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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
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`REVIEW ARTICLE
`
`Solubility Principles and Practices for Parenteral Drug Dosage
`Form Development
`
`STEPHANIE SWEETANA and MICHAEL J. AKERS*
`
`Pharmaceutical Sciences, Lilly Research Laboratories, Indianapolis, Indiana
`
`Introduction
`A common problem experienced in the early develop(cid:173)
`ment of drugs intended for parenteral, especially intrave(cid:173)
`nous, administration is the solubilization of a slightly
`soluble or water insoluble active ingredient. Drug solubi(cid:173)
`lization has been the subject of many scientific articles
`and textbooks (referenced throughout this article); yet
`despite this attention and available literature, product
`development scientists still encounter significant difficul(cid:173)
`ties in solving their solubility problems.
`Theories of solute solubilization are not easy to
`understand. Solubilization processes are amazingly com(cid:173)
`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(cid:173)
`tion and reducing it to simple approaches one can use to
`solve solubility problems. The classical theories of solu(cid:173)
`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.
`
`I. Pertinent Theory of Solubilization of Drugs
`
`Solubility theories deal with conversion of a substance
`from one state to another, and the equilibrium phenom(cid:173)
`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 as 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
`
`Received June 29, 1995. Accepted for publication March 21, 1996.
`* Author to whom correspondence should be addressed: Lilly Corpo(cid:173)
`rate Center, Indianapolis, IN 46285.
`
`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 solution theory assumes solute-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 theory evolved to account for the imbal(cid:173)
`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(cid:173)
`tion theory incorporated additional parameters such as
`dispersion, polar and hydrogen-bonding interactions
`into 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, each
`with different approximations and assumptions (1–4).
`In most pharmaceutical systems, the routine applica(cid:173)
`tion of these models to predict solubility and simplify
`formulation development is complex. Most drugs of
`interest are 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, as a result, influence
`solubility in an unpredictable manner (1). Examples of
`this phenomena are deviations from log-linear solubliza¬
`tion of nonpolar solutes in a polar cosolvent system (5).
`For the models to adequately describe solubility behav(cid:173)
`ior, proper weighting must be assigned to the relative
`importance of competing self-associations and strong
`intermolecular interactions. Currently this is being mod(cid:173)
`eled by various computer intensive group-contribution
`approaches, some of which allow for the mutual interac(cid:173)
`tions of various functional 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-
`
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`Hasselbalch equation is a mathematical expression of
`this relationship (3). In formulation development, con(cid:173)
`sideration of the amount of un-ionized drug in solution
`is helpful to avoid unexpected precipitation of this 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 pH of precipitation and of maximum solubility, if the
`pKa of the molecule and the solubility of the un-ionized
`and ionized forms are known (3, 6). Generally, two pH
`units above or below the pHmax value establishes the
`desired pH for formulation. For drug molecules with
`multiple ionizable groups these equations are more
`complicated to apply and so experimentally generated
`solubility data are usually collected.
`Through our own experience, we find that theory gives
`us some direction with respect to experimental ap(cid:173)
`proaches, but we still need to rely on the empirical
`experimentation to screen for systems which offer the
`most promise in solubilizing water-insoluble drugs.
