harmaceutical Science and Technology
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`Parenteral Dri Asscciation
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`Solubility Principles and Practices for Parenteral Drug
`Dosage Form Development
`stephanie Sweetana and Michael J. Akers
`
`PDA J Pharm Sci and Tech 1996, 50 330-342
`
`AstraZeneca Exhibit 2052 p. 1
`InnoPharma Licensing LLC v. AstraZeneca AB IPR2017-00904
`
`

`

`REVIEW ARTICLE
`
`Solubility Principles and Practices for Parenteral Drug Dosage
`Form Development
`
`STEPHANIE SWEETANA and MICHAEL J, AKERS*
`
`Pharmaceutical Sciences, Lily Research Laboratories, Indianapolis, Indiana
`
`introduction
`
`A common problem experienced in the early develop-
`mentof drugs intended for parenteral, especially intrave-
`nous, administration is the solubilization of a slightly
`soluble or water insoluble active ingredient, Drug solubi-
`lization has been: the subject of. many scientific. articles
`and textbooks (referenced throughout this article); yet
`despite this attention and available Iterature, product
`development scientists still encounter significant dificul-
`ties in solving their solubility problems.
`‘Theories of solute solubilization. are not easy to
`understand. Solubilization processes are amazingly com-
`plex and require a fair amount of expertise in physical
`chemistry to.
`interpret and apply current theoretical
`models. Much of the literature deals with solubilization
`theory and does not offer much practical help to the
`inexperienced scientist under a lot of pressure to find a
`solution to his/her solubility problem.
`This article intends to help-the scientist in early drug
`formulation design for parenterally administered drug
`products by reviewing pertinent literature on solubiliza-
`tion and reducing it to simple approaches one can use-to
`solve solubility problems. The classical theories of solu-
`bility, and how they relate to pharmaceutical systems of
`interest will be reviewed and practical applications
`discussed, Because of the-common concerns regarding
`cosolvent
`‘toxicity and acceptability by medical and
`regulatory bodies, we also will treat this topic in some
`detail,
`
`|. Pertinent Theory of Solubilization of Drugs
`
`Solubility theories deal with conversion of a substance
`from one state to another, and the equilibrium phenom-
`ena that are involved, Through pioneering work of
`Henry, Raoult and -van’t Hoff in the late 1800's, the
`properties of various solutions have been. defined.
`in
`theories. These early theories form the basis by which
`more complex systems, such ag those encountered in the
`biological sciences, are compared and understood.
`No single theory can adequately explain solubility
`behavior of uncharged molecules in a variety of solvent
`systems, Each theory is suited for select combinations of
`
`Recewed June 29, 1995. Accepted for publication March 21, 1996.
`* Author 1o- whom correspondence should be addressed: Lilly Corpo-
`rate Center, Indianapolis, IN 40285.
`
`solutes and solvents where certain intermolecular forces
`are assumed. to predominate, or-conversely,.be- absent.
`The-classical theories of solubility have. been explained
`most simply in terms of intermolecular interactions.
`ideal
`‘salution theory assumes solite-solute, solvent-
`solvent and solute-solvent interactions are completely
`uniform in “strength and. nature. An example of a
`solution behaving. ideally.is a non-polar solute in a
`non-polar solvent such as:naphthalene in benzene.
`Regular solution theary evolved to account for thé imbal-
`ance of intermolecular interactions that often occur
`between dissimilar systems of a solute and solvent. The
`focus of this theory are systems of low polarity such as
`steroids in hydrocarbon solvents, Extended regular solu-
`don theory incorporated additional parameters such as
`dispersion, polar and hydrogen-bonding interactions
`info regular solution theory, Various approaches have
`been used to represent these molecular interactions,
`leading to a variety of models to. predict and-explain
`solubility behavior of polar solutes in polar systems, cach
`with diferent approximations and assumptions (1-4).
`In most pharmaceutical systems, the rouline applica-
`tion of these models to predict. solubility and simplify
`formulation development.is complex. Most drags of
`interest aré ionizable, contain polar polyfunctional
`groups; and are.capable of forming multiple hydrogen
`bonds. The majority of parenterally acceptable cosol-
`vents--such as propylene glycol,-polyethylene glycol,
`ethanol and water—are capable of self association
`through hydrogen bond formation. Such interactions
`may alter solvent structure and, a5 a resull, influence
`solubility in. an unpredictable manner.(1}. Exaraples of
`this phenomena are deviations from log-linear solubliza-
`tion of nonpolar solutes in a polar cosalvent system (5).
`For the models.to adequately describe solubility behav-
`ior, proper weighting must be. assigned io the relative
`importance of competing self-associations and strong
`intermolecular interactions, Currently this is being miod-
`eled by various computer mtensive gronp-contribution
`approaches, some of which allow for the mutual interac-
`tions of various finctiéaal groups (1):
`In the biological sciences, many solutes of interest are
`capable of acting as acids or bases. In an ionizing media
`such as. water, they may dissociate into ions which are
`usually highly water soluble. To what extent a molecule
`is ionized in an aqueous solution is largely dependent on
`its pKa and the pH of the media. The Henderson-
`
`330
`
`PDA Journal of Pharmaceutical Science & Technology
`
`AstraZeneca Exhibit 2052 p. 2
`
`

