`

`Modern Pharmaceutics
`
`Third Edilion, Revised and Exuanded
`
`edited by
`Gilbert S. Banker
`
`University of Iowa
`Iowa City, Iowa
`
`Christopher T. Rhodes
`
`University of Rhode Island
`Kingston, Rhode Island
`
`11
`
`A..
`
`I'.
`
`t_ f L
`
`ll L Ii-.
`
`~
`
`I R
`
`MPI EXHIBIT 1089 PAGE 2
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`MPI EXHIBIT 1089 PAGE 2
`
`

`

`Modern Pharmaceutics
`
`Third Edition, Revised and Exuanded
`
`MPI EXHIBIT 1089 PAGE 3
`
`MPI EXHIBIT 1089 PAGE 3
`
`

`

`Lihrary of Congress Cataloging-in-Puhlication Data
`
`Modern pharmaccu110, / edited hy Gilbert S 8,1nkcr, Chmlophl'I T
`Rl1nde, - 3rd cd . rev and expanded.
`p
`cm -(Drugs and the pharmaceultc:al ,cienLc~ ; v 72)
`Include~ h1hl1ograph1cal ,cft:rcm:e, and rnd,:x
`ISBN O-IQ•i7-tJ371-4 (alk paper)
`I Drug,-Do~agc furm~. 2 81opharmaccut1c,.
`3 Pharm,1cokmct1c~
`4 Pharmaccul1cal rnduslry-Ouahty control
`II Rhodes, Christopher T. JII. Scnc,
`I Banker, G1lhrrl S.
`RS200 Mti3
`I 945
`615' l-dc2()
`
`95-3323/-:
`CH'
`
`The puhlt,hcr offc,~ <lt~rnunh on lht, huok when ordered in hulls 4uant111L·, hll nllltc 111form,1IH>11. w111e
`lo Spcctal Salc~/Profc,,1onal Markclmg al the a<ldrc·,s below
`
`Th 1, hnuk 1, pt tilled nn acrd-frcc papn
`
`C11pyngh1 <~"'I 19% hy Marcel Dcl-kcr. Inc. All R1ghh Rc~cn·cd
`
`Nc1lhcr lh1~ bnllk nor any part may be 1epw<luccd or tran,mitled Ill any form rn h1 any mc:111,, clcctru111c
`,,r mechamutl, mdudrng pholucopy111g. mKrufilmmg. and ri.:cmd111g, or h\' ,my 111tormat1<>11 ,lrnagc ,111d
`1ctncval ,y,Lcm, wllhnul pL·rm1,,io11 111 wnung from the pubh,hi.:r
`
`Ma1ccl Delker, Inc
`270 Madison A\cnuc. Ne"' York. New Yo,k 10()(()
`
`MPI EXHIBIT 1089 PAGE 4
`
`MPI EXHIBIT 1089 PAGE 4
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`

`

`Contents
`
`Preface
`Contributors
`
`1. Drug Products: Their Role in the Treatment of Disease, Their Quality,
`and Their Status as Drug Delivery Systems
`Gilbert S. Banker
`
`2. Principles of Drug Absorption
`Michael Mayersohn
`
`3. Pharmacokinetics
`David W A. Bourne and Lewis W Dittert
`
`4. Factors Influencing Drug Absorption and Drug Availability
`Betty-ann Hoener and Leslie Z. Benet
`
`5. The Effect of Route of Administration and Distribution on Drug Action
`Svein @ie and Leslie Z. Benet
`
`6. Chemical Kinetics and Drug Stability
`J. Keith Guillory and Rolland I. Poust
`
`7. Preformulation
`Jens T. Carstensen
`
`8. Cutaneous and Transdermal Delivery: Processes and Systems of Delivery
`Gordon L. Flynn
`
`iii
`vii
`
`1
`
`21
`
`75
`
`121
`
`155
`
`179
`
`213
`
`239
`
`V
`
`MPI EXHIBIT 1089 PAGE 5
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`MPI EXHIBIT 1089 PAGE 5
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`

