . . .
`42 RespiratoryDrugs
`.
`. . . . ..
`43 Sympathomimetic Drugs . . . . . .
`. . . . .
`. . . .
`.
`.
`
`.
`
`. . .
`
`800
`631
`860
`870
`
`44
`45
`
`46
`47
`45
`49
`50
`51
`52
`53
`54
`55
`56
`57
`58
`59
`60
`61
`62
`63
`64
`65
`66
`67
`68
`69
`70
`
`71
`72
`
`73
`74
`
`75
`76
`77
`73
`79
`B0
`31
`82
`33
`
`64
`35
`36
`87
`86
`89
`90
`9 1
`92
`
`93
`94
`95
`96
`
`xv
`
`. . . .
`
`339
`. . . . . .
`. . . . . .
`. . .
`Chollnomimetic Drugs . . . .
`‘
`Adrenergic and Adrenergic Neuron Blocking
`Drugs 898
`Antlmuscarinic and Antisposmodic Drugs
`. . . . . . .
`907
`1 Skeletal Muscle Relaxants . . .
`. . . . .
`. - -
`- '-
`-
`-
`- - - -
`916
`DlureticDrUgs
`. . . .
`929
`. . . . . . . . . . . . . .
`Uterine and Antimigralne Drugs
`943
`Hormones . . . .
`. .
`. . . .
`. . . .
`. .-.
`. . . . . . . . . . . .
`. . . .
`943
`Vitamins and Other Nutrients .
`. . .
`. . . . . . . . . . . . .
`1002
`Enzymes
`. . . . .
`.
`. . . . .
`. . . .
`.
`.
`. . .
`. . . . . . . . . . . . .
`1035
`General Anesthetics . .
`. . . . . .
`. . .
`. . . . . .
`.
`.
`. . . . .
`1039
`Local Anesthetics . . . . . . . . . . .
`. . .
`. . . . . .
`. . . . . . .
`1043
`Sedatlves and Hypnatics . .
`. . .
`. .
`. . .
`. . . .
`.
`.
`. . . . .
`1057
`Antlepileptlcs
`. . . . . . . . . ..
`1072
`. . .
`Psychopharmacologic Agents
`. . . . . .
`.
`. . . . . .
`1052
`Analgesics and Antlpyreiics .. . . .
`. . .
`. . .
`.
`. .
`. . . .
`1097
`Histamine and Antihistamines . . .
`. . .
`. . .
`.
`. . . . ..
`1123
`Central Nervous System Stimulants . . . . . .
`.
`. . . . .
`1132
`Antineoplastlc and immunosuppressive Drugs . . .
`1133
`Antimicrobial Drugs . . . . . . .
`.
`.
`. . . . . . . . .
`.
`.
`. . . . .
`1163
`Parasiticides . .
`.
`. .
`. . . . . . .
`. . .
`. . . . . . . . .
`.
`. . . . . .
`1242
`Pesticides . . .
`.
`. . . .
`. . . .
`. .
`.
`.
`.
`. . . . . . . . . . . . . . . .
`1249
`Diagnostic Drugs
`. .
`. . . . . . . . . . . . .
`. . . . .
`.
`.
`. . . . .
`1272
`Pharmaceutical Necessities
`. . . . . .
`. . . . .
`.
`.
`. . . . .
`1266
`Adverse Drug Reactions .
`. . . . . . . . . . . . .
`.
`.
`. . . . .
`1330
`_Pharmacogenetics
`1344
`. . . . . . .
`Pharmacological Aspects of Drug Abuse .
`1349
`introduction of New Drugs
`.
`.
`. .
`. . . . . . . . . . . . . . .
`1365
`
`Port 1
`
`Ilioiogical Products
`
`. . .
`. . .
`. .
`. .
`Principles oi Immunology . . .
`immunizing Agents and Diagnostic Skin
`Antigens
`A|iergenicEr-(tracts
`Biotechnology and Drugs . .
`
`.
`
`.
`
`. . .
`
`. . . .
`
`. .
`
`.
`
`.
`
`. . . . .
`
`1379
`
`1369
`1405
`1416
`
`.
`
`.
`
`. . . . .
`
`Part 8
`
`Pharmaceutical Preparations and Their
`Manufacture
`
`. . . . . . . . . . ..
