36
`
`VOLUME I.’ tUHMUMl 10:1" AMI) PACKAGING
`
`(PG), propylene glycol monoester of medium chain fatty acids (Capmul PG),
`glycol
`dimethylsulfoxide (DMSO), and in different combinations of these COSolvents at four different
`temperatures. The degradation of the drug was monitored by HPLC and was found to be
`catalyzed not only by general but also by specific acid and base and followed first—order
`kinetics. The 1‘90 (time for 90% of the drug remaining intact) in pure cosolvent was 25 50 times
`higher than that in water or semi-aqueous vehicles. Figure 4 shows an Arrhenius plot of
`the observed rate constants of SarCNU in the solvent mixtures. There was no significant
`difference in the slopes for the different solvents, suggesting similar degradation mechanism of
`SarCNU in all solvent mixtures. Furthermore, the order of stabilization by these solvents was
`Capmul PG> /EtOH} /PF:> /I’G> /WI'E) fwater, which was in agreement with decreasing
`the polarities of the vehicles. The greatest Sal‘CNU stability, as measured by the degradation
`rate constant derived :99, was observed with Capmul PG as shown in Table 4. Another example
`where the degradation was significantly reduced in the nonaqueous solvents is described for
`Eptifibatide, a peptide compound used as an inhibitor of platelet receptor glycoprotein (42).
`The use of cosolvent to help in solubilization may not, however, lead to favorable stability
`outcome at all the times. Trivedi, et a], (43) showed that as the fraction of organic solvents was
`increased, the degradation of zileuton also increased because of the solvolysis of the drug by
`the cosolvents used.
`
`0.1
`
`0.01
`
`R(11hr)
`
`0.001
`
`0.0001
`
`0.000001
`
`0.00001
`
`2.9 3 3.1 3.2 3.3 3.4 3.5 3.3 3.7 3.3 3.9 4
`1000f]-
`
`F'
`4
`T beh
`-
`f
`333m," figflemfiflfi
`ous cosolvent.
`
`Table 4 Degradation of SarCNU in the Presence of Various Cosolvent Mixtures
`
`(so {days}
`
`Room temperature
`Refrigeration
`
`Solvent
`(ESE)
`{4"0)
`
`Water
`Water + propylene glycol + EtOH
`DMSO
`Propylene glycol
`Propylene glycol + ETOH
`EtOH
`Capmul PG
`Source: From Ref. 41 .
`
`0.25
`0.50
`1 .1 4
`2.92
`3.64
`129
`12.50
`
`5.90
`8.95
`1 9.03
`77.78
`89.50
`199.52
`242.5?r
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`FORMULAHOFJ DEVELOPMEM U!— S‘IMLL HM) LAHGE VOLUMt WJECHONS
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`37
`
`Table 5 Examples of Marketed Injectable Products Containing Cosolvent Mixtures
`Generic name Predominant cosolvent(s) in marketed vehicle Trade name
`
`
`Carrnustine
`BiCNU
`100% ethanol
`Diazepam
`Valium
`Propylene glycol 40%
`Ethyl alcohol 10%
`Propylene glycol 40%
`Ethyl alcohol 10%
`Propylene glycol 60%
`Ethyl alcohol 5%
`Polyethylene glycol 50%
`Propylene glycol 67 ?5%
`Propylene glycol 30%
`Ethyl alcohol 20%
`Propylene glycol 40%
`Ethyl alcohol 10%
`Propylene glycol 40%
`Ethyl alcohol 10%
`N.N dimethylacetamide 6%
`Cremophor 50%
`Ethyl alcohol 40%
`Dooetaxel Polysorbate 80 100% Taxotere
`
`Source. From Refs. 44 and 45.
`
`Lanoxin
`
`Alkeran
`
`Hobaxin
`Terramycin
`Zemplar
`
`Nembutal
`
`Dilantin
`
`Vumon
`
`
`
`Digoxin
`
`Melphalan
`
`Methocabamol
`Oxytetracycline
`Pan'calcitol
`
`Phenobarbital Na
`
`Phenytoin Na
`
`Teniposide
`
`Examples of drugs marketed in water—miscible systems include digoxin, phenytoin,
`diazepam and others as shown in Table 5 (44,45). These injections are formulated in a water‘
`miscible system containing glycols and alcohol and adjusted to a suitable pH. Other cosolvents
`used in the past
`included glycerin in deslanoside, dimethylacetamide in reserpine and
`dimethylsulfoxide in chemotherapeutic agents undergoing clinical testing. Propylene glycol is
`used most frequently as a cosolvent, generally in concentrations of 40%. Although such
`systems are stable in individual vials, care must be exercised on administration. For example,
`phenytoin is dissolved as the sodium salt in a vehicle containing 40% propylene glycol and
`10% ethanol and adjusted to a pH of 12 with sodium hydroxide. However, if this solution is
`added to a large—volume IV solution and the pH is lowered to a value close to the pK,, of the
`drug (pK,1
`. 8.3}, precipitation of the drug can occur. This is due to the fact that in aqueous
`systems at pH below 11, the amount of und issociated phenytoin exceeds its solubility.