`

`vi
`
`Contents
`
`9. Disperse Systems
`S. Esmail Tabibi and Christopher T. Rhodes
`
`10. Tablet Dosage Forms
`Edward M. Rudnic and Mary Kathryn Kottke
`
`11. Hard and Soft Shell Capsules
`Larry L. Augsburger
`
`12. Parenteral Products
`James C. Boylan, Alan L. Fites, and Steven L. Nail
`
`13. Design and Evaluation of Ophthalmic Pharmaceutical Products
`Gerald Hecht, Robert E. Roehrs, John C. Lang,
`Denise P Rodeheaver, and Masood A. Chowhan
`
`14. Pharmaceutical Aerosols
`John J. Sciarra
`
`15. Sustained- and Controlled-Release Drug Delivery Systems
`Gwen M. Jantzen and Joseph R. Robinson
`
`16. Target-Oriented Drug Delivery Systems
`Vijay Kumar and Gilbert S. Banker
`
`17. Packaging of Pharmaceutical Dosage Forms
`Donald C. Liebe
`
`18. Optimization Techniques in Pharmaceutical Formulation and Processing
`Joseph B. Schwartz and Robert E. O'Connor
`
`19. Food and Drug Laws that Affect Drug Product Design,
`Manufacture, and Distribution
`Garnet E. Peck
`
`20. European Aspects of the Regulation of Drug Products
`Brian R. Matthews
`
`21. Pediatric and Geriatric Aspects of Pharmaceutics
`Michele Danish and Mary Kathryn Kottke
`
`22. Biotechnology-Based Pharmaceuticals
`S. Kathy Edmond Rouan
`
`23. Veterinary Pharmaceutical Dosage Forms: An Overview
`J. Patrick McDonnell
`
`24. A View to the Future
`Gilbert S. Banker and Christopher T. Rhodes
`
`Index
`
`299
`
`333
`
`395
`
`441
`
`489
`
`547
`
`575
`
`611
`
`681
`
`727
`
`753
`
`773
`
`809
`
`843
`
`875
`
`887
`
`907
`
`MPI EXHIBIT 1089 PAGE 6
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`

`

`12
`
`Parenteral Products
`
`James C. Boylan
`Abbott Laboratories, Abbott Park, llli11ois
`Alan L. Fites
`Fites Consulting, Greenwood, Indiana
`Steven L. Nail
`Purdue University, West Lafayette, Indiana
`
`I.
`
`INTRODUCTION
`
`The first official injection (morphine) appeared in the British Pharmacopoeia (BP) of 1867. It
`was not until 1898 when cocaine was added to the BP that sterilization was attempted. In this
`country, the first official injections may be found in the National Formulary (NF), published
`in 1926. Monographs were included for seven sterile glass-sealed ampoules. The United States
`Pharmacopeia (USP) published in the same year contained a chapter on sterilization, but no
`monographs for ampoules. The current USP contains monographs for over 400 injectable prod(cid:173)
`ucts [1 ].
`Parenteral administration of drugs by intravenous (IV), intramuscular (IM), or subcutaneous
`(SC) routes is now an established and essential part of medical practice. Advantages for par(cid:173)
`enterally administered drugs include the following: rapid onset; predictable effect; predictable
`and nearly complete bioavailability; and avoidance of the gastrointestinal tract (GIT), and
`hence, the problems of variable absorption, drug inactivation, and GI distress. In addition, the
`parenteral route provides reliable drug administration in very ill or comatose patients.
`The pharmaceutical industry directs considerable effort toward maximizing the usefulness
`and reliability of oral dosage forms in an effort to minimize the need for parenteral adminis(cid:173)
`tration. Factors that contribute to this include certain disadvantages of the parenteral route,
`including the frequent pain and discomfort of injections, with all the psychological fears as(cid:173)
`sociated with "the needle," plus the realization that an incorrect drug or dose is often harder
`or impossible to counteract when it has been given parenterally (particularly intravenously),
`rather than orally.
`In recent years, parenteral dosage forms, especially IV forms, have gained immensely in
`use. The reasons for this growth are many and varied, but they can be summed up as (a) new
`and better parenteral administration techniques; (b) new forms of nutritional therapy, such as
`intravenous lipids, amino acids, and trace metals; (c) the need for simultaneous administration
`of multiple drugs in hospitalized patients receiving IV therapy, (d) the extension of parenteral
`
`441
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`MPI EXHIBIT 1089 PAGE 7
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`