`Preformulation
`Bioavailobility and Bioequivalency Testing . . . . .
`Separation . . .
`. .
`. . . .
`. . . .
`. .
`.
`. . . . .
`. . . . . .
`. . . . .
`Sterilization . . . .
`. . . . . . . . .
`.
`. . .
`. . . . .
`. . . . . . . . .
`Tonlclty, Osmoticity, Osmoiaiity and Osmolarity .
`Plastic Packaging Materials
`.
`.
`. .
`. . . . . . .
`.
`.
`. . . . .
`Stability of Pharmaceutical Products
`. . . . . .
`. . . . .
`Quality Assurance and Control
`. . . . . . . .
`.
`. .
`. . . .
`Solutions, Emulsions, Suspensions and
`Extractives .
`. . . . .
`.
`.
`. . . .
`. . . . .
`.
`.
`. . . . . . .
`Parenteral Preparations . . . . . .
`.
`. .
`. . . . . .
`intravenous Admixtures . . . . . .
`. . .
`. . . . . .
`Ophthalmic Preparations . . .
`.
`.
`. . .
`. . . . . .
`Medicated Applications .
`. .
`. . .
`.
`. .
`. . . . . .
`Powders . . . . . .
`.
`. . .
`. . . . . . .
`.
`.
`.
`. . . . . . . .
`Oral Solid Dosage Forms .
`. . . . .
`.
`. . . . . . . .
`Coating of Pharmaceutical Dosage Forms .
`Sustained-Release Drug Delivery Systems
`Aerosols
`
`. . .
`.
`. .
`.
`. . . . .
`.
`. . . . .
`.
`. . . . .
`.
`. . . . .
`.
`. . . . .
`.
`. . . . .
`. . . . . .
`. . . . . .
`
`1435
`1451
`1459
`1470
`1431
`1499
`1504
`1513
`
`1519
`1545
`1570
`1561
`1596
`1615
`1633
`1666
`1676
`1694
`
`Part 9
`
`Pharmaceutical Practice
`
`. . .
`. .
`Ambulatory Patient Care . . . .
`. . .
`institutional Patient Care .
`.
`.
`. . .
`Long-Term Care Facilities . . . .
`. . . . .
`The Pharmacist and Public Health . .
`
`. . . .
`. . . .
`. . . .
`. .
`. .
`
`.
`.
`.
`.
`
`.
`.
`.
`.
`
`. . . . .
`. . . . .
`. . . . .
`. . . . .
`
`1715
`1737
`1758
`1173
`
`Astrazeneca Ex. 2081 p. 3
`
`

`
`97
`96
`99
`100
`101
`102
`103
`104
`105
`
`The Patient: Behavioral Determinants . .
`Patlentcommunlcotion
`DrugEducation
`. . . . . . .
`. .
`.
`.
`Patient Compliance
`. . . . . ._ . . . .
`.
`The Prescription . . . .
`.
`. . . . . . . . .
`.
`Drug Interactions . . .
`Clinical Drug Literature . .
`. . .
`. . . .
`Health Accessories
`.
`.
`. . . . . .
`. . . .
`
`.
`.
`.
`. . .
`. . .
`.
`.
`.
`.
`.
`.
`
`. . .
`. . .
`. .
`.
`. . .
`. . .
`
`.
`
`. . . . .
`
`.
`
`.
`
`. . . . . . .
`. . . . .
`.
`.
`. . . . .
`.
`.
`. . . . .
`.
`.
`. . . . .
`.
`.-
`
`106
`107
`105
`
`109
`
`1788
`1796
`1803
`1813
`1628
`1642
`1859
`1664
`
`. . . . .
`. . .
`.
`.
`. . . .
`. . . . .
`.
`.
`.
`.
`.
`Poison Control
`. . . . . . . .
`.
`.
`Laws Governing Pharmacy . . .
`Community Pharmacy Economics and
`. . . . . .
`Management
`. .
`. .
`.
`.
`. . . . . . . .
`. .
`.
`. . .
`Dental Services .
`.
`.
`.
`-. . .’.
`. . . . . .
`._
`. . .
`. . . . .
`.
`.
`
`.
`.
`
`.
`.
`
`. . .
`. . .
`
`. . .
