l Pharmaceutical
`Dosage
`Parenteral Medications
`Volume1
`Second Edition, Revised and Expanded
`Edited by
`Kenneth E. Avis
`
`The University of Tennessee
`Memphis, Tennessee
`
`Herbert A. Lieberman
`
`H.H. Lieberman Associates, Inc.
`Consultant Services
`Livingston, New Jersey
`Leon Lachman
`
`Lachman Consultant Services
`Westbury, New York
`
`MARCEl n MARCEL DEKKER, INc.
`
`DEKK ER
`
`NEw YoRK· BASEL
`
`Dr. Reddy's Laboratories, Ltd., et al.
`v.
`Helsinn Healthcare SA, et al.
`U.S. Patent No. 8,729,094
`Reddy Exhibit 1050
`
`Exh. 1050
`
`

`
`First Indian Reprint 2005
`
`Library of Congress Cataloging-in-Publication Data
`
`Pharmaceutical dosage forms, parenteral medications I edited by
`Kenneth E. Avis, Herbert A . Lieberman, and Leon Lachman. -2nd ed.
`rev. and expanded.
`em.
`p.
`Includes bibliographical references and index.
`ISBN 0-8247-8576-2
`1. Parenteral solutions. 2. Pha r maceutical technology. I. Avis,
`Kenneth E. II. Lieberman, Herbert A.
`III. Lachman, Leon.
`[DNLM: .1. Infusions, Parenteral. 2. Technology, Pharmaceutical.
`WB 354 P536)
`RS201 .P37P48 1992
`615'. 19-dc20
`DNLM/DLC
`for Library ~f Congress
`
`91- 38063
`CIP
`
`Copyright@ 1992 by MARCEL DEKKER, INC. All Righ ts Reserved
`
`Neither this book nor any part may be reproduced or transmitted in any form
`or by any means, electronic or mechanical, including photocopying, micro-
`filming, and recording, or by any information storage and retrieval system,
`without permission in writing from the publisher.
`
`MARCEL DEKKER, INC.
`270 Madison Avenue, New York, New York 10016
`
`Printed and bound by Replika Press Pvt. Ltd., India.
`
`FOR SALE IN INDIAN SUBCONTINENT ONLY.
`
`Exh. 1050
`
`

`
`2
`Parenteral Drug Administration: Routes,
`Precautions, Problems, Complications,
`and Drug Delivery Systems
`
`Richard J. Duma
`Medical College of Virginia, Virginia Commonwealth University, Richmond,
`Virginia
`
`Micha,el J. Akers
`Ell Lilly and Company, Indianapolis, Indiana
`
`Salvatore J . Turco
`Temple University, Philadelphia, Pennsylvania
`
`Parenteral, from para enteron (Greek) , meaning "to avoid the intestines,"
`includes in its broadest sense, any drug (or fluid) whose delivery does not
`utllize the alimentary canal for entry into body tissues. Although drugs ap-
`plied topically to the eye, ear, and skin, or even inhaled . may be broadly
`interpreted as parenterals, medical and pharmaceutical health care deliveries
`generally limit the definition to those drugs injected or infused directly into
`tissues, tissue spaces, vessels, or body compartments.
`The development of t echniques for administering pnrentera.ls, coupled
`IYith innovative designs of new devices to achieve and monitor their del! very ,
`occur almost daily and are enabling therapeutics to approach an exact science.
`In addition, parenteral therapy is not restrict ed to hospitals or clinics but is
`being increasingly employed, even in its most invasive forms of delivery (e.g .
`intravenous), to manage patients at home and in the work place. Most pa-
`tients readily accept or easily adapt to almost every form of parenteral ther-
`apy, and many self-administer their own drugs, even when the route of de-
`livery is intravenous (e.g., home infusion programs).