`

`Hasselbaich equation is.a mathematical expression-of
`this relationship (3). Ia formulation development, con-
`sideration of the arnount of un-ionized drug in solution
`is. helpful to avoid unexpected precipitation ofthis form.
`As the pH of a drug solution is changed, the amount of
`free acid or base may Increase and eventually exceed the
`limited solubility of this form. It is possible to calculate
`the oH of precipitation and of maximum solubility, W the
`pKa of the molecule and the solubility of the unionized
`and ionized forms are known (3, 6). Generally, two pH
`units above or below the pHy. value establishes the
`desired pH-for formulation. For drig molecules with
`multiple ionizable. groups.
`these equations are more
`complicated to apply-and:-so experimentally generated
`solubility data are usually collected,
`‘Through owrown experience we find that theory gives
`us some direction with respect
`to experimental ap-
`proaches, but we still need to rely on the empirical
`experimentation © screen for systems which offer the
`most promise in solubilizing water-insoluble. drugs.
`
`ll. Formulation Desiqn
`
`the first approach used to increase the
`Usually,
`solubllity of an insoluble drug in water is to formemore
`water soluble salts. Berge and co-workers (7) wrote what
`is now a near classic review of salt form strategies
`acceptable tor pharmaceuticals. If salt iormation is not
`possible, ¢.g,
`too unstable, or does not render the
`molecule sufficiently water soluble, a series of formula-
`tion approaches may.be investigated. Table | summea-
`rizes these general strategies. Often a-useful approach to
`increase the aqueous solubility of an ionizable drug is
`pH adjustment. The next approach most frequentlytried
`is the use of water-miscible cosolvents: Other ap-
`proaches to be discussed briefly Include the use-of
`surface active.agents and complexing agents. Develop-
`ment of emulsified and colloidal drug delivery systems
`for intravenous administration are becoming more widely
`and successfully applied. They may confer to the en-
`trapped or associated drug significantly different proper-
`
`
`
`TABLE |
`Summary of Parenteral Formulation Approaches
`
`
`inportant Formula
`
`Approach
`Examples
`Considerations
`Useful Tests
`
`pH adjustment
`
`pH 2te ls
`
`Cosolvent
`
`Polyethylene glycol
`Propylene glycol
`Ethanol
`Dimethylacetamide
`
`Surface Active Agents
`
`Palysorbates
`Poloxamers
`Cremophor EL.
`Lecithin
`Bile salts
`
`Complexing Agents
`
`Cyclodexirans
`Water-soluble vitamitis
`
`Dispersed Systems
`
`Eanulsions
`Liposomes
`Nanoparticles
`
`Drug stability
`pH
`ions to buffer or adjust pH
`Drug precipitation upon infusion
`drug concentration
`use of buffer/buffer capacity
`infusion rate
`Formula irritation
`isotonicity
`infusion rate & duration
`drug vs vehicle
`drug precipitation
`
`Systemic toxicity
`total cosolvent administered
`Drug precipitation upon infusion
`drug concentration
`infusion rate
`Formula irritation
`isotonicity
`infusion rate & duration
`drug ve vehicle
`drug precipitation
`
`Hypersensitivity in animals
`Formula intitation
`isotoriicity
`infusion rate & duration
`drug vs vehicle
`
`Purity of excipients and drugs
`Formula irritation
`isotornicity
`pifusion rate & duration
`drugvs vehicle
`
`Sterility
`Particle size
`Pharmacokinetics
`Stability
`
`pH rate profile
`pH solubility profile
`Freezing point depression
`ia vitre precipitation model
`da vive phiebitis model
`Esvitra cell lysis studies
`
`Mixture studies for maximum
`solubility
`firvitre precipitation model
`i#vive phlebitis model
`in virro-cellysis studies
`
`Pe vive phlebitis model
`fa vitro cell lysis studies
`
`Phase solubility diagrams
`ig vive phiebitis model
`Br vitro cell lysis studies
`
`Particle size
`
`Vol. 50,No.5 / September-October 1996
`
`331
`
`AstraZeneca Exhibit 2052 p. 3
`
`