`To be used as solubility/ stability enhancer in injectable products, the cosolvent must
`have certain attributes such as it should be nontoxic, compatibile with blood, nonsensitizing,
`nonirritating and above all physically and chemically stable and inert. Many cosolvent
`formulations contain high concentrations of organic solvent and most are diluted prior to
`injection, however, some may be injected directly and in that case, care must be taken that the
`rate of injection remains slow.
`
`Surfactants as solubilizers The ability of surfactants to enhance the solubility of otherwise
`poorly water~soluble compounds in aqueous solution is widely known and used in many
`injectable formulations. Surfactants are effective solubilizing agents because of their wetting
`properties and association tendencies as they are able to disperse water—insoluble substances.
`Surfactants are also used very widely in the biotechnology area for otherwise water-soluble
`monoclonal antibodies and other proteins and polypeptides, but the primary goal of using
`surfactant in these products is to minimize hydrophobic interaction related aggregation and
`not necessarily for the enhancement of solubility. This aspect will be discussed in detail in
`other chapters.
`Surfactants can be either nonionic or ionic (i.e., the ability to lower surface tension rests
`with the anion or cation in the molecule). In nonionic surfactants, the head groups contain no
`charged moieties and their hyd rophilic properties are due to the presence of hydroxyl groups.
`Nonionic surfactants are most frequently used in pharmaceutical systems because of their
`compatibility with other surfactants, stability, and relatively low toxicity. Some examples of
`
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`VOLUME 1' fUHMUM-H'Ofl AMI) PACKAGING
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`water-soluble nonionic surfactants include long—chain fatty acid analogs such as fatty alcohols,
`glyceryl esters, and fatty acid esters. Among the most widely used water—soluble nonionic
`surfactants in injectable products are polyethylene oxide (PEO) sorbitan fatty acid esters, or
`Polysorbates.
`In anionic surfactants, the head groups are negatively charged. The most widely used
`anionic surfactants are those containing carboxylate groups, such as soaps, sulfonates, and
`sulfate ions. In cationic surfactants, the head groups are positively charged. Some examples
`include amine and quaternary ammonium salts. Cationic surfactants are not used in
`pharmaceutical systems because of their toxicity since they adsorb readily to cell membrane
`structures in a nonspecific manner, leading to cell lysis (46}.
`themselves at polar/nonpolar
`As shown in Figure 5, surfactants typically orient
`interfaces because of the presence of discrete hydrophobic and hydrophilic regions. As the
`bulk concentration of surfactant in solution is increased, the surfactant molecules begin to
`associate into small aggregates called micelles, whereby their hydrophobic regions are
`shielded from aqueous contact by their hydrophilic regions. All surfactant molecules in excess
`of
`that concentration associate into micelles, while the concentration of nonassociated
`surfactant molecules remains nearly constant. The concentration at which such association
`occurs is called critical micelle concentration (CMC). Using soap as a micelle forming
`substance, Lawrence proposed in 1937 that poorly soluble hydrophobic molecules locate in the
`hydrocarbon core of the micelle, while polar molecules would associate with the polar
`end (47). Molecules that contain polar and nonpolar groups align themselves between the
`chains of the micelle with the nonpolar part directed into the central region and the polar end
`extending out into the hydrophilic chains (Fig. 6).
`
`Poiyoxyethylene
`Chains
`
`Polar
`Region
`
`Nonionic
`
`Ionic
`
`Illustration of spherical crien
`Figure 5
`tations of nonicnic and ionic micelles.
`
`Surfactant Molecules
`
`gii/ 5%qu 9gb
`C’fi‘s one 15:“
`
`Nonpolar Drugs
`(I)
`
`Semipolar Drugs
`(I)
`
`Polar Drugs
`(n)
`
`Figure 6 Schematic representation of mechanisms of mioeller solubilization.