`
`II. Formulation Design
`
`Usually, the first approach used to increase the
`solubility of an insoluble drug in water is to form more
`water soluble salts. Berge and co-workers (7) wrote what
`is now a near classic review of salt form strategies
`acceptable for pharmaceuticals. If salt formation is not
`possible, e.g. too unstable, or does not render the
`molecule sufficiently water soluble, a series of formula(cid:173)
`tion approaches may be investigated. Table I summa(cid:173)
`rizes these general strategies. Often a useful approach to
`increase the aqueous solubility of an ionizable drug is
`pH adjustment. The next approach most frequently tried
`is the use of water-miscible cosolvents. Other ap(cid:173)
`proaches to be discussed briefly include the use of
`surface active agents and complexing agents. Develop(cid:173)
`ment of emulsified and colloidal drug delivery systems
`for intravenous administration are becoming more widely
`and successfully applied. They may confer to the en(cid:173)
`trapped or associated drug significantly different proper-
`
`TABLE I
`Summary of Parenteral Formulation Approaches
`
`Approach
`
`Examples
`
`pH adjustment
`
`pH 2 to 12
`
`Cosolvent
`
`Polyethylene glycol
`Propylene glycol
`Ethanol
`Dimethylacetamide
`
`Surface Active Agents
`
`Polysorbates
`Poloxamers
`Cremophor EL
`Lecithin
`Bile salts
`
`Complexing Agents
`
`Cyclodextrans
`Water-soluble vitamins
`
`Dispersed Systems
`
`Emulsions
`Liposomes
`Nanoparticles
`
`Important Formula
`Considerations
`
`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 vs vehicle
`drug precipitation
`
`Hypersensitivity in animals
`Formula irritation
`isotonicity
`infusion rate & duration
`drug vs vehicle
`
`Purity of excipients and drugs
`Formula irritation
`isotonicity
`infusion rate & duration
`drug vs vehicle
`
`Sterility
`Particle size
`Pharmacokinetics
`Stability
`
`Useful Tests
`
`pH rate profile
`pH solubility profile
`Freezing point depression
`In vitro precipitation model
`In vivo phlebitis model
`In vitro cell lysis studies
`
`Mixture studies for maximum
`solubility
`In vitro precipitation model
`In vivo phlebitis model
`In vitro cell lysis studies
`
`In vivo phlebitis model
`In vitro cell lysis studies
`
`Phase solubility diagrams
`In vivo phlebitis model
`In vitro cell lysis studies
`
`Particle size
`
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`ties from the free form, providing the opportunity to
`prolong drug presence in the bloodstream or to alter
`disposition in the body. "Heroic" methods, reported in
`the literature for various cancer drugs, will also be
`reviewed although these methods use types and amounts
`of excipients that probably would not commonly be
`considered approvable for intravenous administration.
`The basis for reliable formulation development is
`accurate determination of solubility. Traditional method­
`ology is the "equilibrium method" (8) 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
`concentration over a period of time and equilibration is
`demonstrated by uniformity of the data over the time
`interval. For sparingly soluble drugs where equilibria are
`slow, accurate determinations of solubility may be diffi­
`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 affect reproducibility of drug
`solubility determinations.
`
`A. pH Adjustment
`
`Current FDA approved marketed parenteral prod­
`ucts range in pH from 2 to 11. A comprehensive listing of
`these products may be found in Table II. For biocompat-
`ability reasons, formulation of injectables within the pH
`ranges of 4 to 8 is most common. However, to achieve
`sufficient drug solubility, a pH outside this range may be
`necessary.
`The pH at which a product is formulated is usually
`determined from the pH solubility and pH rate profiles
`of the drug (9). 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
`concentration. 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 maintains a
`narrow pH range of 7.38 to 7.42. For example, a low
`incidence 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 is plotted as a
`function of dilution, and in vitro 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 et al. (14) showed that in vivo precipita­
`tion of the pH-solubilized drug ditekiren was dependent
`upon drug concentration and infusion rate. Low concen­
`tration drug solutions, which are rapidly diluted below
`
`saturation solubility, and rapid infusions were preferred
`to minimize precipitation.
`The most commonly used buffer components 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 must also be considered, since it may be
`influenced by the ions in solution (9). Examples of buffer
`catalyzed solution degradation include famotidine, a
`histamine H2 receptor inhibitor (15) and loracarbef, a
`zwitterionic cephalosporin (16).
`
`B. Use of Cosolvents
`In recent years, surveys of FDA-approved parenteral
`products (17–19) show five water-miscible cosolvents—
`glycerin, ethanol, propylene glycol, polyethylene glycol,
`and N,N,-dimethylacetamide—as components of sterile
`formulations (Table III and IV). Cosolvents are em­
`ployed in approximately 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.