`

`ties from the free form. providing the opportunity to
`prolong drup presence in-vhe bloodstream or fo aller
`disposition if the body.."Heroic” methods. reported in
`the liferature for various cancer drags. will alsa he
`reviewed although these methods use types-and amounts
`of excipients that probably would not commonly be
`considered approvable for intravenous administration,
`is
`The basis for reliable formulation development.
`accurate determination of solubility. Traditional method-
`ology is the “equilibrium method” ($) where excess drug
`is added to the solvent system, and some means of
`agitation is employed under constant
`temperature.
`Samples are withdrawn, filtered, and analyzed for drug
`coricentration over a period of time and equilibration. is
`demonstrated by uniformity of the data aver ihe time
`interval. For sparingly soluble drugs where equilibria are
`slow, accurate determinations of solubility may be-diff-
`cult. Useful techniques. in. these instances include using
`highly specific analytical methods to detect parent com-
`pounds, minimizing the amount of excess solid added,
`and assuring sufficient equilibration time (1). Solid state
`factors and batch-to-batch variation (different poly-
`morphs, hydration state, crystallinity, crystal homogene-
`ity, and impurities) may aflect reproducibility of. drug
`solubility determinations.
`
`A. pH Adjusiment
`
`Current FDA approved marketed: parenteral: prod-
`ucts range in-pl from 2 to. 1 L-A.comprehensive listing of
`these products. may be found in Table 11. For biocompat-
`ability reasons, formulation of injectables within the pH
`ranges of 4 to 81s most common. However, to achieve
`sufficient drug solubility, a pH outside this range may be
`necessary.
`The pH at whith 4 product is formulated is usually
`determined from the pH solubility and pH rate profiles
`of the drug (©). A recent example of their application to
`aid parenteral formulation development is CI-988, a
`cholecystokinin-B receptor antagonist (10).
`Additional formulation variables to be considered are
`the necessity of a buffer, buffer capacity. and. drug
`eoncentration. These can influence supersaturated drug
`concentrations in the bloodstream, a. condition that may
`lead to in vivo drug precipitation. The blood is very
`efficient at pH neutralization and normally maimtains a
`narrow pH range of 7.38 to 7.42. For example, a low
`meidence of phlebitis was observed in the rabbit ear vein
`model when solutions over the pH range-of 3 to 11. with
`buffer concentrations of approximately 0.3 M, were
`administered in a single small volume (1 mL.) bolus dose
`(11). Simple screening tests consisting.of a computa-
`tional model where drug solubility i plotted. as a
`function of-dilution, and in viro. dilution experiments
`were shown to be effective tools in evaluating the ability
`of the pH-solubilized drug to remain in solution dilution
`(12,13). Davio etal. (14) showed that in vive precipita
`tion of the pH-solubilized drug ditekiren was dependent
`upon driig concentration and infusion rate. Low concen-
`tration drug solutions, which aré rapidly diluted below
`
`322
`
`saturation solubility, and rapid infusions were preferred
`tominimtize precipitation.
`The most commonly used buffer cormponents in paren
`teral products and their pKa’s are: citric acid (3.13, 4.76,
`6.40), acetic acid (4.76) and phosphoric acid (2.15, 7.20.
`12.33). When: buffers are employed, the stability-of the
`molecule ist alse be considered, since i may he
`influenced by the tonsin solution (9). Examples of buffer
`catalyzed solution degradation include famotidine, a
`histamine. HZ .receptor inhibitor (15) and loracarbel, a
`awitterionic cephalosporin (16),
`
`B. Use af Cosolvents
`In recent years, surveys of FDA-approved parenteral
`products (17-19) showfive water-miscible cosclvents—
`glycerin, ethanol, propylene glycol, polyethylene glycol,
`and N,N,-dimethylacetamide—as comporients of sterile
`formulations (Table [1 and PV). Cosolvents are em-
`ployed in-approximatély 10% of FDA approved paren-
`teral products. ‘They are useful because they may often
`provide exponential increases in solubility (20) and. also
`allow exclusion of water for compounds susceptible to
`hydrolysis.
`Invesiigation of the solubilizing potential of various
`cosolvents may be approached empirically by determin-
`ing the compounds solubility in cosolvent compositions
`simular to marketed products (21-23), or by one of
`several systematic approaches, such aslog-linear solubil-
`ity relationships or statistical experimental design.
`In the study of log-linear solubility relationships,
`Yalkowsky and -Roseman-(20) investigated a range -of
`solutes in binary cosolvent mixtures of ethanol, propyl-
`ene glycol, and glycerin im water and discussed the
`closeness of fit of apparent solubility to a log-linear
`solubility equation. Briefly, this technique involves experi-
`mentally determining the solubility. of a compound in
`increasing percentages of a cosolvent and generating.a
`sémi-logarithtnit plot of the apparent-salubility of the
`drug as a function of the volure-fraction of the cosol-
`vent, Using the slope and the solubility of the compound
`in pure water, an equation may be written. to describe
`the solubility ina binary system.
`Assuming that the log-linear increases in solubility of
`individual cosolvents are additive, equations-may also. be.
`written for-ternary and quaternary mixed cosoivent
`systems (24).. Mathematically, these relationships are
`described by the following equations:
`
`Binary cosolvent syster
`
`log Cy = log C,.+ af
`
`Ternary cosolvent sysiem
`
`jog C. = loge C+ age + oh,
`
`Qualernary cosolvent spsiem
`
`log C, = log Cy + of + Oafy + Of,
`
`where Cy is the drug solubility in water: o's are the
`slopes of the semi
`logarithmic plots; C,
`is the drug
`solubility, fis the volume fraction of the cosolvent; and
`the subscripts a, 6x denote the coselvents A, B, and X
`
`PDA Journal of Pharmaceutical Science & Technology
`
`AstraZeneca Exhibit 2052 p. 4
`
`