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`f'OHMULAHOfl UthtOPth Uf— S‘IMLL AND LAHGE VOLUMt WJECHONS
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`39
`
`Table 5 Effect of Surfactants on the Solubility of Furosemide
`
`
` Distilled water 0.1 N hydrochloric acid
`
`Surfactant “a, (wfv)
`0
`
`Polysorbate 20 (C12)
`0.005
`0.05
`0.5
`1.0
`5.0
`
`Polysorbate 40 (016]
`0.005
`0.05
`0.5
`1.0
`5.0
`
`Polysorbate 80 (C18)
`0.005
`0.05
`0.5
`1.0
`5.0
`
`Source. From Hot. 49.
`
`Total solubility
`(ugtmL)
`41.2
`
`Mioeller solubility
`([19me}
`
`Total solubility
`{ugl'mL)
`15.0
`
`Miceller solubility
`(timel
`
`31 .2
`45.0
`5?.0
`167.0
`?05.0
`
`32.5
`45.0
`112.5
`143.?
`?92.5
`
`43.?
`43.?
`141.2
`205.0
`980.0
`
`3.?
`15.?
`125.?
`663.?
`
`3.?
`?1.2
`102.4
`?51 .2
`
`2.4
`2.4
`100.0
`163.?
`936.?
`
`40.0
`41.1
`50.0
`145.0
`6?0.0
`
`25.0
`22.5
`72.5
`13?.5
`88?.0
`
`15.9
`1 8.?
`T40
`160.0
`800.0
`
`26.1
`35.0
`130.0
`655.0
`
`?.5
`5?.5
`122.5
`8?2.0
`
`0.9
`3.?
`59.0
`145.0
`?93.0
`
`Generally, the solubili7ation capacity of a same amount of surfactant is high for those
`with lower CMC value. The solubilizing ability of non ionic surfactant toward water—insoluble
`drugs has been extensively studied (48). Akbuga and Gursoy (49} showed how the solubility of
`furosemide, a very insoluble compound commonly used as diuretic, was dramatically affected
`by the surfactant concentration and alkyl chain length (Table 6).
`The CMC can be measured by a variety of techniques, for example, surface tension, light
`scattering, osmometry, all of which show a characteristic break point in the plot of the
`operative property as a function of concentration. Figure 7, a plot of surface tension against
`concentration of surfactant shows a break in the linearity of the curve, indicating the CMC (50}.
`Many factors such as temperature, pH of the solution, electrolytes, and other ingredients affect
`micellization and hence solubilization (51,52). For nonionic Surfactants,
`the CMC value
`decreases with increasing temperature whereas for ionic surfactants,
`it
`increases as the
`temperature increases (53). Since the pH can affect the equilibrium between ionized and
`nonionized solute species, it can have an effect on the capacity of micellar solubility as shown
`by Castro et al, for atenolol, nadolol, midazolam and nitrazepam (54). For ionic surfactant
`micelles, electrolyte addition causes a decrease in the CMC resulting in an increase in the
`micellar solubilization capacity (5'5), whereas in the case of nonionic surfactant, polysorbate 80,
`the solubility of furosemide increases in the presence of sodium chloride because of increased
`micellar packing and micelle volume (56). Other ingredients present in the formulation can
`also have a profound effect on the solubilizing capacity of surfactants. Surfactants may
`precipitate in the presence of some organic additives or micellization may be abolished if high
`enough concentrations of, for example, alcohols are present. Excipients such as phospholipids
`also affect the CMC. Many water-soluble drugs themselves are remarkably surface active: they
`lower the surface and interfacial
`tension of water, promote foaming, and associate into
`micelles, such as antibacterial (hydrochlorides of acridines, benzalkonium chloride, cetylpyr—
`idinium chloride} tranquilizers (hydrochlorides of reserpine and phenothiazine derivatives),
`local anesthetics (hydrochlorides of procaine, tetracaine, dibucaine, and lidocaine), nonnarcotic
`analgesic (propoxyphene hydrochloride} and narcotic analgesic {morphine sulfate and
`meperidine hydrochloride}, antim uscarinic drugs {propan theline bromide, methantheline
`bromide, methixene hydrochloride), cholinergic agents (pilocarpine hydrochloride, and other
`
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`90
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`VOLUME 1' MHMUMHOFI' AMI) PACKAGWG
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`
`
`
`
` 8SURFACETENSION.1..Gym“uni-'1 a
`
`8
`
`35
`A”
`
`—2.50 4” 4"“
`4‘”
`4.”