`Parenteral administration offers many advantages over therapy given by
`nonparenteral routes. Most notably, therapeutists can reliably predict with
`considerable accuracy the pharmacokinetics and pharmacology of the agents
`they prescribe; they can quickly Interdict a rapidly progressive lethal pro-
`cess or disease; and, even though the physiology and pathology of patients
`may be complicated, t hey can "fine tune," stratify and quantitate r esults.
`However, despite these advantages, parenteral administration is not without
`
`17
`
`Exh. 1050
`
`

`
`18
`
`Duma et al.
`
`certain, measurable risks and limitations that the professional must intelligent-
`ly weigh in terms of risks, benefits, and costs.
`This chapter will attempt to review and update the usage of parenteral
`administration in today's practice of medicine. However, since the subject is
`dynamic and the technology is growing. the reader must appreciate that some
`of the material contained herein may become quickly outdated.
`
`I. GENERAL INDICATIONS FOR PARENTERAL
`ADMINISTRATION OF DRUGS
`
`The parenteral routes of drug administration are indicated for one or more
`of the following reasons :
`
`1. To ensure delivery of adequate concentrations of the drug in ques-
`tion to diseased tissues or target areas of the body, especially when
`inadequate or marginal transport of that drug into the tissues or tar-
`get areas is anticipated. Example: Direct intraventricular injection
`of drugs (e.g., antibiotics such as the aminoglycosides) which cross
`the "blood-brain-meninges barrier" poorly may be used in certain
`patients with bacterial or fungal meningitis and /or ventriculitis.
`2. To permit the user to exert direct control over certain pharmacologic
`parameters, such as the time of drug onset, serum peak and trough
`levels, tissue concentrations, and rate of elimination of the drug from
`the body. Example: Intravenous or direct cardiointraventricular
`routes may be desirable to achieve immediate effects in emergencies
`such as might occur in the control of life-threatening hypotension,
`hypertension, or arrhythmias; or intramuscular routes may be desir-
`able to obtain p1·otracted or sustained effects, such as the use of
`benzathine penicillin G in the treatment of infections .
`3. To allow the therapist. when outpatient management is desirable, to
`guarantee dosage and drug compliance, especially when the patient
`cannot be relied upon to self-medicate. Example: The use of long-
`acting (monthly) intramuscular penicillins may be used to manage
`children prophylactically for rheumatic heart disease In order to pre-
`vent Group A streptococcal pharyngitis.
`4. To deliver a biologic effect that cannot be achieved through oral ad-
`ministration, perhaps because of nonabsorbance from the alimentary
`canal or degradation by gastric acidity. Example: Therapeutic pep-
`tides and proteins such as insulin, human growth hormone, other
`product s from recombinant DNA technology, and polyene antibiotics
`(such as the antifungal agent amphotericin B).
`5. To administer a drug when the desired route (e.g. , oral) may not be
`available. Example:
`In patients who are aspirating or who have had
`the upper gastrointestinal tract stream diverted or removed (e.g. ,
`because of a carcinoma) a parenteral route may be necessary.
`6. To provide a local effect when it is desirable to minimize or avoid sys-
`temic toxic effects or reactions. Example: Methotrexate may be given
`intrathecaJly to patients with leukemia and leukemic involvement of
`the meninges to avoid the systemic, toxic effects that would occur if
`an intravenous route was employed.
`
`' < f
`
`'
`
`,.
`
`;I
`
`Exh. 1050
`
`

`
`Parenteral Drug Administration
`
`l9
`
`7. To administer drugs to the unconscious, uncooperative, or uncon-
`trollable patient. Example: Patients with uncontrollable grand mal
`seizures often will not cooperate in the oral administration of drugs
`or will be at risk to aspirate if compelled to take medicines by mouth.
`Similarly, patients unconscious from narcotic abuse, artesthetlc usage,
`or trauma, or uncooperative patients such as those suffering delcrium
`tremens or a psychosis, may be satisfactorlly managed by using paren-
`teral routes.