`. . .
`
`1905
`1914
`
`1940
`1957
`
`Index
`
`Surgical Supplies . . . . .
`
`. . . . . . . . .
`
`. . .
`
`. .
`
`. . . . . .
`
`. .
`
`1895'
`
`Alphabetic Index .
`
`. . . . . . . . . . .
`
`.
`
`.
`
`. . . .
`
`. . . . .
`
`.
`
`. .
`
`1967
`
`xvi
`
`Astrazeneca Ex. 2081 p. 4
`
`

`
`CHAPTER 75
`
`, Preformulafion
`
`
`Louis J llavln. PhD
`Department of Pharmaceutics
`Research 6 Development
`Smith Kline 6 French Laboratories
`King of Prussia. PA 19406
`
`Galen W Radebough. PhD
`Director of Pharmaceutics
`Parke-Davis Pharmaceutical Research Division
`Warner-Lambert Co
`Morris Plains, NJ 07950
`
`areas of science in order to acquire scientific information
`about the drug substance which is necessary to develop an
`optimum dosage form. The pharmaceutical industry is in
`an era in which one can no longer rely on past experience to
`formulate. A thorough understanding of the physical and
`chemical properties as well as the pharmacokinetic and bio-
`pharmaceutical behavior of each drug substance being de-
`veloped is necessary.
`In short, as much information as pos-
`sible must be acquired about the drug substance very early
`in its development. This requires an interdisciplinary ap-
`proach at the preformulation stage of development. Fig 75-
`1 schematically indicates that the development of any drug
`product requires a multidisciplinary approach, involving ba-
`sic science, during the preformulation stage followed by ap-
`plied science during the development stage.
`This chapter will discuss the physical-chemical evaluation
`that takes place during the preformulation stage of develop-
`ment.
`In addition, consideration will be given to some spe-
`cialized formulation ingredients that may require discretion
`in their selection.
`Preformulation may be described as a stage of develop-
`lment during which the physical pharmacist characterizes
`the physical-chemical properties of the drug substance in
`question which are considered important in the formulation
`of a stable, effective and safe dosage form. Such parameters
`as crystal size and shape, pH-solubility profile, pl-I-stability
`profile, polymorphism, partitioning effect, drug permeabili-
`ty and dissolution behavior are evaluated. During this eval-
`uation possible interactions with various inert ingredients
`intended for use in the final dosage form also are considered.
`The data obtained from this evaluation are integrated with
`data obtained from the preliminary pharmacologic and bio-
`chemical studies and provide the formulating pharmacist
`with information that permits selection of the optimum dos-
`- age form containing the most desirable inert ingredients for
`use in its development.
`
` TOXICOLOGY
`
`
`_, PHARMACOLOGY
`
`
`
`ANALYTICAL
`
`PREFORMULANON
`FORMUlAYION
`
`MARKETING
`
`The attention presently being given to multisource phar-
`maceutical products regarding their equivalency places
`much emphasis on the formulation of these products.
`In
`some instances, the bioavailability of a drug formulation
`represents a quality parameter of enormous proportion.
`It
`is a matter of record that with certain drugs, depending on
`the formulation, the rate at which the drug substance be-
`comes available can vary significantly from very high to none
`at all. As a result, the effectiveness of these formulations
`will range dramatically from that expected to no effect. Un-
`fortunately, most examples are less dramatic and fall some-
`where in between. The difference in the bioavailability of
`these drug products is less readily discernible, but nonethe-
`less real. This has led to a great deal of confusion and
`information which, though understood by the scientist, is
`unclear and jumbled to the practitioner. That information
`which is available also has been interpreted differently by
`different individuals or groups, depending very often on the
`motivation, viewpoint and attitude of the interpreter.
`Drug products indeed do vary in their bioavailability char-
`acteristics and this variation, in most instances, is related
`directly to formulation considerations. To optimize the
`performance of drug products, it is necessary to have a com-
`plete understanding of the physical-chemical properties of
`drug substances prior to formulating them into drug prod-
`ucts. The development of an optimum formulation is not an
`easy task, and many factors readily influence formulation
`properties. Drug substances rarely are administered as
`chemical entities, but almost always aregiven in some kind
`of formulation. These may vary from a simple solution to a
`very complex drug delivery system. The complexity usually
`is not intentional, but rather is determined by the properties
`that are expected from or built into the dosage form and by
`the resulting composition that is required to achieve these
`qualities.