`LOG OOMCENTRA'I'ION. gnu mt
`
`Figure 7 Surface tension versus concentration of
`surfactant. Break in the curve denotes CMC.
`Source: From Ref. 50.
`
`alkaloidal salts), antihistamines (pyrilarnine maleate, tripelennamine hydrochloride, chlorcy—
`clizine hydrochloride, diphenhydramine hydrochloride), anthelmintics (lucanthone hydro—
`chlorid e}, and antibiotics (sodium fusidate, some penicillins, and cephalosporins) (46).
`Selection of surfactant in the injectable products should be based on its safety and
`toxicology profile (U350,
`tissue tolerance, liemolysis, etc.), solubility of the drugJ in the in
`surfactant, and drug—surfactant compatibility. Since surfactants act as nonspecific solubilizers,
`stabilizers, emulsifiers and wetting agents, they can also cause toxicity and disrupt normal
`membrane structure. As mentioned earlier, only nonionic surfactants are generally used in
`parenterals because of their relative less destruction to biological membranes. Table 7 lists
`some commonly used surfactants,
`their properties, and examples of marketed injection
`products that contain surfactants for the purpose of solubility enhancement. Polysorbate 80 is
`
`Table 7 List of Some Surfactants in Injectable Products and Their Properties
`
`Injection product (chemical!
`
`
`
` Surfactant Chemical name HLB“ value CMC We wlw} brandP/n surtactant)
`
`
`
`
`
`Cremophor
`
`Solutol HS
`
`Pluronic F63
`
`Polyoxyethylated
`castor oil
`
`Polyethylene glycol
`660 hydroxystearate
`Polaxomer
`
`Polysorbates
`
`Tween 30
`
`12 14
`
`14 16
`
`0.02
`
`0.03
`
`Paclitaxelttaxolrsa?
`TenoposideNumom’SS
`CyclosporinefsandimmunerGS
`Vitamin K {Aqua mephytonl‘25
`
`>24
`
`15
`
`0.1
`
`0.0014
`
`Recombinant Growth
`hon‘nonefaccretropinf02
`Amiodoronefcordaroneflo
`docetaxell‘taxoterefloo
`Vitamin A palmitatefaquasol N12
`AmphotericinffungizonefOA
`0.08
`16
`Sodium desoxycholate
`
`
`40Sodium dodecyl sulfate Aldesleukimproleukim0018 0.03
`
`
`“Hydrophilic Lipophilic Balance
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`POHMULAHOFJ UEVtLOPMEm U!— SMHLL AM) MHGE VOLUMt WJECHONS
`
`91
`
`the most commonly used surfactant and is used in the range from fraction of percent in many
`products to 100% in the case of taxotere injection.
`
`Cyclodexirins as solubilizers Cyclodextrins are oligomers of glucose produced by enzymatic
`degradation of starch. The number of at—‘lA—linked glucose units determine the classification
`into at, B, or 7 cyclodextrins having six, seven, or eight glucose units, respectively (57 59). The
`cyclodextrins exert their solubilizing effect by forming soluble inclusion complexes in aqueous
`solutions. The cyclodextrins are amphipathic {i.e.,
`the exterior is hydrophilic due to the
`hydroxy groups oriented on the exterior while the interior is hydrophobic) and can form
`soluble, reversible inclusion complexes with water-insoluble compounds. The unsubstituted
`cyclodextrins are too toxic for parental use but the chemically modified cyclodextrins appear to
`be well tolerated when administered parenterally and have been shown to effectively enhance
`the solubility of several drugs including steroids and proteins (60,61). The solubility of
`alfaxalone, an insoluble anesthetic, was increased by 5000 times to 19 mg/mL in 20%
`hydroxypropyl—B—cyclodextrin (62). Some other examples of injectables that are currently in the
`market which contain chemically modified cyclodextrin for the purpose of enhancement of
`solubility are: Aripiprazole {Abilify'fi} (63), ziprasidone (Geodon'fi) (64} and voriconazole
`(Wt-2nd“) {65) coutaining sulfobutylether [l cyclodextrin (SBECD), itraConazole (Sporanox'K')
`(66) containing hyd roxypropyl—[l—cyclodextrin, and others.
`Having reviewed the factors that govern solubility and solubilization during the
`formulation development of injectable products, the next considerations are the elements of
`formulations.