`

`442
`
`Boylan et al.
`
`therapy into the home; and (e) an increasing number of drugs that can be administered only
`by a parenteral route.
`Many important drugs are available only as parenteral dosage forms. Notable among these
`are biotechnology drugs; insulin; several cephalosporin antibiotic products; and drugs such as
`heparin, protamine, and glucagon. In addition, other drugs, such as lidocaine hydrochloride
`and many anticancer products, are used principally as parenterals. The reasons that certain
`drugs are administered largely or exclusively by the parenteral route are very inefficient or
`unreliable absorption from the GIT, destruction or inactivation in the GIT, extensive mucosal
`or first-pass metabolism following oral administration, or clinical need in particular medical
`situations for rapid, assured high blood and tissue levels.
`Along with this astounding growth in the use of parenteral medications, the hospital phar(cid:173)
`macist has become a very knowledgeable, key individual in most hospitals, having responsi(cid:173)
`bility for hospital-wide IV admixture programs, parenteral unit-dose packaging, and often cen(cid:173)
`tral surgical supply. By choice, by expertise, and by responsibility, the pharmacist has
`accumulated the greatest fund of information about parenteral drugs-not only their clinical
`use, but also their stability, incompatibilities, methods of handling and admixture, and proper
`packaging. More and more, nurses and physicians are looking to the pharmacist for guidance
`on parenteral products.
`To support the institutional pharmacist in preparing IV admixtures (which typically involves
`adding one or more drugs to large-volume parenteral fluids), equipment manufacturers have
`designed laminar flow units, electromechanical compounding units, transfer devices, and filters
`specifically adaptable to a variety of hospital programs.
`The nurse and physician have certainly not been forgotten either. A wide spectrum of IV
`and IM administration devices and aids have been made available in recent years for bedside
`use. Many innovative practitioners have made suggestions to industry that have resulted in
`product or technique improvements, particularly in IV therapy. The use of parenteral products
`is growing at a very significant rate in nonhospital settings, such as outpatient surgical centers
`and homes. The reduction in costs associated with outpatient and home care therapy, coupled
`with advances in drugs, dosage forms, and delivery systems, has caused a major change in the
`administration of parenteral products [2].
`
`11. ROUTES OF PARENTERAL ADMINISTRATION
`
`The routes of parenteral administration of drugs are (a) subcutaneous, (b) intramuscular, and
`(c) intravenous; other more specialized routes are (d) intrathecal, (e) intracisternal, (f) intra(cid:173)
`arterial, (g) intraspinal, (h) intraepidural, and (i) intradermal. The intradermal route is not
`typically used to achieve systemic drug effects. The similarities and differences of the routes
`or their definitions are highlighted in Table 1. The major routes will be discussed separately.
`
`A. The Subcutaneous Route
`
`Lying immediately under the skin is a layer of fat, the superficial fascia (see Fig. 1 in Chapter
`8), that lends itself to safe administration of a great variety of drugs, including vaccines, insulin,
`scopolamine, and epinephrine. Subcutaneous (SC; also SQ or sub-Q) injections are usually
`administered in volumes up to 2 ml using a 1h- to 1-in. 22-gauge (or smaller) needle. Care
`must be taken to ensure that the needle is not in a vein. This is done by lightly pulling back
`on the syringe plunger (aspiration) before making the injection. If the needle is inadvertently
`located in a vein, blood will appear in the syringe and the injection should not be made. The
`injection site may be massaged after injection to facilitate drug absorption. Drugs given by this
`
`MPI EXHIBIT 1089 PAGE 8
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`