`Investigation of the solubilizing potential of various
`cosolvents may be approached empirically by determin­
`ing the compounds solubility in cosolvent compositions
`similar to marketed products (21–23), or by one of
`several systematic approaches, such as log-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 in 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
`semi-logarithmic plot of the apparent solubility of the
`drug as a function of the volume-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 in a 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 cosolvent
`systems (24). Mathematically, these relationships are
`described by the following equations:
`
`Binary cosolvent system
`
`log Cx = log Cw. + αxfx
`Ternary cosolvent system
`
`log Cx = log Cw. + αxfx + αafa
`Quaternary cosolvent system
`
`log Cx = log Cw + αxfx + αafa + αbfb
`
`where Cw is the drug solubility in water; α's are the
`slopes of the semi logarithmic plots; Cx is the drug
`solubility; f is the volume fraction of the cosolvent; and
`the subscripts a, b, x denote the cosolvents A, B, and X
`
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`TABLE II
`Examples of Marketed Parenteral Products with Solution pH Outside Range of 4 to 8 (18, 19)
`
`pH
`Adjustment
`
`Generic
`Name
`
`Trade Name
`
`Marketed
`Form
`
`Routes
`
`Lactic acid, NaOH
`Benzenesulfonic acid
`
`Amrinone Lactate
`Atracurium Besylate
`
`Inocor (Sanofi Winthrop)
`Tracrium (Burroughs
`Wellcome)
`Librium (Roche)
`Emete-Con (Roerig)
`Cipro I.V. (Miles)
`DTIC-Dome (Miles)
`Intropin (DuPont)
`Cardizem (Marion Merrell
`Dow)
`Vibramycin IV (Roerig,
`Elkins-Sinn)
`Inapsine (Janssen)
`Ergotrate Maleate (Lilly)
`
`Solution
`Solution
`
`Powder
`Powder
`Concentrate
`Powder
`Solution
`Solution
`
`IB, IF
`IB, IF
`
`IB
`IM, IF
`IF
`IB, IF
`IF
`IF, IB
`
`Powder
`
`IF
`
`Solution
`Solution
`
`IM, IF, IB
`IM, IB
`
`Innovar (Janssen)
`
`Solution
`
`IM, IB, IF
`
`Robinul (Robins)
`Haldol (McNeil)
`Normodyne (Schering)
`Trandate (Glaxo)
`Aldomet Ester HCl(Merck)
`Methergine (Sandoz)
`
`Versed (Roche)
`Primacor (Sanofi Winthrop)
`Minocin (Lederle)
`Nubain (DuPont)
`Narcan (DuPont)
`Zofran (Cerenex)
`Pitocin (Parke-Davis)
`Papaverine HCl (Lilly)
`Pyridoxine HCl (Steris)
`Priscoline HCl (Ciba)
`
`Solution
`Solution
`Solution
`
`Solution
`Solution
`
`Solution
`Solution
`Powder
`Solution
`Solution
`Solution
`Solution
`Solution
`Solution
`Solution
`
`IM, IB
`IM
`IB, IF
`
`IF
`IM, F
`
`IM, IF
`IF
`IF
`IM, IB
`IM, IB, IF
`IF
`IF
`IB, IF
`IM, IB
`IB, IM
`
`Diamox (Lederle)
`Zovirax (Burroughs
`Wellcome)
`Aminophylline (Abbott,
`Elkins-Sinn, American
`Regent)