`

`TABLE li
`Exampies of Marketed. Parenteral Producis wilh Solution pH Outside Range of 4 to 8.18, 19)
`
`pH
`pH
`Generic
`Marketed
`
`(constituted)
`Adjustment
`Namie
`Trade Name
`Form
`Routes
`
`Solution
`Solution
`
`Powder
`Powder
`Concentrate
`Powder
`Solution
`Solution
`
`Poweder
`
`
`
`
`
`Solution
`Sohition
`
`Sohution
`
`Solution
`Solution
`Solution
`
`Solution
`Solution
`
`Solution
`Solution
`Powder
`Solution
`Solution
`Solution
`Solution
`Solution
`Solution
`Solution
`
`IBLTF
`18, IF
`
`IB
`IMIF
`IF
`IB TF
`IF
`IF, IB
`
`IF
`
`IM, IP, IB
`IM, 1B
`
`IM, 1B, IF
`
`IM, 1B
`IM
`1B, IF
`
`iF
`IM, IF
`
`IM. 1F
`IF
`IF
`IM, 18
`IM, TRL IF
`IF
`iF
`1B, IF
`IM, 1B
`TB.IM
`
`Powder
`Powder
`
`TM, D8, TF
`iP
`
`Solution
`
`IB, TF
`
`Powder
`Powder
`
`Powder
`
`Solution
`
`Powder
`Solution
`Solution
`
`IM. TF
`IBCTF
`
`IMIBIP
`
`TB; EM
`
`TBp TE
`IB
`Ir
`
`Solution
`Sohution
`Solution
`
`iBIF
`1B
`IM, TRO IF
`
`pu<4
`3.24
`325-365
`
`Amrnone Lactate
`Lactic acid, NaOH
`Benzenesulfonic acid —Atracurium Besylate
`
`3
`ie
`3.33.9
`oad
`25-45
`SI
`
`LB-3.3
`
`33:8
`23S
`
`3.2-3.8
`
`a3
`3-3.6
`3-4
`
`34.2
`27-35
`
`3
`32-4
`2-28
`38
`3-4
`3.34
`25-45
`34
`238
`3-4
`
`pli>s§
`a2
`1O0.5-DL.6
`
`8.069
`
`9.6-10.4
`9.6
`
`8-10
`
`8.5
`
`92-10
`116
`9-105
`
`Lactticacid, WC)
`Citric acid
`NaOH, HC)
`Cittie acid, Nacitrate
`
`Lactic acid
`Lactic acid, ethyl
`lactate
`Lactic acid
`
`NaOH/HO
`Lactic acid
`
`NaOH, citric acid
`Tartaric acid
`
`NaOHHC
`
`Na citrate,citric acid.
`Hcl
`Citric acid, Na citrate
`Acetic acid
`NaQH
`
`Tartaric acid, Na
`cltrate
`
`HCUNaOtH
`
`NaOH
`
`NazsHFOy, NaGH
`
`NaOH
`NaQH
`
`O28
`8-11
`89.3
`
`NaQH
`NaQh
`NaQH
`
`Chiordiazepoxide HC].
`Benzquinamide HCl]
`Ciprofloxacin
`Dacarbazine
`Dopamine HCl
`Dildazem HCl
`
`Doxyeyeline Hyctate
`
`Droseridol
`Ersonovine Maleate
`
`Fentanyl Citrate and
`Droperido!
`Glycopyrrolate
`Haloperide! Lactate
`Labetalol HCI
`
`Methyidopate HC!
`Metivlergonovine
`Maleate
`Midazolam HC!
`Murinone Lactate
`Minocyeline HC)
`Nalbuphinc HC]
`Naloxone HCl
`Ondansetron HO
`Oxytocin
`Papaverine HC!
`Pyridoxine HE)
`Tolazoline HC]
`
`Acelavolamide Na
`Acyclovir Na
`
`Asninophylline
`
`Amobarbital Na
`Azaihioprine Na
`
`Anipicihi Na
`
`Betamethasone Na
`PO,
`Chiorothiazide Na
`Diazoxide
`Diethylstilbestrol
`Diphesphate
`Fluerouracti
`Folie aciel
`Lasix
`
`Inocor (Sanoh Winthrop)
`Tracrium (Burroughs
`Wellcome)
`Librium (Roche)
`Emete-Con (Roerig)
`Cipro TV. (Miles)
`DTEC-Dome (Miles)
`Intropin (DuPont)
`Cardizem (Marion Merrell
`Dow)
`Vibramycin TV (Roerig,
`Elkins-Sinn)
`Inapsine Ganssen)
`Ergotrate Maleate (Lilly)
`
`Tonovar Janssen)
`
`Robinul (Robins)
`Haldel (McNeil)
`Normodyne (Schering)
`Trandate (Glaxa)
`Aldomet Ester HCl (Merck)
`Methergine {Sandoz}
`
`VYersed (Roche)
`Primacor (Sanofi Winthrop}
`Minocin (Lederle}
`Nubain (DuPont)
`Narean (DuPont)
`Zotran (Cerenex)
`Pitocin.(Parke-Davis)
`Papaverine FIC) {Lilly}
`Pyridoxine HG! (Steris)
`Priscollne HCI (Ciba)
`
`Diamox (Lederle)
`Zoviras (Burrougss
`Welicomé}
`Aminophylline (Abbott,
`Elkins-Sing, American
`Regent}
`Anylal Na (hilly)
`Imuran (Burroughs
`Wellcome)
`Polvedlin-N (Apothecon)
`Totacillin-N (Beecham)
`Onupen-N Wyeth)
`Celestone Phosphate
`(Schering)
`Sodium Diuril (Merck)
`Hyperstat (Schering)
`Silphostrol (Miles)
`
`Fluorouracil (Roche)
`Folvite (Lederle)
`Furosemide
`(Hoechst-Roussel)
`TF
`Powder
`Cytovene (Syntex)
`Ganciclovir Na
`lt
`Bl
`Leueovorin Ca
`Wellcovarin (immunex,
`Powder
`IML TB, TR
`Burroughs Wellcome)
`
`95-105
`Na carbonate
`Methohexital Na
`Brevital Na (Lilly)
`Powder
`1B, TF
`IM-= intramuscular, IF = intravenous infusion, IB = intravenous direct injection.
`
`Vol 5O,No.45: / September~October 1996
`
`339
`
`AstraZeneca Exhibit 2052 p. 5
`
`