`
`Types of vehicles
`Aqueous The vast majority of injectable products are administered as aqueous solutions
`because of the physiological compatibility of water with body tissues. Additionally, the high
`DC of water makes it possible to dissolve ionizable electrolytes, and its hydrogen—bonding
`potential facilitates the solution of alcohols, aldehydes, ketones, and amines. The current USP
`(1) has monographs for purified water, sterile purified water, WFI, sterile WFI, bacteriostatic
`WFI, sterile water for inhalation, and sterile water for irrigation.
`WFI is the solvent of choice for making parenterals. It must be prepared fresh and be
`pyrogen—free. It must meet all the chemical requirements for sterile purified water and in
`addition the requirements for bacterial endotoxins. The tests required for WFI are generally the
`same among the various pharmacopeias but differences do exist with regards to limits. WFI may
`be prepared by either distillation or reverse osmosis but the distillation method is by far the most
`common and accepted method. Because of the excellent solvent properties of water, it is both
`difficult to purify and maintain purity. Microorganisms, dissolved gases, organic and inorganic
`Substances, and foreign particulate matter are the most common contaminants of water.
`Prior to distillation,
`the water used as the source for WFI is usually subjected to
`chlorination, carbon treatment, deioniza tion, and, sometimes, reverse osmosis treatment (forced
`passage through membrane materials). After distillation, it is filtered and then stored in a
`chemically resistant tank {stainless steel, glass, or blocked tin} at a cold temperature around 5"C
`or at an elevated temperature between 65"‘C and 85C to inhibit microbial growth and prevent
`pyrogen formation. Generally, the hot water is continually circulated in the manufacturing areas
`during storage and usually filtered again prior to use. Sterile WFI and Bacteriostat-ic WFI are
`permitted to contain higher levels of solids than WFI because of the possible leaching of glass
`container constituents into the water during sterilization and storage. Bacteriostatic WFI, which
`generally contain 0.9% {9 mg/ml.) of benzyl alcohol as a bacteriostatic preservative, should not
`be sold in containers larger than 30 ml. to prevent injection of unacceptably large amounts of
`bacteriostatic agents (such as phenol and thimerosal).
`Other water-miscible cosolven‘ts These have been discussed earlier.
`
`Nonaqueous vehicles Drugs that are insoluble in aqueous systems are often incorporated in
`metabolizable oils. Steroids, hormones, and vitamins are incorporated in vegetable oils such as
`peanut, sesame, corn, olive, and cottonseed. Oil
`injections are only administered intra—
`muscularly. There are strict specifications for the vegetable oils used in manufacturing
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`92
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`VOLUMI‘: T.’ fUHMULflHOfl AMI) PACKAGING
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`Table 8 Official Injections Containing Oils as Vehicles
`USP (1) Oil commonlyr used
`
`
`
`Sesame
`Desoxyoorticosterone acetate
`Sesame, cottonseed
`Diethylstilbestrol
`Peanut
`Dimercaprol (suspension)
`Cottonseed
`Estradiol cypionate
`Sesame
`Estradiol valerate
`Sesame
`Estrone
`Poppyseeo
`Ethiodized iodine
`Sesame
`Fluphenazine decanoate
`Sesame
`Fluphenazine enanthats
`Sesame
`Hydroxyprogesterone caproate
`Sesame
`Menadione
`Sesame
`Nandrolone decanoate
`Sesame
`Nandrolone phenpropionate
`Vegetable
`Penicillin G procaine (combinations)
`Peanut
`Propyliodone (suspension)
`Cottonseed
`Testosterone cypionate
`Sesame
`Testosterone enanthate
`
`Testosterone propionate Sesame
`
`intramuscular injections. Storage of these preparations is important if stability is to be
`maintained. For example, they should not be subjected to conditions above room temperature
`for extended periods of time. Although the oils used for injections are of vegetable origin,
`federal regulatiOns require that the specific oil be listed on the label of a product, because some
`patients have exhibited allergic responses to certain vegetable oils.
`Sesame oil is the preferred oil for most of the compendial injections formulated with oil.
`is the most stable of the vegetable oils (except
`to light), because it contains natural
`It
`antioxidants. Sesame oil has also been used to obtain slow release of fluphenazine esters given
`intramuscularly (67}. Excessive unsaturation of oil can produce tissue irritation. In recent
`years,
`the use of injections in oil has diminished somewhat
`in preference to aqueous
`suspensions, which generally have less irritating and sensitizing properties. Benzyl benzoate
`may be used to enhance steroid solubility in oils if desired. Table 8 lists the oil injections official
`in the current USP (1).