`8. To per mit rapid correction of fluid and electrolyte imbalances and to
`supply short - or long-term nutritional needs (hyperalimentation or
`parenteral feeding). E.-x:ample: Patients suffering severo dehydration
`or electrolyte depletion for a variety of reasons (e.g., heat stroke)
`can be rapidly corrected with intravenous electrolyte solution.s; and
`patients whose intestinal tracts have been resected for one reason
`or another may be intravenously "fed" a complete d:iet of all the neces·
`sary amino acids. glucose, minerals, and vitamins for prolonged and
`indefinite periods of time.
`9. To achieve a desired local effect. Example: Local anesthetics for
`tooth extractions or local anti-inflammatory agents for inflamed joints
`may be injected directly into the site In question to avoid systemic
`effects or "systemic" dosages .
`
`II. PHARMACEUTICAL FACTORS AFFECT I NC
`PARENTERAL ADMI NISTRATION
`
`Certain pharmaceutical characteristics dicta·te the method or route of paren-
`teral administration. and once the dosage form Is Injected or infused; influ-
`ence the rate and extent of drug availability. These characteristics will be
`reviewed briefly in t his section. but the reader is also referred to Chapter 3
`for a more d etailed treatment of the biopharmaceutical factors affecting paren-
`teral drug availability.
`
`A. Solubility of the Drug and ·Volume of the Injection
`A drug must be completely solubilized, prefer ably in water , before it can be
`administered by intravenous injection. Both the extent of drug solubility in
`Its intended vehicle and the dose required for the desired therapeutic effect
`will determine the volume of the injection. Parenteral routes other than the
`intravenous one have limitations regarding the maximum volume of medication
`administered (e. g . , intradermal, intramuscular, intraocular, intraventricular,
`and intrathecal, to name a few).
`
`B. Vehicle Characteristics
`Drugs in aqueous vehicles may be administered by any parenteral route.
`whereas drugs in nonaqueous vehicles. which may or may not be water mis-
`cible, are administered most frequently by the intramuscular route. The in -
`travenous route may be used for a few drugs in mixed solvent systems (e .g.,
`diazepam, digoxin, and phenytoin}, but precautions must be applied in adjust -
`ing the rate of drug infusion to avoid drug precJpltation at the site of infusion.
`
`Exh. 1050
`
`

`
`20
`
`Duma et al.
`
`.. .
`
`Large volume parenteral fat emulsions are also available by the intravenous
`route. Nonaqueous vehicles that are more viscous than water vehicles will
`affect the rate of injection through a small- gauge needle and the rate of ab-
`sorption from the injection site.
`
`C. pH and Osmolality of Injectable Solutions
`Ideally, administered injections should be formulated at a pH and osmolality
`similar to that of biological fluids. Unfortunately, this 'is not possible for
`many parenteral dosage forms, as many parenteral drugs are unstable at neu-
`tral pH. Therefore, such drugs are formulated at the pH at which they are
`most stable. For example, diazoxide (a non diuretic benzothiadiazine deriva-
`tive) is formulated at a pH of 11.6, the pH at which it is most stable. Many
`parenteral drugs are salt forms of weak bases. Thus the pH of a dosage form
`containing the salt of a weak base may be as low as 2. 0 (e.g. , tetracycline
`hydrochloride) , or the pH of a dosage form containing the salt of a weak acid
`may be as high as 12.0 (e.g. , Dilantin) in order to maintain the active in-
`gredient in solution. Although dosage forms with extreme pH values may be
`administered by any parenteral route, the rate and volume of inject.ion must
`be controlled to minimize pain and irritation to the patient and damage to the
`surrounding tissues.
`Certain parenteral formulations are hyperosmotic with biological fluids
`and contain a relatively high dose of active ingredient(s) in order to achieve
`a desired level of biological activity. For example, water- soluble contrast
`media, spinal anesthetics, ophthalmic sodium sulfacetamide, diazox:ide, and
`osmotic diuretics are a few hypertonic parenteral formulations containing high
`drug concentrations to achieve an appropriate biological. action(s). Products
`of parenteral nutrition are formulated or admixed with high concentrations
`of amino acids, dextrose, and other essential ingredients, resulting in very
`hypertonic solutions . These solutions, called hyperalimentation solutions,
`are so hypertonic that they must be administered via a large vein such as the
`subclavian. The blood in this vein enters directly into the heart , which allows
`the hypertonic solution to be rapidly diluted by a still larger volume of blood.