`

`TABLE Hl
`Cosolvent Concentrations:in- Some Currently Marketed: Parenterais (16, 19)
`
`Coselvent in
`Marketed Vehicle
`
`Appx.
`Vehicle
`Marketed
`Generic
`Name
`Trade Name
`Form
`Routes
`Administration
`per Dese
`
`
`Ethanol WO
`
`Crrmmrstine
`
`BICNU(Bristol Myers Drug
`Oncology)
`+.Dibvent
`
`iF
`
`Dilete bid
`
`aml
`
`Propylene glycol
`Ethyl alcohol 10%
`
`Diazepam
`
`Valnon (Roche)
`
`Solution
`
`IMJIB
`
`Direct Injection
`
`O34 mi
`
`Propylene Glycol 409)
`Alcohol. 106
`
`Digoxin
`
`Larioxin (Burroughs
`Wellcome)
`
`Dimenhydrinate
`(Steris)
`
`Solution
`
`iB
`
`Direct injection
`
`[~S-ml
`
`Solution
`
`IM. IF
`
`Dilate 1:10
`
`tml
`
`Dimealydrinate
`
`Benzyl alcohol 5%
`Propylene glycol 50%
`
`Propylene glycol 250°
`Ethanol 25%
`
`Esmolel AC!
`
`Breviblec (DuPont)
`
`Concentrate JF
`
`Dilute 1:25
`
`1-10 nil
`
`Hydralazine HC]=Apresoline HCL (Ciba). Solution IM, TB Direct injection (h3—1 mil
`
`
`Propylene glycol
`136%
`
`
`
`
`
`Ethanol 10°
`
`Ketorolac
`‘Tromethamine
`
`Lorazepam
`
`Toradol (Syntex)
`
`Solution
`
`IMenly
`
`DirectinjectionIM imi
`
`Ativan (Wyeth-
`Ayerst}
`
`Solution
`
`IMTB
`
`IM Direct Injection. Lol
`Delate ISDE
`
`PEG 4000.18 mi/ml
`Benzyl aleahol 2%
`Propylene-glycol
`
`Povidone 20 mg
`Diuent (10 mi)
`Propylene elycal 6m
`Ethanol 052 ml
`
`Ethanol 30%
`Propylene glycol 30%
`
`Metphalan HCI
`
`Alkeran (Burroughs
`Wellcome)
`
`Drug
`+ Dilwent
`
`iF
`
`Dilate constinte ml
`2119
`
`Nitroglycerin
`
`Tridd (DuPont)
`
`Concentrate
`
`IF
`
`Dilute 1:100
`
`23-10 ml
`
`Peniobarbital Na=Nembutal (Abbott) Sotation IM: 1B Slow direct injection. 2 ml
`
`
`Propylene-glyenl 40%
`Alcohol 10%
`
`
`
`
`
`Alcohol 10%
`Propylene glycol 67.8%
`
`Propylene glycal 40%
`Aleohal 10%
`
`Phenobarbital Na
`
`Phenytonr Na
`
`Luminal Na (Sanofi
`Winthrop)
`Dileotin (Parke Davis)
`
`Polyethylene glycol 50%
`
`Secobarbital Na
`
`Secobarbital Na
`C(Wyeth-Ayerst)
`
`Propylene ghyeol 40c%
`Ethanol 10%
`
`Trimethoprin-Sul- Septra (Burroughs
`famethoxazole
`Wellcome)
`Bactrim (Roche)
`
`Solution
`
`TM TB
`
`Direet injection
`
`tml
`
`Solution
`
`IM.TB
`
`Direct imection
`
`3-3 mm)
`
`Solution
`
`IML TBTF Direct injection
`
`i-S im
`
`Concentrate:
`
`TF
`
`Dilute P25
`
`S—10 ml
`
`Agmsacrine
`
`N.N-Dimethylacet-
`amide LOU.
`
`Lam
`Dilute 1500
`IF
`Drug
`Amsidine.Coneén-
`
`trate (Parke-Davis)! + Dituent
`iM = intramuscular [F = intravenous infusion, 18 = intravenous direct injection.
`* Drag available outside the United States
`
`respectively. In iis simplest form, determining the drug
`solubility in water and pure cosdivents would. allow
`estimation of the amount and type of cosolvent required
`to aitaim-a desired solubility.
`in most cases however,
`deviations from log-linear increases of solubility occur in
`aqueous cosolvent mixtures.as indicated by curvature in
`the solubility plots. The deviations are attributed to
`solvent-solvent interactions (5,25).
`this
`For first approximations of solubility however,
`approach has. been shawn to be useful (26-27). Chien
`(28) used this technique and. polarity indexes of cosol-
`vets to calculate the polarity.of a selution that pro-
`duced the greatest solubility of the drug metronidazole.
`
`Aqueous/casolvent ratios of corresponding polarity could
`then be calculated for other cosolvent systems to provide
`qualitative identification of solubility maximums. (29,
`30). Polarity indexes of common water miscible cosol-
`vents have been tabulated and discussed by Rubino and
`Yalkowsky. These indexes reflect the cohesive proper-
`hes of the solvent (solubility parameter and interfacial
`tension}, hydrogen bonding ability (proton donor and
`acceptor density), and polarity (dielectric constant).
`Another. solubdity. determination. approach. particu-
`lariv belpful for complex mixtures is a statistical experi-
`mental design (31). Identifying the optimum combina:
`vion of coselvents for solubilization may reduce the net
`
`334
`
`PDA Journal-ot Pharnaceutical Solence & Technology
`
`AstraZeneca Exhibit 2052 p. 6
`
`