`

`Table 1 Various Parenteral Routes of Drug Administration
`
`,
`
`Routes
`
`Primary parenteral routes
`Small-volume parenterals
`Subcutaneous
`Intramuscular
`
`Intravenous
`
`Large-volume parenterals
`
`2
`2
`
`50
`
`100 and larger
`(infusion unit)
`
`2-20
`
`1-4
`
`6-30
`
`Other parenteral routes
`Intra-arterial: directly into an
`artery (immediate action sought
`in peripheral area)
`lntrathecal (intraspinal; into spinal
`canal)
`lntraepidural (into epidural space
`near spinal column)
`lntracisternal: directly into caudal
`region of the brain between the
`cerebellum and the medulla
`oblongata
`Intra-articular: directly into a joint, 2-20
`usually for a local effect there,
`as for steroid anti-inflammatory
`action in arthritis
`lntracardial: directly into the heart
`when life is threatened
`(epinephrine stimulation in
`severe heart attack)
`Intrapleural: directly into the
`pleural cavity or a lung (also
`used for fluid withdrawal)
`Diagnostic testing
`Intradermal
`
`0.2-1
`
`2-30
`
`10
`
`Usual volume
`(ml)
`
`Needle commonly
`used
`
`Formulation constraints
`
`Types of medication
`administered
`
`"V
`Q
`;
`
`:::, -
`
`II)
`
`Q.
`"V
`0
`Q.
`C
`0
`it
`
`'/• in., 23 gauge
`1 ¼ in., 22 gauge
`
`Veinpuncture l 1/2 in.,
`22 gauge
`Venoclysis 1 '/2 in.,
`19 gauge
`
`Need not be isotonic
`Can be solutions, emulsions,
`oils, or suspensions, isotonic
`preferably
`Solutions and some emulsions
`
`Solutions and some emulsions
`
`20-22 gauge
`
`Solutions and some emulsions
`
`24-28 gauge
`
`Must be isotomc
`
`5 in., 16-18 gauge
`
`Must be isotonic
`
`Must be isotonic
`
`Insulin, vaccines
`Nearly all drug classes
`
`Nearly all drug classes
`
`Nearly all drug classes (see
`precautionary notes in text)
`
`Radiopaque media,
`antineoplastics, antibiotics
`
`Local anesthetics, analgesics;
`neurolytic agents
`Local anesthetics, narcotics, a,-
`agonists, steroids
`
`1.5-2 in., 18-22
`gauge
`
`Must be isotonic
`
`Morphine, local anesthetics,
`steroids, NSAIDs, antibiotics
`
`5 in., 22 gauge
`
`Cardiotonic drugs, calcium
`
`2-5 in., 16-22
`gauge
`
`Local anesthetics, narcotics,
`chemotherapeutic agents
`
`'Is in., 26 gauge
`
`Should be isotonic
`
`Diagnostic agents
`
`t
`
`c.,
`
`MPI EXHIBIT 1089 PAGE 9
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`

`

`,
`
`444
`
`Boylan et al.
`
`route will have a slower onset of action than by the IM or IV routes, and total absorption may
`also be less.
`Sometimes dextrose or electrolyte solutions are given subcutaneously in amounts from 250
`to 1000 ml. This technique, called hypodermoclysis, is used when veins are unavailable or
`difficult to use for further medication. Irritation of the tissue is a danger with this technique.
`Administration of the enzyme hyaluronidase can help by increasing absorption and decreasing
`tissue distention. Irritating drugs and vasoconstrictors can lead to abscesses, necrosis, or in(cid:173)
`flammation when given subcutaneously. Body sites suitable for SC administration include most
`portions of the arms and legs plus the abdomen. When daily or frequent administration is
`required, the injection site can and should be continuously changed or rotated, especially by
`diabetic patients self-administering insulin.
`
`B. The Intramuscular Route
`
`The IM route of administration is second only to the IV route in rapidity of onset of systemic
`action. Injections are made into the striated muscle fibers that lie beneath the subcutaneous
`layer. The principal sites of injection are the gluteal (buttocks), deltoid (upper arm), and vastus
`lateralis (lateral thigh) muscles. The usual volumes injected range from 1.0 to 3.0 ml, with
`volumes up to 10.0 ml sometimes being given (in divided doses) in the gluteal or thigh areas
`(see Table 1). Again, it is important to aspirate before injecting to ensure that the drug will
`not be administered intravenously. Needles used in administering IM injections range from 1
`to 1 ½ in. and 19 to 22 gauge, the most common being 1 ½ in. and 22 gauge.
`The major· clinical problem arising from IM injections is muscle or neural damage, the
`injury normally resulting from faulty technique, rather than the medication.
`Most injectable products can be given intramuscularly. As a result, there are numerous
`dosage forms available for this route of administration: solutions, oil-in-water (o/w) or water(cid:173)
`in-oil (w/o) emulsions, suspensions (aqueous or oily base), colloidal suspensions, and recon(cid:173)
`stitutable powders. Those product forms in which the drug is not fully dissolved generally
`result in slower, more gradual drug absorption, a slower onset of action, and sometimes longer(cid:173)
`lasting drug effects.
`Intramuscularly administered products typically form a "depot" in the muscle mass from
`which the drug is slowly absorbed. The peak drug concentration is usually seen within 1-2
`hr. Factors affecting the drug-release rate from an IM depot include the compactness of the
`depot (the less compact and more diffuse, the faster the release), the rheology of the product
`(affects compactness), concentration and particle size of drug in the vehicle, nature of the
`solvent or vehicle, volume of the injection, tonicity of the product, and physical form of the
`product.
`
`C. The Intravenous Route
`
`Intravenous medication is injected directly into a vein either to obtain an extremely rapid and
`predictable response or to avoid irritation of other tissues. This route of administration also
`provides maximum availability and assurance in delivering the drug to the site of action.
`However, a major danger of this route of administration is that the rapidity of absorption makes
`antidoting very difficult, if not impossible, in most instances. Care must also be used to avoid
`too rapid a drug administration by the IV route because irritation or an excessive drug con(cid:173)
`centration at the target organ ( drug shock) can occur. The duration of drug activity is dependent
`on the initial dose and the distribution, metabolism, and excretion properties (pharmacokinetics)
`of the drug. For most drugs, the biological half-life is independent of the initial dose, because
`the elimination process is first-order. Thus, an intravenous drug with a short half-life would not
`
`MPI EXHIBIT 1089 PAGE 10
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`