`Generally, hypertonic parenteral dosage forms are contraindicated for
`subcutaneous or intramuscular injections. Whereas the vitreous humor, can
`tolerate only very narrow ranges of osmotic values from an injected medication.
`Therefore, although stability and solubility problems may prevent dosage forms
`from being formulated at physiological pH, they should be formulated with
`solute contents .approximately equal to those of biological fluids.
`
`D. Type of Dosage Form
`Parenteral dosage forms include solutions, suspensions, and sterile solids
`for reconstitution . Jf the dosage form is a suspension, it may be administered
`only by the intr·amuscular or subcutaneous route. Particles should not be
`present in dosage forms administered intravenously or by other parenteral
`routes in which the medication enters directly into a biological fluid or sensi-
`tive tissue (e. g., brain or eye). Reconstituted solids should be completely
`dissolved in the reconstituting diluent before they are administered intr.aven-
`ously.
`
`. {
`
`.I
`
`.. . •
`
`Exh. 1050
`
`

`
`Pal"enteraf Drug Administration
`
`21
`
`E. Formulation Ingredients
`As discussed in Chapter 5, parenteral formulations may contain various active
`and inactive excipients other than the main therapeutic agent, for a variety
`of reasons. For multidose parenterals, antimicrobial agents are added to the
`formulation for the preservation of sterility. However, these agents may be
`contraindicated in medications to be administered into the cerebrospinal fluid
`or intraocular fluid because of the toxicity they may produce. Several paren-
`teral formulations contain surface-active agents (such a.s polysorbate 80) to
`maintain drug s-olubility in the solution vehicle. Surface-active agents are
`known to alter membrane permeability, so their presence must be recognized
`when administering such dosage forms by the subcutaneous or intramuscular
`routes.
`The expanding field of sustained and prolonged release of drug delivery
`employs various formulations and additives that at times aid in achieving the
`desired duration of drug action . These additives are primarily high-molecular-
`weight polymers or oily solvents. Formulations containing these macromole-
`cules are administered by the subcutaneous or intramuscular routes to permit
`the delayed release of the active ingredient within deeper tissues of the body.
`
`Ill. SPECIFIC ROUTES OF ADMINISTRATION
`
`Three primary routes of parenteral administl'ation are commonly employed:
`intramuscular, intravenous, and subcutaneous. These three routes satisfy
`to a large extent the four principal reasons for administering parenterals:
`(1) for therapy (definitive or palliative), {2) for prevention, (3) for diagnosi.s,
`and (4) for temporarily altering tissue functlon(s) in order to facilitate other
`forms of therapy. Besides these three primary routes, additional ones are
`utilized under special circumstances: for example, 'subconjunctival, intra-
`ocular, intrathecal, intra- articular , and so on. In the sections to follow,
`the primary and special routes of parenteral administration are reviewed in
`alphabetical order. Each review will include four subheadings: description,
`indications, precautions, and method of drug or fluid delivery.
`
`A. Primary Routes
`Intramuscular
`Injection directly into the body of a relaxed muscle.
`Description.
`t ndications. The intramuscular (i. m.) route is one of the most popular
`and convenient routes available, both for the administrator and for the patient
`( 1) , especially for a child ( 2). Therefore, whenever it is possible and prac-
`ticable, the intramuscular route is used. The intramuscular route provides
`a means for prolonged release of drugs formulated as aqueous or oily solutions
`or suspensions. The intramuscular route is preferred over the subcutaneous
`route when a rapid rate of absorption is desired and over the intravenous
`route when for one reason or another the drug cannot be administered direct-
`ly into the vascular compartment.