`

`Paclitaxel
`
`Taxol (Bristol-Myers
`Squibb}
`
`Multivitaniuns
`
`MOV.L-12 (Astra)
`
`IPF
`
`IF
`
`Chiordiazepoxide HC]
`
`Librium (Roche)
`
`IM only
`
`Cyclosporine
`
`Sandimmune (Sandoz)
`
`IF
`
`Eroposide
`
`VePesid (Bristal-Myers
`Oncology)
`
`IP
`
`
`
`THlute 1:5 or 1:20
`
`20 ml
`
`Dilete 1:100-0r-:300: Sm
`
`Direct injection IM
`
`Dilute 1:20-1:100
`
`Dilute 1:100
`
`2 ml
`
`Smal
`
`Sami
`
`Cremophor EL 527
`me/ral
`Ethanol 49.7%
`
`Propylene giveal 50%
`Polysorbate 801,69
`Polysorbate 20 0.028%
`
`Polysorbate 604%
`Propylene glycol 207.
`
`Cremophor E1650
`mg/ml
`Alcohol. 32.9%
`
`Polyethylene glycol. 300
`630-me/ml
`Ethyl aleohol 305% viv
`Polysorbate 80.8%
`
`Polyoxyethylated fatty
`acid 7.0%
`
`PEG40 castor o1hO.T1S
`mimi
`
`TABLE TV
`Surlactant Concentrations in Some Currently Marketed Paranterals (18, 19)
`
`
`Generic Name
`Trade Name
`Routes
`Administration
`
`Appx.
`Vehicle
`per Dose
`
`Teniposide
`
`Vumion (Bristol-Myers:
`Squibb}
`
`IF
`
`THlnte :1Qorit4d00
`
` §-Oml
`
`Solubilizer in
`Marketed Vehicle
`
`NN-dimethylacetamide 60
`mg/ml
`Cremopbor ELS00
`ma/ml
`Dehydrated alcohol
`427%
`
`
`Polysorbate 8020 mg/ml Direct injection IM=1-25 mlPhivtonadione Konakion (Roche) IM only
`Propylene giyeol 207
`ma/ml
`
`
`
`
`
`
`
`Phytonadione
`
`AquaMEPAYTON
`(Merck)
`
`IM_ TB
`
`Direct inject IM,
`preferred
`
`12:5 mi
`
`Miconazole
`
`Monistativ. (Janssen)
`
`IF
`
`Dilute 1:10
`
`20 mi
`
`Polysorbate 80-12%
`
`Vitamin A
`
`Polysorbate 80 0.008%
`Na desoxycholate 0.41%
`
`Polysorbate 20 0.40%
`
`Alteplase
`Amphotericin B
`Calcitriol
`
`Polysorbate 80.0.04%
`
`Celazolin Na
`
`Polysorbate 60 0.004%
`
`FPilerastim
`
`Sodium dodecyl sulfate
`0.18 me/mil
`
`Aldesieukin
`
`Aquasol A Parenteral
`(Astra)
`
`Activase (Genentech)
`Fungizone (Apothecon).
`Calejex (Abbott)
`
`IM
`
`IF
`IF
`IB
`
`Direct injection IM.
`
`1-2 ml
`
`Direct infusion
`Dilete 1:0
`Direct injection
`
`20-100. ml
`3-20-mil
`05-1 ml
`
`Kelzol (Lilly)
`Ancef (SmithKline
`Beecham)
`
`Neupogen (Amgen)
`
`Proleukin (Cetus
`Oncology)
`
`IM. TF, TB Direct injection
`
`IB
`
`IP
`
`Direct injection
`
`025-3 ml
`
`Dilute 1:42
`
`Limi
`
`3-7 aml
`Dilute 1:50
`IF
`Cordarone STV (Sanofi:
`Amiodarone HCl
`Polysorbate 80 10%
`Winthrop|
`IM = intramuscular, IF = intraverious infuanin, 1B = intravenous direct injection.
`“ Drug availableoutside the Limited States
`
`the formula (26). They also
`in-
`amount of cosolvent
`facilitate the. study of-systems characterized by non-
`linear Increases in solubility. Optimization techniques in
`pharmaceutical
`formulation have recently been ré-
`viewed (32). An example of their use is a simplex search
`for solvent blends producing maximum drug solubility
`
`tions are not. easily defined. A review of currently
`
`marketed parenteral products shows that percentages
`range from.10 to 100% (Table TLL and TV}. Appropriate
`prodiict amounts are offen.a matter-of considering a
`diverse set of factors such as: 1} administration concll-
`tions, 2) total dose, 3) target population and 4) duration
`af therapy. Toxicity and adverse clinical effects of
`chifittion. cosolvents. are summarized (33-34). Recent
`safety assessment reviews of propylene glycol (35) poly-
`ethylene glycol (36) and glycerol (37) have been pub-
`
`QQ).*ccna levels of cosolvent in parenteral formula-
`
`Vol. 80,No.5 ) September-October 1996
`
`$35
`
`AstraZeneca Exhibit 2052 p. 7
`
`