`

`Parenteral Products
`
`445
`
`provide a sustained blood level. The usual method of administration for drugs with short half(cid:173)
`lives is to use continuous IV drip. Intravenous injections (vein puncture) normally range from
`1 to 100 ml and are given with either a 20- or 22-gauge 1 ½-in. needle, with an injection rate
`of 1 ml/10 sec for volumes up to 5 ml and 1 ml/20 sec for volumes over 5 ml. Only drugs in
`aqueous or hydroalcoholic solutions are to be given by the IV route.
`Large proximal veins, such as those located inside the forearm, are most commonly used
`for IV administration. Because of the rapid dilution in the circulating blood and the general
`insensitivity of the venous wall to pain, the IV route may be used to administer drugs that
`would be too irritating or caustic to give by other routes (e.g., nitrogen mustards), provided
`that proper dosing procedures are employed. The risk of thrombosis is increased when extrem(cid:173)
`ity sites such as the wrist or ankle are used for injection sites, or when potentially irritating
`IV products are used, with the risk further increasing in patients with impaired circulation.
`The IV infusion of large volumes of fluids (100- 1000 ml) has become increasingly popular
`(Figs. 1 and 2). This technique, called venoclysis, utilizes products known as large-volume
`parenterals (LVPs). It is used to supply electrolytes and nutrients, to restore blood volume, to
`prevent tissue dehydration, and to dilute toxic materials already present in body fluids. Various
`parenteral drug solutions may often be conveniently added to the LVP products as they are
`being administered (Figs. 3 and 4), or before administration, to provide continuous and pro(cid:173)
`longed drug therapy. Such drug additions to LVP has become very common in hospitals.
`Combining parenteral dosage forms for administration as a unit product is known as IV ad(cid:173)
`mixtures. Pharmacists practicing such IV additive product preparation must be very knowl(cid:173)
`edgeable to avoid physical and chemical incompatibilities in the modified LVP, creation of any
`therapeutic incompatibilities with other drugs being given parenterally or by any other route,
`or loss of sterility or addition of extraneous matter.
`Commonly administered large-volume parenterals include such products as sodium chloride
`injection [USP] (0.9% saline), which replenish fluids and electrolytes, and 5% dextrose injec(cid:173)
`tion (USP], which provides fluid plus nutrition (calories) or various combinations of dextrose
`and saline. In addition, numerous other nutrient and ionic solutions are available for clinical
`use, the most popular of which are solutions of essential amino acids or lipid emulsions. These
`solutions are modified to be hypertonic, isotonic, or hypotonic to aid in maintaining both fluid,
`nutritional, and electrolyte balance in a particular patient according to need. Indwelling needles
`or catheters are required in LVP administration. Care must be taken to avoid local or systemic
`infections or thrombophlebitis owing to faulty injection or administration technique.
`
`D. Other Parenteral Routes
`
`Other more specialized parenteral routes are listed and described briefly in Table 1. The intra(cid:173)
`arterial route involves injecting a drug directly into an artery. This technique is not simple and
`may require a surgical procedure to reach the artery. It is important that the artery not be
`missed, since serious nerve damage can occur to the nerves lying close to arteries. Doses given
`by this route should be minimal and given gradually, since, once injected, the drug effect
`cannot be neutralized. As shown in Table 1, the intra-arterial route is used to administer ra(cid:173)
`diopaque contrast media for viewing an organ, such as the heart or kidney, or to perfuse an
`antineoplastic agent at the highest possible concentration to the target organ.
`The intrathecal route is employed to administer a drug directly into the cerebrospinal fl_uid
`at any level of the cerebrospinal axis. This route is used when it is not possible to achieve
`sufficiently high plasma levels to accomplish adequate diffusion and penetration into the cere(cid:173)
`brospinal fluid. This is not the same route used to achieve spinal anesthesia, for which the
`drug is injected within the ducal membrane surrounding the spinal cord, or in extradural or
`
`MPI EXHIBIT 1089 PAGE 11
`
`MPI EXHIBIT 1089 PAGE 11
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`