`Many factors affect the rate of drug- absorption from an intramuscular
`injection ( 21; they will be discussed later in this chapter. Drugs commonly
`
`Exh. 1050
`
`

`
`22
`
`Duma et al.
`
`injected by intramuscular administration include lidocaine, cephalosporins,
`aminoglycosides, diazepam, insoluble salts of penicillin G (procane penicillin
`G), corticoste1·oids, narcotics, narcotic antagonists, and contraceptive steroids,
`to name a few.
`Precautions. Although intramuscular injections are much easier to ad-
`minister than other injections, the main precaution is to avoid entering a blood
`vessel (especially an artery), which m:ight lead to infusion of a toxic agent
`or a toxic vehicle directly to an organ or tissue. This can be prevented usu-
`ally by pulling back on the pi unger of the syringe; if blood does not appear,
`the needle is probably not in a vessel. Also, the accidental striking of or
`injection into a peripheral nerve may result in a peripheral nerve palsy with
`or without sensory damage. Occasionally, when a larg·e bolus of drug is in-
`jected into the muscle, local damage or muscle infarction may result, le·ading
`to a sterile abscess or to elevation of serum levels of muscle enzymes. The
`latter complication may present confusing diagnostic problems, especially in
`patients under suspicion of having a myocardial infarct ion or hepatitis ..
`If materials contaminated with microorganisms are injected, a septic abscess
`may result. Therefore, appropriate precautions must be taken to ensure ster-
`ility prior to injection .. In patients with poor hygiene or skin care, microorga-
`nisms from the skin flora may be punched in by the ne.edle at the time of in-
`jection. resulting in staphylococcal or streptococcal abscesses; and rarely in
`such situations as gas gangrene ( 3] (especially if epinephrine is injected)
`or tetanus [ 4].
`the intramuscular route shm,1ld never be
`An important note of caution:
`employed in patients with significant heart failure or shock, when uptake into
`the vascular compartment may be expectantly poor. This caution should be
`followed especially if immediately high serum or plasma concentrations of the
`drug are desired or if rapid distribution to a distal organ is mandatory.
`Method. Various muscle sites are available for delivery (Fig. 1), includ-
`ing the gluteal, deltoid, triceps, pectoral, and vast us lateralis muscles. In
`adults the site of choice often is the gl uteal muscle, because large volumes
`of drug may be injected and tolerated. However, the vast us lateralis of the
`thigh may also be used because it not only tolerates large volumes of medica-
`tion, but it is also away from any major vessels or nerves. For rapid absorp-
`tion and small volumes ( <2 ml), the deltoid muscle is preferred, as some stud-
`ies suggest that blood flow in the deltoid muscle is 7% greater than that of
`the vast us lateralis and 17% greater than that of the gluteus maxim us [ 5].
`For t his reason, in adults t he deltoid is the preferred site for vaccine admin-
`istration.
`In infants and small children, the vast us lateralis of the thigh is
`often preferred because it is better developed than other muscle groups, de-
`pending on the site selected. The skin is first cleaned with alcohol or a suit-
`able disinfectant, and the plunger on the syringe is always retracted prior
`to injeciton to be sure that the needle is not in a vessel. For deep intramus-
`cular injections, as might be used 'cor irritating medications such as iron prep-
`arations, a "z-track" injection method is employed.
`
`Intravenous
`Description.
`
`Injections or infusions directly into a vein.
`
`Exh. 1050
`
`

`
`Parenteral Drug Administration
`
`23
`
`Figure 1 Some common sites employed for intramuscular injections. Upper
`left: posterior gluteal, located in the outer upper quadrant about Z in. below
`the iliac crest. Upper right: deltoid located about 2 in. below the acromion
`process. Lower left: ventrogluteal, located in the triangle formed by one
`finger on the anterior superior iliac spine nnd the other on the iliac crest.
`Lower right: vast us lateralis, located along the middle third and lateral as-
`pect of the thigh. The "bull's-eye" indicates the approximate site of injection.