`

`TABLE .V
`Some Currently Marketed Parenterals Utilizing Complexing
`Agents, Mixed Micelles, or Lipid Systems
`
`Sohubilizer
`Generic
`
`Systent
`Name
`Trade Name
`
`Complexing Agents
`Hydrolyzed
`gelatin 0.7
`Ethvienediamine Aminophylline
`
`Corticotropin
`
`Athear.(Ahone-
`Poulené Rorer)
`Aminophylline
`(Abbett, Elkins
`Sinn, American
`Regent)
`Amphotericin B Aleleet (The Lipo-
`some Co.
`
`investigation. (41). Detaved reviews of micelle struc-
`tures, characterization techniques, and pharmaceutical
`applications have been published (42,43).
`The toxicity of surfactants reported in the literature
`priorto 1983 are summarized by Attwood. and Florence
`(43). Reviews on the pharmacology of polysorbate 80
`(44) and the incidence of clinical side effects of Cremo-
`
`phor EL® (42) have been: published, Children and
`newborns may be particularly sensitive to these. agents
`and admimistration to. this population is discussed (46).
`
`DL Use af Compleving Agents
`
`Valium MM
`Roche}
`Konakion/120
`(Roche)"
`
`DMPG and
`PMPC lipid
`Complexation of water msoluble drags usually in-
`complex
`volves the uicorporation of the drug within the inner
`
`Na cholesteryl Amphotericin B|Amphocil (Lipo-
`sulfate, col-
`some. Tech-
`core of the complexing agent.so that the outer hydro-
`loidal disper-
`nology)
`philic groups of the complexing agent interacts with
`sion
`water rendering the complex soluble.
`Mixed. Micelles
`An example of successful application of this technol-
`Glycocholicacid- Diazepam
`ogy is Amphocil®, a lipid complex. formed between
`lecithin
`Glycocholie'acid- Vitarnin K
`amphotericin B and sodium cholesteryl sulfate, a natu-
`lecithin
`rally occurring cholesterol metabolite (47), In solution;
`Emulsions of Lipdsomes
`the complex.
`is postulated to be a stable disc-like
`Lipid emulsion
`Diazepam
`structure that remains intact inthe systemic circulation.
`Comparative studies in animals with micelle solubilized
`amphotericin B (Fungizone®) have showtr a significant
`reduction in systemic touicity as.a result of altered
`systemic distribution and elimination characteristics (48).
`Naturally oceurring cyclodextrins, particularly B-cyclo-
`dextrin, are able to complex water insoluble drugs and
`render them soluble in water. However, 8-cyclodextrin
`have been associated with renal toxicity upon parenteral
`administration. The toxicity has been attributed the low
`aqueous solubility of 6-cyclodextrin and precipitation in
`the kidney. Newer cyclodextrins are chemically modified
`to improve water solubility and increase their usefulness
`(49). Brewster et al. (50) have described the préparation
`anc successful use of chemically modified. cyclodextrins
`such as 2-lvdroxypropyl-B-cyclodextrin.
`in. solubilizing
`anc everstabilizing various proteins and peptides.
`An example where the drug was not
`incorporated
`within some kind of matrix, but combined with an
`additive fo obtain basically a soluble salt complex
`ifivolved ascorbic acid (51). Similarly, tromethamine has
`been reported to solubilize zomepirac, an anionic drug,
`by. micelle (association colloid) formation (52). The
`aqueous solubility of metronidazole was reporied to be
`enhanced by the water soluble vitamins nicotinamide,
`ascorbic acid or pyridoxine HCI (323. A cage-ltke struc-
`ture formed by the vitarnins around molecules of metro-
`nidazole was postulated,
`
`Lipid emulsion
`Lipid emulsion
`
`Dizae (Ghmeda)
`Diazemuls
`(Dumex)!
`Diprivan (Zeneca)
`Propofol
`Perfluorodeealin Flucsol-DA(Alpha
`Therapeutics)
`AmBisome
`Amphotericin B
`Liposome
`
`(Vestary’
`TM. = intramuscular. TF = intravenous infusion; IB. intrevenaus
`direct-injection,
`* Dnig available outside the United States,
`