`
`Added Substances
`
`Added substances such as buffers, antioxidants, antimicrobial preservatives, tonicity adjusting
`agents, bulking agents, chelating agents, solubilizing agents, and surfactants must frequently
`be incorporated into parenteral formulas in order to provide safe, efficacious, and elegant
`parenteral dosage forms. However, any such additive may also produce negative effects such as
`loss of drug Solubility, activity, and/or stability. Any additive to a formulation must be justified
`by a clear purpose and function. No coloring agent may be added, solely for the purpose of
`coloring the finished preparation, intended for parenteral administration (1). The reader is
`encouraged to refer to a number of publications that provide comprehensive listing of
`formulation components used in all marketed injectable products (1,68 74). Hospital
`pharmacists who are involved in IV additive programs should be aware of the types of
`additives present in products that are being combined. Commonly used parenteral additives
`and their usual concentrations are listed in Table 9.
`
`Pharmacopeias often specify the type and amount of additive substances that may be
`included in injectable products. These requirements often vary from compendia to compendia,
`so it is important to refer to the specific pharmacopeia that applies to the product in question.
`USP (1) specifies following maximum limits in preparations for injection that are administered
`in a volume exceeding 5 mL: for agents containing mercury and the cationic surface—active
`compounds, 0.01%; for chlorobutanol, cresol, phenol, and similar types of substances, 0.5%;
`and for sulfur dioxide, or an equivalent amount of the sulfite, bisulfite, or nietabisulfite of
`
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`93
`
`0.01
`0.01
`1 2
`0.25 0.5
`0.1 0.3
`0.1 0.3
`0.5
`0.002
`0.18
`0.02
`0.015
`0.01
`
`Table 9 Commonly Used Parenteral Additives and Their Usual Concentration
`Added substance
`Usual concentrations (‘33)
`Antibacterial preservatives
`Benzalkonium chloride
`Benzethonium chloride
`Elenzyl alcohol
`Chlorobutanol
`Chlorocrosol
`Metacresol
`Phenol
`Phenylmercunc nitrate and acetate
`Methyl p hydroxybenzoate
`Propyl p hydroxybenzoate
`Elutyl p hydroxybenzoate
`Thimerosal
`Antioxidants
`Acetone sodium bisulfite
`Ascorbic acid
`Ascorbic acid esters
`Butylhyclroxyanisole (BHA)
`Butylhydroxy‘toluene (BHT)
`Cysteine
`Nordihydroguaiaretic acid (NDGA)
`Monothioglycerol
`Sodium bisulfite
`Sodium metabistltite
`Tocopherols
`Glurathione
`
`0.2
`0.01
`0.015
`0.02
`0.02
`0.5
`0.01
`0.5
`0.15
`0.2
`0.5
`0.1
`
`0.01 0.075
`0.01 0.075
`
`Chelating agent
`Ethylenediaminetetraacetic acid salts
`DTPA
`Buffers
`Acetic acid and a salt, pH 3.5 5.?
`Citric acid and a salt. pH 2.5 6
`Glutamic acid, pH 8.2 10.2
`Phosphoric acid salts, pH 6 8.2
`Tonicity adjustment
`4 5.5
`Dextrose
`0.5 0.9
`Sodium chloride
`
`Mannitol 4 5
`
`1 2
`1 5
`1 2
`0.8 2
`
`potassium or sodium, 0.2%. Ethylenediaminetetraacetic acid derivatives and salts are
`sometimes used to complex and thereby inactivate trace metals that may catalyze oxidative
`degradation of drugs. The properties and functiOn of these added substances will be reviewed
`next, except solubilizing agents and surfactant, which have been reviewed earlier.
`
`Buffers. Maintenance of appropriate pH of the formulation is essential for proper solubility
`and stability. Changes in the pH of a formulation may occur during storage because of
`degradation reactions within the product, interaction with container components (i.e., glass or
`rubber}, and absorption or evolution of gases and vapors. Buffers are added to many products
`to resist a change in pH. Excellent reviews on pH control within pharmaceutical systems by
`Flynn (75} and Nema et al (76} are recommended to the reader. A suitable buffer system should
`have an adequate buffer capacity to maintain the pH of the product at a stable value during
`storage. while permitting the body fluids to adjust the pH easily to that of the blood following
`administration. Therefore, the ideal pH to select would be 7.4, the pH of the blood. Extreme
`deviation from this pH can cause complications. Tissue necrosis often occurs above pH 9,
`while extreme pain and phlebitis are experienced below pH 3. The acceptable range for IV
`injections is 3 to 9 because blood itself is an excellent buffer and can very quickly neutralize the
`
`Regeneron Exhibit 1015.108
`
`3 D
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`ownloadedfrominfonnahcallhcarccmbyMcGillUniversityon01.3150For
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`94
`
`VOLUME T.’ fUHMULAHOfl AME) PACKAGWG
`
`onwrcrmn
`
`/
`
`mmornzcmms
`
`
`
`ll
`
`:-
`
`8
`
`I. g
`
`F
`ll 3bl
`I) “a
`H
`II E
`' H
`I
`
`P“
`
`Solubilitylstability pH profile of pro
`Figure B
`caine penicillin. Source: From Ref. 7?.