`The high degree of uniformity, physiological availability
`and therapeutic quality expected of modern medicinal prod-
`ucts usually are the results of considerable effort and exper-
`tise on the part of the formulating pharmacist. These quali-
`ties are attained by careful selection and control of the quali-
`W of the various ingredients employed, appropriate
`manufacturing according to well—defined processes and,
`most importantly, adequate consideration of the many vari-
`ables that may influence the composition, stability and utili-
`W of the product.
`In dealing with the formulation of new
`Products it has become necessary to apply the best research
`methods and tools in order to develop, produce and control
`.
`the potent, stable and effective dosage forms which make up
`3|ocHEMl5n-H -
`
`our modern medical armamentarium.
`The pharmaceutical formulator has need for specialized
`Fig 75-1. The wheels of product development.
`1435
`
`
`
`
`MEDICINAL
`
`
`
`ORGANIC
`
`SCIENTIFIC SUPPORT
`
`~
`
`_?._J
`cum:/i|_
`
`
`
`gm.»-:;~v-/
`
`Astrazeneca Ex. 2081 p. 5
`
`

`
`1436
`
`CHAPTER 75
`
`Preformulation work usually is initiated after a compound
`has shown sufficient activity to merit further testing in hu-
`mans. When this decision is made, the various disciplines
`begin to generate data essential for properly evaluating the
`performance of the drug substance. A stability-indicating
`analytical assay is very important. Since this often takes
`considerable time, it sometimes is necessary to rely on thin-
`layer chromatographic procedures to determine if a drug
`molecule is degrading. Accelerated testing procedures are
`used to promote breakdown of the compound being tested.
`Attempts are made to isolate and characterize the break-
`down products in order to identify the mechanism of break-
`down. This information provides a lead to the development
`pharmacist in his efforts to formulate the product.
`During a preformulation study it is necessary to maintain
`some degree of flexibility. Problem areas must be identified
`early. For example, selection of a suitable salt form of the
`drug may be critical. Toxicity studies usually are scheduled
`early. Consequently, if the salt form under consideration
`has some deficiencies, they should be pointed out so that
`alternate salts may be prepared and evaluated prior to be-
`ginning toxicity studies.
`'
`When preformulation studies are initiated, the chemical
`usually is in short supply; 25 g of chemical is an ample
`supply, but many preliminary evaluations have been done
`with less. The initial supply usually originates as excess
`from batches prepared by the medicinal chemists. They
`usually have preliminary data such as melting point, solubil-
`ity, spectral data and structure of the compound. The di-
`rection taken for the evaluation is determined by the struc-
`ture and the intended dosage forms to be developed (eg, one
`would.not waste time determining the stability of a solution
`of a compound if there was no interest in a liquid dosage
`form). Many areas must be evaluated critically for each
`compound, and it is essential that problem areas be identi-
`fied early, otherwise delays could occur if a problem surfaced
`during the development phase for the compound. Some
`consequences of poor preformulation work are
`Possible use of unsatisfactory salt form.
`Poor stability of the active ingredient.
`Testing compound of marginal activity.
`Increased development costs.
`Increased development time.
`
`When preformulation studies are completed, the data are
`compiled and transferred to the development pharmacist,
`who, in turn, uses this information to plan his development
`work on the finished dosage forms.
`
`'
`
`Physical Properties
`
`Description
`
`Since the pure drug entity is in short supply at the outset
`of most preliminary evaluations, it is extremely important to
`note the general appearance, color and odor of the com-
`pound. These characteristics provide a basis for compari-
`son with future lots. During the preparation of scale-up lots
`the chemist usually refines or alters the original chemical
`synthetic route. This sometimes results in a change in some
`of the physical properties. When this takes place, compari-
`sons can be made with earlier lots and decisions made re-
`garding solvents for recrystallization.
`Taste usually warrants some consideration, especially if
`the drug is intended for oral use in pediatric dosage forms.
`In such cases consideration should be given to the prepara-
`tion of alternate salt forms or possible evaluation of excipi-
`ents that mask the undesirable taste.