`toxicity of several cosolvent vehicles in
`lished. Local
`animals is summarized in Table VL
`
`C. Use of Surface Active Agents
`
`Surlace active agents are usually incorporated into
`parenterals to provide one of several desirable proper-
`ties; 1) increase drug solubility-through micellization, 2)
`to preven! drug -preciptialion upon dilution (38), 3)
`improve the stability of a drug in solution by incorpora-
`tion-of the drug into a micellar structure (39)..and 4) in
`protein formulations, prevent aggregation due to tiquid/
`air or liquid/solid interiucial mteractions.
`‘Table TV provides examples of FDA-approved paren-
`teral products containing surface active agents. While
`many diflerent types of surfactants exist (40), only an
`extreme few have precedence for use in parenteral
`sroducts, For example, for stabilization..of proteins
`against problems of aggregation, only polyoxyethylene
`sorbitan monodleate (polyscrbate 80)
`is an FDA-
`approved surfactant (18). Other surfactants which have
`been used in parenteral products are poloxamer 158
`(polyoxyethylene-polyoxypropylene copolymer), polysor-
`bate 20 and 40 (polyoxyethylene-polyoxypropylene (poly-
`oxyethylene sorbitan monofatty acid esters), Cremophor
`EL* and Emulphor EL.710® (polyethoxylated fatty acid
`esters and oils). Which surfactant is most effective as. a
`solubiliger or stabilizer is often a matter of enrpirical
`
`336
`
`£.. Emulsion Systems
`
`ifamoleculé has sufficient Hpid solubility, emulsions
`may be employed. Typical emulsions contain trigiyceride-
`rich vegetable oils and lecithin and. may also contain
`nonionic surface active agents as emulsifying agents.
`Insoluble drugs may be incorporated into commercial
`fat enmilsions or
`through emulsification of the cil-
`solubilized drug. The former. is usually not. successful
`
`PDA Journal of Pharmaceutical Science & Technology
`
`AstraZeneca Exhibit 2052 p. 8
`
`

`

`because drugs influence the stability of these commer-
`cial ermuilsions (53).
`
`Emulsion formulas have shown advantages over high
`cosolvent levels by reducing local venous. irritation (54).
`While emulsions hold potential as carriers for ipophilic
`drugs, great challenges exist in; 1) efficient incorpora-
`tion of the drug inte the dispersed phase,2) validation of
`consistency In preparation and sterilization, and 3)
`dependable. biological evaluation .of
`the safety and
`efficacy of drugs delivered from emulsions. These topics
`are addressed in some detail in several review articles
`(35-38).
`More recent examples include a parenteral water-in-
`oil envulsion of an LH-RH analog (59) and solubilization
`of an anti-HIV thiocarbamate drug by extemporaneous
`emulsification (60). The patent literature contains @
`large number of referencesclaiming safe and stable
`emulsion. systems for parenteral injection. The commer-
`clal application for drug delivery has yet to be pro-
`nounced in the United States. Marketed: products are
`mostiy found in the European and Japanese market
`(Table V).
`Microemulsion systems are thermodynamically stable
`transparent colloidal dispersions. The advantages they
`have over macroemulsions are their stabiliry and ease of
`manufacture. Droplet sizes are typically 1) times smaller
`than macroemulsions and are on the order of 16-100
`am. Te achieve such a small size, usually high amounts
`of surfactant-are required (43). Microernulsion systems
`have found utility in enhancing- penetration by the
`topical and recently oral route (61, 62). Requirements
`for-such high levels: of surfactants have amposed limite:
`tions on their use by the parenteral route,
`
`F.. Mixed Micelles
`
`Mixed mitelle systenis are ustially composed of two
`different amphiphili