`Amytal Na (Lilly)
`Imuran (Burroughs
`Wellcome)
`Polycillin-N (Apothecon)
`Totacillin-N (Beecham)
`Omnipen-N (Wyeth)
`Celestone Phosphate
`(Schering)
`Sodium Diuril (Merck)
`Hyperstat (Schering)
`Stilphostrol (Miles)
`
`Powder
`Powder
`
`IM, IB, IF
`IF
`
`Solution
`
`IB, IF
`
`Powder
`Powder
`
`Powder
`
`IM, IF
`IB, IF
`
`IM, IB, IF
`
`Solution
`
`IB, IM
`
`Powder
`Solution
`Solution
`
`Solution
`Solution
`Solution
`
`Powder
`Powder
`
`Powder
`
`IB, IF
`IB
`IF
`
`IB, IF
`IB
`IM, IB, IF
`
`IF
`IM, IB, IF
`
`IB, IF
`
`333
`
`pH
`(constituted)
`
`p H <4
`3.2–4
`3.25–3.65
`
`3
`3–4
`3.3–3.9
`3–4
`2.5–4.5
`3.7–4.1
`
`1.8–3.3
`
`3–3.8
`2.7–3.5
`
`3.2–3.8
`
`2–3
`3–3.6
`3–4
`
`3–4.2
`2.7–.5
`
`3
`3.2–4
`2–2.8
`3.5
`3–4
`3.3–4
`2.5–4.5
`3–4
`2–3.8
`3–4
`
`pH>8
`9.2
`10.5–11.6
`
`8.6–9
`
`9.6–10.4
`9.6
`
`8-10
`
`8.5
`
`9.2–10
`11.6
`9–10.5
`
`9.2
`8–11
`8–9.3
`
`11
`8.1
`
`Lactic acid, HC1
`Citric acid
`NaOH, HC1
`Citric acid, Na citrate
`
`Lactic acid
`Lactic acid, ethyl
`lactate
`Lactic acid
`
`NaOH/HC1
`Lactic acid
`
`NaOH, citric acid
`Tartaric acid
`
`NaOH, HCl
`
`Na citrate, citric acid
`HCl
`Citric acid, Na citrate
`Acetic acid
`NaOH
`
`Tartaric acid, Na
`citrate
`
`HCl/NaOH
`
`NaOH
`
`Na2HPO4, NaOH
`
`NaOH
`NaOH
`
`NaOH
`NaOH
`NaOH
`
`Chlordiazepoxide HCl
`Benzquinamide HCl
`Ciprofloxacin
`Dacarbazine
`Dopamine HCl
`Diltiazem HCl
`
`Doxycycline Hyclate
`
`Droperidol
`Ergonovine Maleate
`
`Fentanyl Citrate and
`Droperidol
`Glycopyrrolate
`Haloperidol Lactate
`Labetalol HCl
`
`Methyldopate HCl
`Methylergonovine
`Maleate
`Midazolam HCl
`Milrinone Lactate
`Minocycline HCl
`Nalbuphine HCl
`Naloxone HCl
`Ondansetron HCl
`Oxytocin
`Papaverine HCl
`Pyridoxine HCl
`Tolazoline HCl
`
`Acetazolamide Na
`Acyclovir Na
`
`Aminophylline
`
`Amobarbital Na
`Azathioprine Na
`
`Ampicillin Na
`
`Betamethasone Na
`PO4
`Chlorothiazide Na
`Diazoxide
`Diethylstilbestrol
`Diphosphate
`Fluorouracil
`Folic acid
`Lasix
`
`Ganciclovir Na
`Leucovorin Ca
`
`Vol.50, No. 5 / September–October 1996
`
`Fluorouracil (Roche)
`Folvite (Lederle)
`Furosemide
`(Hoechst-Roussel)
`Cytovene (Syntex)
`Wellcovorin (Immunex,
`Burroughs Wellcome)
`Methohexital Na
`Na carbonate
`9.5–10.5
`Brevital Na (Lilly)
`IM = intramuscular, IF = intravenous infusion, IB = intravenous direct injection.
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`TABLE III
`Cosolvent Concentrations in Some Currently Marketed Parenterals (18, 19)
`
`Cosolvent in
`Marketed Vehicle
`
`Generic
`Name
`
`Ethanol 100%
`
`Carmustine
`
`Trade Name
`
`Marketed
`Form
`
`BiCNU (Bristol-Myers
`Oncology)
`
`Drug
`+ Diluent
`
`Routes
`
`Administration
`
`Appx.