`
`Indications. Intravenous (i. v.) administration of drugs, fluids, and/or
`electrolytes is one of the most common parenteral routes employed in hospitals
`today. It is especially convenient for rapidly infusing large volumes of fluid.
`The most common indication for use of this route are:
`( 1) to guarantee de-
`livery and distribution when hypotension or shock exists; C 2) to restore rapid-
`ly electrolyte and fluid balance; ( 3) to achieve an immediate pharmacologic
`effect, especially in emergencies, such as the treatment of certain arrythmias
`or of seizures; ( 4) to treat serious, life-threatening Infections or conditions;
`(5) to provide continuous nutrition (hyperallmentation) when pntients are
`unable to be fed by mouth; and ( 6) to avoid complications which might result
`if other administration routes were employed (e.g. , hematomas at the site of
`Intramuscular inje<:tions in a patient with a bleeding diathesis). In addition,
`the intravenous route may be used for a variety of other purposes, such as
`plasmapheresis, b lood transfusion, and hemodynamic monitoring, to name a few.
`
`Exh. 1050
`
`

`
`24
`
`Duma et al.
`
`Precautions. A large number and variety of complications may occur us-
`ing the intravenous route. A few of these are:
`(1) thrombosis with or with-
`out complicating infection at the site of injection or infusion; ( 2) injection of
`microorganisms, toxins, particulate matter, or air; ( 3) the occurrence of phys-
`ical or chemical incompatibilities between agents prior to or at the time of in-
`jection; ( 4) uncontrolled or excessive administration of drugs or fluids; and
`(5) extravasation of injections or infusions at the site of administration. When
`indwelling catheters are utilized, rarely the catheter tip may break off and
`lodge in a major vessel, in the heart, or in the lung.
`Method. The upper extremities are chosen whenever possible for the
`site of injection or infusion. As many venous sites as possible should be pre-
`served for future use; thus the most peripheral veins (e.g., those over the
`han d) are selected for initial use. When arm sites are no lo:nger available ,
`the leg veins (femoral and saphenous) or dorsal foot veins may be utilized;
`and in small children the scalp veins.
`Selection of a vein depends on the size of the needle or catheter intended
`for use , type of fluids to be infused, flow rate anticipated, volume to be re-
`ceived. concomitant medications to be given, degree of patient mobility de-
`sired, and of course the skill of the person performing the venipuncture or
`catheterization. The veins in the ante-cubi.tal fossa are among the most com-
`monly chosen, because they are large and readily punctured. Other veins
`utilized commonly ar e basilic, cephalic, radial at the wrist, and the metacarpal
`and dorsal venons plexuses,
`Although the risk of infection appears to be less with needles than with
`indwelling intravenous catheters [ 6], an 8-in. long intravenous, plastic cathe-
`ter is commonly used for delivery of fluids via peripheral veins. Such cathe-
`ters reduce the risk of infil tration considerably, thus providing more comfort
`to the patient, reducing time and labor costs of nursing in managing the in-
`fusion, rendering pharmacokinetic predictions more reliable, and avoiding
`adverse side effects, such as cellulitis and occasionally tissue sloughing. If
`peripheral insertion sites become exhausted , surgical cut-downs of deep veins
`IVith Implantation of indwelling catheter s may be performed. When long-term ,
`repeated, or prolonged usage is anticipated, the subclavian or internal jugu-
`lar (central) veins in the upper chest may be utilized. These veins are es-
`pecially useful if hyperosmolar fluids are to be infused, as physicochemical
`irritation and venospasm produced by the hyperosmolarity or chemical formu-
`lation of the fluids may be reduced or negated. In such Instances, sllastic
`tunnelled, implanted, central venous access catheters (e.g. , Broviac, Hick-
`man, Groshong, Port- A- Cath) tailored to each patient so that the tip of the
`catheter rests just above the right atrium, are often utilized. These devices
`are designed so that t hey can remain in place and be maintained Indefinitely
`for the life of the patient.