`
`Microscopic Examination
`
`scopic examination gives a gross indication of particle size
`and characteristic crystal properties. These photomicro-
`graphs are useful in determining the consistency of particle
`size and crystal habit from batch to batch, especially during
`the early periods of chemical synthesis; if a synthetic step is
`changed, they also give an indication of any effect the change
`may have on crystal habit. One must keep in mind that the
`photomicrograph only gives a qualitative indication of parti-
`cle size distribution; it always is necessary to do a particle-
`size analysis for a more accurate picture of the distribution
`of particles in any particular batch of drug substance.
`
`Particle Size
`
`The uses of pharmaceutical products in a finely divided
`form are diverse. From knowledge of their particle size,
`such drugs as griseofulvin, nitrofurantoin, spironolactone,
`procaine penicillin and phenobarbital have been formulated
`so as to optimize activity. Other drugs, formulated in sus-
`pension or emulsion systems, in inhalation aerosols or in oral
`dosage forms, may contain finely divided material as an
`essential component. One of the basic physical properties
`common to all these finely divided substances is the particle-
`size distribution, ie, the frequency of occurrence of particles
`of every size. What is of practical interest usually is not the
`characteristics of single particles but rather the mean char-
`acteristics of a large number of particles. It must be empha-
`sized, however, that knowledge of size characteristics is of no
`value unless adequate correlation has been established with
`functional properties of specific interest in the drug formu-
`lation. Many investigations demonstrating the significance
`of particle size are reported in the literature.
`It has been
`shown that dissolution rate, absorption rate, content unifor-
`mity, color, taste, texture and stability depend to varying
`degrees on particle size and distribution. In preformulation
`work it is important that the significance of particle size in
`" relation to formulation be established early. Preliminary
`physical observations sometimes can detect subtle differ-
`ences in color.
`If this can be attributed to differences in
`particle-size distribution, it is important to define this dis-
`tribution and recommend that more attention be given to
`particle size in preparing future batches of drug substance.
`This effect also is evident when preparing suspensions of
`poorly soluble materials. One may observe batch—to-batch
`differences in the color of a suspension which can be related
`to differences in particle size. Sometimes, when small parti-
`cles tend to agglomerate, a subtle change in color or texture
`may be evident.
`'
`Sedimentation and flocculation rates in suspensions are in
`part governed by particle size.
`In concentrated deflocculat-
`ed suspensions the larger particles exhibit hindered settling
`and the smaller particles settle more rapidly.
`In flocculated
`suspensions the particles are linked together into flocs which
`settle according to the size of the floc and porosity of the
`aggregated mass. Flocculated suspensions are preferred
`since they have less tendency to cake and are more rapidly
`dispersible. Thus, it is apparent that the ultimate height,
`H“, of sediment as a suspension settles depends on particle
`size. The ratio H,,/H,,, or the degree of suspendibility as
`affected by particle size, is valuable information for the
`formulator in order to prepare a satisfactory dosage form.
`The rate of dissolution of small particles usually is faster
`than that of larger ones because rate of dissolution depends
`on the specific surface area in contact with the liquid medi-
`um. This usually is described by the modified Noyes-Whit-
`ney equation for dissolution rate dA/dt
`dA
`E; = KS(C, — C)
`
`(1)
`
`Each lot of drug substance, regardless of size, is examined
`microscopically and a photomicrograph taken. The micro-
`
`where A is the amount of drug in solution, K is the intrinsic
`dissolution rate constant, S is the surface area, C, is the
`
`Astrazeneca Ex. 2081 p. 6
`
`

`
`concentration of a saturated solution of the drug and C’ is the
`drug concentration at time t. The surface area of an object,
`regardless of shape, varies inversely with its diameter and
`confirms the above effect of particle size on dissolution rate.
`Solubility also has been observed to depend on particle size.
`Dittert, et al,1 reported data for an experimental drug, 4-
`acetamidophenyl 2,2,2-trichloroethyl carbonate, which
`demonstrated that the dissolution rate and, in turn, bio-
`availability were affected by particle size. Although the
`ultimate amount of drug in solution may not be significant
`with respect to the dose administered, the formulator should
`be aware of this potential. With poorly soluble drugs it is
`extremely important to take these factors into account dur-
`ing the design of the dosage form.