`
`pH outside of 7.4. Parenterals administered by other routes are generally adjusted to a pH
`between 4 and 8.
`
`A suitable buffer system can be selected from knowledge of a solubility/ stability pH
`profile of the drug in solution. A typical pH profile of both solubility and stability is shown
`in Figure 8 for procaine penicillin G (77). By following the degradation over a given pH range
`and plotting the rate constants verSus pH, the pH of maximum stability (pH 6.6} can be
`determined. In the case of procaine penicillin G, the solubility is lowest between the pH 6
`and 7, which is desirable since the product is formulated as a suspension. Once the desired pH
`is determined, a buffer system that provides sufficient buffer capacity can be selected. The
`buffer capacity, 13, is an indication of the resistance to change in pH upon the addition of either
`basic or acid substances and can be represented by the following expression:
`
`K.H'
`dB
`.— —— :r 2.3 —'l—
`,G de
`03cm +H+J
`
`1
`(1 )
`
`where
`
`dB = change in concentration of base or acid,
`de =
`change in pH,
`C = molar concentration of buffer system, and
`K. -— dissociation constant of the buffer.
`
`A hypothetical plot of [l versus pl-l—pKa is illustrated in Figure 9 for a monobasic acid. A
`maximum value at zero indicates that the greatest buffer capacity occurs at a pH equal to the
`pK.. of the buffer system and further suggests that a buffer system with a pK.. within :l:‘l.[‘,| unit
`of the desired pH should be selected.
`Buffer systems for parenterals generally consist of either a weak base and the salt of a
`weak base or a weak acid and the salt of a weak acid. Figure 10 shows the effective range of
`typical pharmaceutical buffers. The distance indicated by the arrows represents the effective
`buffer range for each system and the dashed lines represent the pK. for the system. Commonly
`used buffers are phosphates, citrate, acetate, and glutamates.
`The Henderson—Hasselbach relationship is used to calculate the quantities of buffer
`species required to provide a desired pH.
`
`
`
`{1 2}
`
`Regeneron Exhibit 1015.109
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`3 D
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`ownloadedfromint'ennalicalthcarccombyMcGillUniversityonUltiir‘lFor
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`

`f'OHMULAHOfl UEVELOPMEM 0f— S‘WILL MU LAHGt VOLUMt WJECHONS
`
`95
`
`
`
`10.0
`
`GLUTAMATE
`
`
`
`TRIETHA NOLAMISE
`
`Figure 9 Theoretical buffer capacity curves
`of a monobasic acid.
`
`
`
`CITRATE
`.oooo-unoooo-
`
`pk. (I): 3.14
`
`pK. (2): u
`cw‘rmxn:
`
`
`9K. to: 1:9
`menus
`
`
`3.0
`
`2.0
`
`1.0
`
`Effective range of pharma
`Figure 10
`ceutical butters. indicated by the arrows.
`The dashed line represents the pKa
`value.
`
`Where Cam and Cami are the molar concentrations of the salt form and the acid form,
`respectively. As shown from the following calculation, an acetate buffer system (13K,
`4.8}
`consisting of DJ M acetic acid and 0.05 M sodium acetate would result in a pH of 4.5.
`
`0.05
`0.1
`
`-
`
`: 4.8
`
`0.3 -._ 4.5
`
`pH: 4.8+log
`
`Although buffers assure the stability of pH of solution, the buffer system itself can affect other
`properties such as reaction kinetics and solubility aspects. Buffers can act as general acid or
`general base catalysts and cause degradation of some drug substances. Such a mechanism occurs
`with a number of amine and amine derivative drugs in systems containing polycarboxylic
`acids (e.g., citric, tartaric, and succinic). In one such case, as shown in Figure 11, the degradation
`of vitamin 31 increases with increase in citrate buffer concentration (78).