`If needles are to be used for intravenous infusion, a 1- to 2-ln. long,
`beveled, 18 to 22 gauge (Table 1), stainless steel needle is commonly used,
`Whether usln g a catheter or needle, the device is inserted pe1·cutaneously
`into the vein only after thoroughly cleanin~r the skin-insertion site and pre-
`paring it as eptically. Since infections appear to be more commonly associated
`with indwell1ng intravenous catheters than with needles, more time and care
`needs to be given to skin preparation with catheter use t han wit h needle in-
`sertion. Such aseptic practices are especially important when "long· term"
`
`Exh. 1050
`
`

`
`Par·enteral Drug Administration
`
`Table 1 Needle Selection
`
`Injection site
`
`Length range ('In.)
`
`Gauge range
`
`25
`
`Intra-abdominal
`Int ra-articular
`Intracardlac
`Intradermal
`Intraocular
`Anterior chamber
`Intravitreal
`Retrobulbar
`Subconjunctial
`Intrapleural
`In trathecal
`Adult
`Pediatric
`Neonatal
`Intravenous
`Met(ll needle
`Winged needle
`Plastic needle
`lntracatheter
`In-lying catheter
`Sllastlc catheter
`Hypodermoclysis
`Adult
`Pediatric
`Subcutaneous
`
`4-6
`1-3
`4-6
`1/4-5/8
`
`1-3
`1-3
`H
`H
`5- 6
`
`3-5
`1-H
`1/2-1
`
`1- 2
`3/4-H
`3-5
`8-lH
`12, 26
`13-23
`
`2
`1-1!
`1/4-5/8
`
`14-18
`19-22
`18-21
`24- 26
`
`25
`25
`25
`25
`13-18
`
`20-22
`25
`27
`
`15-25
`16-23
`15-21
`15-21
`14, IS
`12-19
`
`19
`20-22
`24-25
`
`silastic catheters inserted into the subclavian vein or vena cava are utilized
`(vide supra). The mechanics of insertion usually involve a tourniquet being
`applied proximal to the site of insertion in order to congest the vein (thus,
`expanding the vein), so that the device may be easily inserted. If a catheter
`is used, it is inserted over a needle used for the initial puncture. Afterwards,
`the needle is removed, and the catheter is left in place. The indwellin g cathe-
`ter or needle. whichever is utilized, is anchored to the extremity or body
`by means of appropria'te, sterile occlusive or nonocclusive dressings, often
`impregnated with antibiotic ointments to reduce the risk of a complicating in-
`fection.
`indwelling catheters often contain heparin locks to ensure against
`clotting and loss of patency from venous thrombosis.
`
`Subcutaneous
`Injection into the loose connective and adipose tissue beneath
`Description.
`the skin (dermis).
`
`Exh. 1050
`
`

`
`4
`Preformulation Research of
`Parenteral Medications
`
`Sol Motola•
`Whit ehall Laboratories, Hammonton, New Jersey
`
`Shreeram N. Aghar kar
`Bristol-Myers Squibb Company, Syracuse, New York
`
`I. I NTRODUCTION
`
`Prcform\llntion r!;lsearch relates to pharmaceuticol and analytical investigations
`that both preceed and support formulation development efforts for all dosage
`forms. Experiments are designed to generate data characterizing specific,
`pharmaceutically important, physicochemical properties of the drug s ubstance
`and its combination with selected solvents, excipients, and packagiug com-
`ponents. These studies are carried out under stressed conditions of tempera-
`ture, light, humidity, and oxygen in order to accelerate and detect potential
`reactions. Taking into account early pharmacological and biopharmaceutlcal
`data , preformulation studies yield key information necessary to guide the form-
`ulator and analyst toward the development of an elegant, stable dosage form
`with good bioavailabi!ity. Prior to development of the clinical and marketed
`dosage form, preformulation studies yield basic knowledge necessary to de-
`velop suitable formulations for toxicological use.
`Due to important research leads in a highly competitive field, rapid pro-
`gress is essential, and clinical studies should be initiated as soon as possible.