`Flow properties of drugs can be influenced by particle size,
`and particle size reduction to extremely small sizes (less than
`10 um) may be inadvisable for some drug substances. En-
`trapped air adsorbed on the surface of the particles and/or
`surface electrical charges sometimes impart undesirable
`properties to the drug. For example, adsorbed air at the
`drug-particle surface may prevent wetting of the drug by
`surrounding fluid, and electrically induced agglomeration of
`fine particles may decrease exposure of the drug surface to
`surrounding dissolution medium. Such effects act as disso-
`lution rate-limiting steps since they minimize maximum
`drug surface-liquid contact.
`Crystal growth is also a function of particle size. Finer
`particles tend to dissolve and subsequently recrystallize and
`adhere to larger particles. This phenomenon is referred to
`as Ostwald ripening. Protective colloid systems can be used
`to suppress this nucleation. Preformulators can generate
`information concerning the effectiveness of different col-
`loids that is extremely important to the formulator when he
`is given the task of preparing a suspension dosage form.
`Particle-size reduction may be deleterious for some drug
`substances.
`Increasing surface area by milling or other
`methods may lead to rapid degradation of a compound.
`Drug substances also may undergo polymorphic transforma-
`tion during the milling process. The preformulator must
`always be cognizant of these potential problems, and when-
`ever the decision is made to reduce particle size, the condi-
`tions must be controlled and the stability profile evaluated.
`If a problem does arise, it is the responsibility of the prefor-
`mulator to note it and attempt to resolve it prior to turning
`the drug substance over to the formulating pharmacist.
`Gastrointestinal absorption of a poorly soluble drug may
`be affected by the particle-size distribution.
`If the dissolu-
`tion rate of the drug is less than the diffusion rate to the site
`of absorption and the absorption rate itself, then the particle
`size of the drug is of great importance. Smaller particles
`should increase dissolution rate and, thus, bring about more
`rapid gastrointestinal absorption. One of the first observa-
`tions of this phenomenon was made with sulfadiazine.
`Blood-level determinations showed that the drug in suspen-
`sion containing particles 1 to 3 pm in size was absorbed more
`rapidly and more efficiently than from a suspension contain-
`ing particles 7 times larger. Maximum blood levels were
`about 40% higher and occurred 2 hours earlier.
`Increased
`bioavailability with particle-size reduction also has been ob-
`served with griseofulvin. The extent of absorption of an
`oral dose increased 2.5 times when the surface area was
`increased approximately sixfold. Micronized griseofulvin
`permits a 50% decrease in dosage to obtain a satisfactory
`clinical response.
`On the other hand, it was found that with nitrofurantoin
`there was an optimal average particlesize that minimized
`side effects Without affecting therapeutic response.
`In fact,
`a commercial product containing large particles is available.
`For chloramphenicol, particle size has virtually no effect on
`total absorption but it significantly affects the rate of ap-
`pearance of peak blood levels of the drug. After administra-
`
`PREFORMULATION
`
`. 1437
`
`tion of 50-pm particles, as well as 200-pm particles, peak
`levels occurred in 1 hour; with 400-/rm particles peak levels
`occurred in 2 hours; with 800-pm particles peak levels oc-
`curred in 3 hours. All four preparations had the same phys-
`iological availability, which implies that the absorption of
`chloramphenicol occurs uniformly over a major portion of
`the intestinal tract.
`Reduction of particle size also may create adverse re-
`sponses. For example, fine particles of the prodrug trichlo-
`roethyl carbonate were more toxic in mice than regular and
`coarse particles?
`Increasing the surface area for water-
`soluble drugs, and possibly for weakly basic drugs, appears
`to be of little value. Absorption of weak bases usually is
`rate-limited by stomach emptying time rather than by disso-
`lution. As previously mentioned, particle size is of impor-
`tance only when the absorption process is rate-limited by the
`dissolution rate in gastrointestinal fluids.
`The previous discussion considered the effect of particle
`size of the drug substance and its relationship to formula-
`tion. The particle size of the inert ingredients merits some
`attention. When one is concerned with particle size, all
`ingredients used in preparing the dosage form should be
`evaluated and some recommendation regarding their control
`should be made prior to full-scale development of a dosage
`form.