`

`

`

`,.
`
`Parenteral Products
`
`447
`
`• . 4l
`~ .. ·'·
`
`::.,_ : .
`
`,- ---~itll:'
`
`.,
`
`/
`
`·: ..
`
`-~
`\-J,. 'i•
`Fig. 2 Direct intravenous administration using gum rubber injection site.
`
`"I
`
`epidural anesthesia (caudal or sacral anesthesia), for which the drug is deposited outside the
`dural membrane and within the body spinal caudal canals. Parenteral products administered by
`the intrathecal, intraspinal, and intracisternal routes must be especially carefully formulated,
`with ingredients of the highest purity because of the sensitivity of nerve tissue.
`Intradermal (ID) administration involves injection into the skin layer (see Fig. 3 in Chapter
`8). Examples of drugs administered by this route are allergy test materials. Since intradermal
`drugs are normally given for diagnostic purposes, it is important that the product per se be
`nonirritating. Volumes are normally given at 0.05 ml/dose and the solutions are isotonic. In(cid:173)
`tradermal medication is usually administered with a ½- or 5/s-in., 25- or 26-gauge needle,
`inserted at an angle nearly parallel to the skin surface. Absorption is slow and limited from
`this site, since the blood vessels are extremely small, although the area is highly vascular. The
`site should not be massaged after the injection of allergy test materials. Skin testing includes
`not only allergens, such as pollens or dust, but also microorganisms, as in the tuberculin or
`histoplasmin skin tests.
`
`Ill. SPECIALIZED LARGE-VOLUME PARENTERAL AND
`STERILE SOLUTIONS
`
`Large-volume parenterals designed to provide fluid (water), calories (glucose solutions), elec(cid:173)
`trolytes (saline solutions), or combinations of these materials have been described. Several
`other specialized LVP and sterile solutions are also used in medicine and will be described
`
`MPI EXHIBIT 1089 PAGE 13
`
`MPI EXHIBIT 1089 PAGE 13
`
`

`

`

`

`Parenteral Products
`
`449
`
`Fig. 4
`.. Piggybacking"' of a small-volume intravenous fluid into the primary large-volume intravenous
`solution.
`
`well as to treat acute renal insufficiency. Peritoneal dialysis solutions contain glucose and have
`an ionic content similar to normal extracellular fluid. Toxins or metabolites diffuse into the
`circulating dialysis fluid through the peritoneum and are removed. At the same time, excess
`fluid is removed from the patient if the glucose content renders the dialysis solution hyperos(cid:173)
`motic. An antibiotic is often added to these solutions as a prophylactic measure.
`
`C.
`
`Irrigating Solutions
`
`Irrigating solutions are intended to irrigate, flush, and aid in cleansing body cavities and
`wounds. Although certain IV solutions, such as normal saline, may be used as irrigating so(cid:173)
`lutions, solutions designed as irrigating solutions should not be used parenterally. Since irri(cid:173)
`gating solutions used in treatment of serious wounds infuse into the bloodstream to some
`degree, they must be sterile, pyrogen-free, and made and handled with the same care as par(cid:173)
`enteral solutions.
`
`IV. PHVSICOCHEMICAL FACTORS AND COMPONENTS
`
`Physicochemical properties of the active drug and the components used in a parenteral dosage
`form can significantly affect the availability of the drug substance. Other factors that influence
`drug availability are physiological (biological conditions and disease state of the patient), the
`route of administration, and the type of dosage form. Intramuscular and subcutaneous routes
`
`MPI EXHIBIT 1089 PAGE 15
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`