`The ionic strength contributions of the buffer system can also affect both isotonicity and
`stability. For example, if adjustment of pH is made with sodium hydroxide, say of a solution
`
`Regeneron Exhibit 1015.110
`
`3 D
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`ownloadedfrominl'onnahcalthcarccombyMcGillUniversityon01.31551For
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`96
`
`VOLUME 1' f‘UHMUM-‘fflfl AMI) PACKAGING
`
`pH
`
`‘1 5.20
`4— d 60
`
`4— 4 40
`
`q— 4.00
`
`4— 3.60
`
`4— 3.00
`
`4— 2.50
`
` o
`
`0.04
`
`0-08
`
`0.12
`
`0-16
`
`0-20
`
`Effect of citrate buffer concentration
`Figure 11
`on thiamine hydrolysis (vitamin B” at 96.4 C Ell
`Constant ionic Strength and at different pH values.
`Scarce: From Hot. }'8.
`
`TOIAI. CITRAI'E {monitor}
`
`containing monosodium phosphate, the effect of the generation of disodium salt on isotonicity
`and the effect of HI’O4 '2 must be taken into account (79,80).
`
`Antioxidants. Many drugs in solution are subject to oxidative degradation. Such reactions are
`mediated either by free radicals or by molecular oxygen and often involve the addition of
`oxygen or the removal of hydrogen. For products in which oxygen is directly involved in the
`degradation, protection can be afforded by displacing oxygen (air) from the system. This is
`accomplished by bubbling nitrogen, argon, or carbon dioxide through the solution prior to
`filling and sealing in the final container. Oxidative decompositiOn is catalyzed by metal,
`hydrogen, and hydroxyl
`ions. Drugs possessing a favorable oxidation potential will be
`especially vulnerable to oxidation. For example, a great number of drugs are formulated in
`the reduced form (e.g., epinephrine, morphine, ascorbic acid, menadione, etc.) and are easily
`oxidized. Oxidation can be minimized by increasing the oxidation potential of the drug.
`As illustrated in Figure 12 (8]), lowering the pH of the solution will increase the oxidation
`potential. This occurs because according to a simplified version of the Nernst equation:
`
`RT
`E _ E”+—log
`2
`
`[HT'] - [Ox]
`[Rd]
`
`“3)
`
`an increase in hydrogen ion concentration causes an increase in the actual oxidation potential,
`E. In this equation E" is the standard oxidation potential, R the gas constant, T the absolute
`temperature, and constant 2 represents the number of electrons taking part in the oxidation—
`reduction reactiou.
`
`Agents that have a lower oxidation potential than the drug in question, and thus can be
`preferentially Oxidized, are called antioxidants. Such agents are added to parenteral solutions
`either alone or in combination with a chelating agent or other antioxidant and ftmction in at
`least two ways: (i) by being preferentially oxidized and thereby gradually consumed or (if) by
`blocking an oxidative chain reaction in which they are not usually consumed.
`Morphine in aqueous solution undergoes a pH—dependent oxidative degradation. The
`rate is slow and constant between pH 2 and 5, where morphine exists in the prolonated form as
`
`Regeneron Exhibit 1015.111
`
`0.100
`
`0.075
`
`0.050
`
`0.025
`
`0.1130
`
`_
`'I.
`
`S u
`
`?§
`
`-I
`
`g
`
`h...‘
`'-
`
`3 D
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`ownloadedfrominfomahcallhcarccmbyMcGillUniversityon01.31551For
`
`

`

`EOHMULAHOFJ UEVELUPMEM 0!— S‘WILL AND LARGE VOLUMt WJECHONS
`
`9?
`
`
`
`pH “
`'2
`w
`'
`§
`‘
`1
`neunon BETWEEN onmnon ton-3111M. AND pH
`
`Figure 12 Relationship between oxide
`tion potential and pH. Source: From
`Ref. 81.
`
`4.3
`
`4.5
`
`-I.‘I
`
`4.9
`
`4.!
`
`4.3
`
`-2.5
`
`4.1
`
`‘13
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`P"
`
`Figure 13 Reaction rate constant for the first
`order oxidative degradation of morphine at 95 'C as
`a function of pH. Source From Ref. 82.
`
`E3
`
`EG
`
`U im
`
`e g
`
`shown in Figure 13. However, above pH 5, the oxidation increases with increase in pH (82).
`Theref