`It is recommended highly that particle size and its
`distribution be determined, optimized, monitored and con-
`trolled when applicable, particularly during early preformu-
`lation studies when the decision is made with regard to a
`suitable dosage form. The more common methods of deter-
`mining particle size of powders used in the pharmaceutical
`industry include sieving, microscopy, sedimentation and
`stream scanning.
`Sieving or Screening—Sieving or screening is probably
`one of the oldest methods of sizing particles and still is used
`commonly to determine the size distribution of powders in
`the size range of 325 mesh (44 pm) and greater. These data
`serve usually as a rough‘ guideline in evaluatingraw materi-
`als with regard to the need for milling. The basic disadvan-
`tages of screen analysis are the large sample size required
`and the tendency for blinding of the screens due to static
`charge or mechanical clogging. The advantages include
`simplicity, low cost and little skill requirement of the opera-
`tor.
`
`Microscopy——Microscopy is the most universally accept-
`ed and direct method of determining particle-size distribu-
`tion of powders in the subsieve range, but this method is
`tedious and time-consuming. The preparation of the slide
`for counting particles is important because the sample must
`represent the particle-size distribution of the bulk sample.
`Extreme care must be taken in obtaining a truly representa-
`tive sample from the bulk chemical. The cone and quarter-
`ing technique usually gives a satisfactory sample. The sam-
`ple should be properly suspended, dispersed and mixed
`thoroughly in a liquid which has a different refractive index
`from the particles being counted. A representative sample
`is mounted on a slide having a calibrated grid. For counting,
`random fields are selected on the slide and the particles are
`sized and counted. Between 500 and 1000 particles should
`be counted to make statistical treatment of the data mean-
`ingful.
`,
`Sedimentation—Sedimentation techniques utilize the
`dependence of velocity of fall of particles on their size. Ap-
`plication is made of the Stokes equation (see page 295) which
`describes a relationship between the rate at which a particle
`settles in a fluid medium to the size of that particle.
`’Al-
`though the equation is based on spherical-shaped particles,
`it is used widely, to determine the weight-size distribution of
`irregularly shaped particles. Data obtained by this proce-
`dure are usually reliable; however, the result may not agree
`with those obtained by other methods because of the limita-
`tions of the shape factor.
`
`Astrazeneca Ex. 2081 p. 7
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`

`
`1438
`
`CHAPTER 75
`
`40
`
`30
`
`ParticleSizeinMicrons
`
`8.0
`
`20
`
`16.7
`14.2
`
`10
`
`0
`
`80
`60
`40
`20
`Cumulative “lo Less Than
`
`100
`
`Particle size distribution of NBS glass beads (Standard
`Fig 75-2.
`Reference Material No 1003) expressed in terms of O = number ol
`particles; 0 = weight of particles; ® = surface area of particles.
`
`The Andreasen Pipette Method is used most commonly
`for sedimentation studies. Exact volumes are withdrawn at
`prescribed times and at a specified liquid depth. The liquid
`is evaporated and the residue of powder is weighed. The
`data are used in the Stokes equation and a weight-size distri-
`bution is calculated. Precautions must be observed with
`this method. Proper dispersion, consistent sampling, tem-
`perature control of the suspending medium and concentra-
`tion should be achieved in order to obtain consistent results.
`Stream Scanning—-Stream scanning is a technique in
`which a fluid suspension passes through a sensing zone
`where the individual particles are electronically sized,
`counted and tabulated. The great advantage of this tech-
`nique is that data can be generated in relatively short peri-
`ods of time with reasonable accuracy. Literally thousands
`of particles can be counted in seconds and used in determin-
`ing the size-distribution curve. The data are in a number of
`particles per class interval and can be expressed mathemati-
`cally as the arithmetic mean diameter and graphed accord-
`ingly. Fig 75-2 illustrates a plot of typical data obtained for
`NBS Standard Reference Material No 1003.
`The Coulter Counter and the HIAC Counter are used
`widely in the field of particle-size analysis in the pharmaceu-
`tical industry. They can be used to follow crystal growth in
`suspensions very effectively. Figure 75-3 shows the change
`in particle size. with time for an aqueous suspension of Form
`I of an experimental drug. It appears that the growth of the
`particles decreases sign