`

`450
`
`Boylan et al.
`
`of parenteral administration require drug absorption before blood or cerebrospinal fluid levels
`can be achieved. The rate at which the drug is absorbed has a significant influence on the
`concentration of the drug in the blood. With an IM suspension, drug dissolution is usually the
`rate-limiting step in the absorption of the drug at the injection site [3]. The absorption of the
`drug following IM administration is greatly influenced by the physicochemical properties of
`the drug.
`Components that are incorporated into parenteral dosage forms may have very rigid speci(cid:173)
`fications and standards. Because of these requirements, extensive analytical and toxicological
`testing is performed to ensure that a chemical is acceptable. Thorough toxicity testing is re(cid:173)
`quired of a new drug or other component not previously approved for parenteral use, and the
`accumulated data are evaluated. Testing may be done on the individual components as well as
`the final dosage forms. Given such explicit qualities as purity, safety, and lack of (or minimum)
`pharmacological effect required of parenteral additives, the formulator is restricted to a very
`few materials as excipients, preservatives, suspending agents, and surfactants. Because of the
`very extensive pharmacological and toxicological data required to obtain approval for any new
`additive, most formulators continue to depend on materials of known acceptability.
`
`A. The Active Drug
`
`A thorough evaluation of properties of the active drug or drugs is essential in developing a
`stable and safe parenteral dosage form. The physical and chemical factors that may significantly
`affect the development of a parenteral dosage form are discussed in Chapter 7 and by Motola
`and Agharkar [ 4]. Important properties include solubility and rate of solution. Factors that
`influence solubility include particle size; salt, ester, or other chemical form; solution pH; poly(cid:173)
`morphism; purity; and hydrate formulation.
`
`Crystal Characteristics
`Control of the crystallization process to obtain a consistent and uniform crystal form, habit,
`density, and size distribution is particularly critical for drug substances to be utilized in sus(cid:173)
`pensions or powders. For example, when the crystallization of sterile ceftazidime pentahydrate
`was modified to significantly increase the density to reduce the volume of the fill dose, the
`rate of dissolution increased significantly. Many dry solid parenteral products, such as the
`cephalosporins, are prepared by sterile crystallization techniques.
`To obtain a uniform product from lot to lot, strict adherence to the procedures developed
`for a particular crystallization must be followed, including control of pH, rates of addition,
`solvent concentrations and purity, temperature, and mixing rates. Each crystallization procedure
`has to be designed to ensure sterility and minimize particulate contamination. Changes, such
`as using absolute ethyl alcohol instead of 95% ethanol during the washing procedure, can
`destroy the crystalline structure if the material being crystallized is a hydrate structure.
`Drugs that associate with water to produce crystalline forms are called hydrates. Water
`content of the hydrate forms of sodium cefazolin as a function of relative humidity is seen in
`Fig. 5. As shown in Fig. 5, the sesquihydrate is the most stable structure when exposed to
`extreme humidity conditions [5]. This figure also reveals the importance of choosing the proper
`combination of hydrate and humidity conditions when designing a manufacturing process or
`facility.
`
`Chemical Modifications
`Improvement of the properties of a drug may be achieved by the chemical modification of the
`parent drug. The preparation of an ester, salt, or employed other modification of the parent
`structure may be employed with parenteral drugs to increase stability, alter drug solubility,
`
`MPI EXHIBIT 1089 PAGE 16
`
`MPI EXHIBIT 1089 PAGE 16
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`