`Thus an expeditious preformulation program (i.e., one typically t aking 6 to
`10 weeks to complete) is generally required. If clinical program acceleration
`is desired, it may be necessary to s treamline studies and develop cr ucial de-
`cision-making data in shorter time periods. Should interim results indicate
`that a more stable or more soluble drug form is needed, expansion of the
`original program will be necessary. Additionally, areas of p articular interest
`may arise, such as the elucidation of a reaction mechanism or the investigation
`of unusual solubility phenomena. Such studies may be of prime importance
`and are often addressed either initially or ns second-phase preformulation
`studies, depending on their potential impact on the overall program.
`
`"Current affl!!ation; Wyeth-Ayerst Laboratories, Radnor, Pennsylvania
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`Exh. 1050
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`116
`
`Motola and Agharkar
`
`The general subject of preformulation research has been described in de-
`tall by several investigators r 1 5] and is in wide use throughout the pharma-
`ceutical industry. These presentations have dealt mainly with studies designed
`for solid dosage forms. Some specific applications have been mode to certain
`areas of parenteral interest (6,7]. The objective of this chapter is to outline
`methods used in developing preformulation data necessary to characterize
`significant physicochemical properties of new drugs important to a poren-
`tcral formulation development program.
`
`II. DRUG SUBSTANCE PHYSICOCHEMICAL PROPERtiES
`
`Typical physicochemical properties of drug substances that either characterize
`or may exert significant influence on the development of a parenteral formula-
`tion are listed in Table 1.
`
`A. Molecu lar St ructure and Weight
`These are the most basic characteristics of a drug substance and are among
`the first items to be known. From the molecular structure the investigator
`can make initial judgments regarding potential properties and functional group
`reactivities, as described in Section IV.
`
`B. Color
`Color is generally a function of a drug's inherent chemical structure relating to
`a certain level of unsaturation. Color intensity relates to the extent of conju-
`gated unsaturation as well as the presence of chromophores s uch as -NH2• -NOz,
`and -CO- (ketone), which intensify color. Some compounds may appear to have
`color although structurally saturated. Such a phenomenon can often be due to
`the presence of minute t races of highly unsaturated, intensely colored impul'ities
`andlor degradation products. These substances may be prone to increased
`color formation under stress conditions of heat, oxygen, and light. A signifi -
`cant color change can become a limiting factor to the shelf life of a parenteral
`product even before a significant change in chemical stability is noted.
`
`Table 1 Physicochemical Properties of Drug Substances
`
`Molecular structure and weight
`Color
`Odor
`Melting point
`T hermal analytical profile
`Particle size and shape
`Hygroscopicity potential
`Ionization constant
`Optical activity
`
`Solubility
`pH solubility profile
`Polymorphism potential
`Solvate formation
`Absorbance spectra
`Light stability
`Ther mal stability
`pH stability profile
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`140
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`Motola and Agharkar
`
`An asymmetric carbon atom is one that has four different atoms or groups
`bonded to It. An example Is shown below for eplnevllrine. During chemical
`synthesis a 50; 50 mixture of both the d and l forms is obtained and since they
`have the same specific optical rotation [a], the resulting molecule may show a
`zero specific rotation. The form t hat is more biologically active is selected
`for development.
`I n the case of epinephrine, only the I form is an active vaso-
`constrictor. Because of this an equal mixture of d and 1 would be 50% as po-
`tent and the d form , which in this example is t otally inactive.
`
`OH
`HO -\Q)-t~CH2NHCH3
`HO
`H
`Epinephrine
`
`Considering the above, when working with an optically active compound dur-
`ing preformulation studies, It is essential to monitor optical rotation stnce
`chemical assay alone will not always coincide with biological activity. Examples
`of optically active pharmaceutical compounds used In parenterals are listed in
`Table 11.
`
`Ill, ACCELERATED STABI LI TY EVALUATION
`A. Drug Substance
`Various stress tests are performed on solid and solution samples to estnblish
`the effect