`

`

`

`452
`
`Boylan et al.
`
`Studies of polymorphs in recent years have pointed out the effects of polymorphism on solu(cid:173)
`bility and, more specifically, on dissolution rates. The aspect of polymorphism that is of concern
`to the parenteral formulator is basically one of product stability [7]. Substances that form
`polymorphs must be evaluated so that the form used is stable in that particular solvent system.
`Physical stresses that occur during suspension manufacture may also give rise to changes in
`crystal form [8].
`
`pH and pK,
`Profiles of pH versus solubility and pH versus stability are needed for solution and suspension
`formulations to help assure physical and chemical stability as well as to maximize or minimize
`solubility. This information is also valuable for predicting the compatability of drugs with
`various infusion fluids.
`In summary, the physical and chemical data that should be obtained on the drug substance
`include the following:
`
`Molecular structure and weight
`Melting point
`Thermal profile
`Particle size and shape
`Hygroscopicity potential
`Ionization constant
`Light stability
`Optical activity
`pH solubility profile
`pH stability profile
`Polymorphism potential
`Solvate formation
`
`B. Added Substances in Parenteral Formulations
`
`To provide efficacious, safe, and elegant parenteral dosage forms, added substances must fre(cid:173)
`quently be incorporated into the formula to maintain pharmaceutical stability, control product
`attributes, ensure sterility, or aid in parenteral administration. These substances include anti(cid:173)
`oxidants, antimicrobial agents, buffers, bulking materials, chelating agents, inert gases, solu(cid:173)
`bilizing agents, protectants, and substances for adjusting toxicity. In parenteral product devel(cid:173)
`opment work, any additive to a formulation must be justified by a clear purpose and function.
`In addition, every attempt should be made to choose added substances that are accepted by
`regulatory agencies throughout the world, since most pharmaceutical development is interna(cid:173)
`tional in scope.
`Some of the added substances most commonly used are listed in Table 2. Pharmacists
`involved in IV additive programs must be aware of the types of additives that may be present
`in the products being combined.
`
`Antioxidants
`,
`Salts of sulfur dioxide, including bisulfite, metasulfite, and sulfite, are the most common an(cid:173)
`tioxidants used in aqueous parenterals. These antioxidants maintain product stability by being
`preferentially oxidized and gradually consumed over the shelf life of the product. Irrespective
`of which salt is added to the solution, the antioxidant moiety depends on the final concentration
`of the thio compound and the final pH of the formulation [9]. While undergoing oxidation
`
`MPI EXHIBIT 1089 PAGE 18
`
`MPI EXHIBIT 1089 PAGE 18
`
`

`

`r
`
`Parenteral Products
`
`Table 2 Classes and Examples of Parenteral Additives
`
`Additive class
`
`Antimicrobial
`
`Antioxidants
`
`Buffers
`
`Bulking agents
`
`Chelating agents
`
`Protectants
`
`Solubilizing agents
`
`Surfactants
`
`Tonicity-adjusting agents
`
`Examples of parenteral additives
`
`Benzalkonium chloride
`Benzyl alcohol
`Chlorobutanol
`Metacresol
`Butyl p-hydroxybenzoate
`Methyl p-hydroxybenzoate
`Propyl p-hydroxybenzoate
`Phenol
`Thimerosal
`Ascorbic acid
`Cysteine
`Monothioglycerol
`Sodium bisulfite
`Sodium metabisulfite
`Tocopherols
`Acetates
`Citrates
`Phosphates
`Lactose
`Mannitol
`Sorbitol
`Glycine
`Salts of ethylenediaminetetraacetic
`acid (EDTA)
`Sucrose
`Lactose
`Maltose
`Human serum albumin
`Ethyl alcohol
`Glycerin
`Polyethylene glycol
`Propylene glycol
`Lecithin
`Polyoxyethylene
`Sorbitan monooleate
`Dextrose
`Sodium chloride
`
`453
`
`Usual
`concentration
`(%)
`
`0.01
`1-2
`0.25-0.5
`0.1-0.3
`0.015
`0.1-0.2
`0.2
`0.25-0.5
`0.01
`0.01-0.05
`0.1-0.5
`0.1-1.0
`0.1-1.0
`0.1-1.0
`0.05-0.5
`1-2
`1-5
`0.8-2.0
`1-8
`1-10
`1-10
`1-2
`0.01-0.05
`
`2-5
`2-5
`2-5
`0.5-2
`1-50
`1-50
`1-50
`1-50
`0.5-2.0
`0.1-0.5
`0.05-0.25
`4-5
`0.5-0.9
`
`reactions, the sulfites may be converted to sulfate and othe