`Vehicle
`per Dose
`
`IF
`
`Dilute 1:10
`
`3 ml
`
`Propylene glycol 40%
`Ethyl alcohol 10%
`
`Propylene Glycol 40%
`Alcohol 10%
`
`Benzyl alcohol 5%
`Propylene glycol 50%
`
`Propylene glycol 25%
`Ethanol 25%
`
`Propylene glycol
`10.36%
`
`Ethanol 10%
`
`Diazepam
`
`Valium (Roche)
`
`Solution
`
`IM, IB
`
`Direct injection
`
`0.5–4 ml
`
`Digoxin
`
`Dimenhydrinate
`
`Lanoxin (Burroughs
`Wellcome)
`
`Dimenhydrinate
`(Steris)
`
`Solution
`
`IB
`
`Direct injection
`
`1–3 ml
`
`Solution
`
`IM, IF
`
`Dilute 1:10
`
`1 ml
`
`Esmolol HCl
`
`Brevibloc (DuPont)
`
`Concentrate
`
`IF
`
`Dilute 1:25
`
`1–10 ml
`
`Hydralazine HCl
`
`Apresoline HCl (Ciba)
`
`Solution
`
`IM, IB
`
`Direct injection
`
`0.5–1 ml
`
`Ketorolac
`Tromethamine
`
`Lorazepam
`
`Toradol (Syntex)
`
`Solution
`
`IM only
`
`Direct Injection IM
`
`1 ml
`
`Solution
`
`IM, IB
`
`PEG 400 0.18 ml/ml
`Benzyl alcohol 2%
`Propylene glycol
`
`Povidone 20 mg
`Diluent (10 ml)
`Propylene glycol 6 ml
`Ethanol 0.52 mL
`
`Ethanol 30%
`Propylene glycol 30%
`
`Propylene glycol 40%
`Alcohol 10%
`
`Alcohol 10%
`Propylene glycol 67.8%
`
`Propylene glycol 40%
`Alcohol 10%
`
`Ativan (Wyeth-
`Ayerst)
`
`IM Direct Injection
`Dilute 1:1 IV
`
`1 ml
`
`Melphalan HC1
`
`Alkeran (Burroughs
`Wellcome)
`
`Drug
`+ Diluent
`
`IF
`
`Dilute constitute
`> 1:10
`
`10 ml
`
`Nitroglycerin
`
`Tridil (DuPont)
`
`Concentrate
`
`IF
`
`Dilute 1:100
`
`2.5–10 ml
`
`Pentobarbital Na
`
`Nembutal (Abbott)
`
`Solution
`
`IM, IB
`
`Slow direct injection
`
`2 ml
`
`Phenobarbital Na
`
`Luminal Na (Sanofi
`Winthrop)
`
`Solution
`
`IM. IB
`
`Direct injection
`
`1 ml
`
`Phenytoin Na
`
`Dilantin (Parke Davis)
`
`Solution
`
`IM, IB
`
`Direct injection
`
`3–5 ml
`
`Polyethylene glycol 50%
`
`Secobarbital Na
`
`Propylene glycol 40%
`Ethanol 10%
`
`Trimethoprim-Sul(cid:173)
`famethoxazole
`
`Secobarbital Na
`(Wyeth-Ayerst)
`
`Septra (Burroughs
`Wellcome)
`Bactrim (Roche)
`
`Solution
`
`IM, IB, IF
`
`Direct injection
`
`1–5 ml
`
`Concentrate
`
`IF
`
`Dilute 1:25
`
`5–10 ml
`
`Amsacrine
`
`N,N-Dimethylacet-
`Drug
`Amsidine Concen(cid:173)
`amide 100%
`+ Diluent
`trate (Parke-Davis)"
`IM = intramuscular. IF = intravenous infusion, IB = intravenous direct injection.
`a Drug available outside the United States.
`
`IF
`
`Dilute 1:500
`
`1.5 ml
`
`respectively. In its simplest form, determining the drug
`solubility in water and pure cosolvents would allow
`estimation of the amount and type of cosolvent required
`to attain 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).
`For first approximations of solubility however, this
`approach has been shown to be useful (26–27). Chien
`(28) used this technique and polarity indexes of cosol(cid:173)
`vents to calculate the polarity of a solution that pro(cid:173)
`duced the greatest solubility of the drug metronidazole.
`
`Aqueous/cosolvent 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(cid:173)
`vents have been tabulated and discussed by Rubino and
`Yalkowsky. These indexes reflect the cohesive proper(cid:173)
`ties of the solvent (solubility parameter and interfacial
`tension), hydrogen bonding ability (proton donor and
`acceptor density), and polarity (dielectric constant).
`Another solubility determination approach particu(cid:173)
`larly helpful for complex mixtures is a statistical experi(cid:173)
`mental design (31). Identifying the optimum combina(cid:173)
`tion of cosolvents for solubilization may reduce the net
`
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`
`TABLE IV
`Surfactant Concentrations in Some Currently Marketed Parenterals (18, 19)
`
`Solubilizer in
`Marketed Vehicle
`
`NN-dimethylacetamide 60
`mg/ml
`Cremophor EL 500
`mg/ml
`Dehydrated alcohol
`42.7%
`
`Polysorbate 80 20 mg/ml
`Propylene glycol 20.7
`mg/ml
`
`Cremophor EL 527
`mg/ml
`Ethanol 49.7%
`Propylene glycol 30%
`Polysorbate 80 1.6%
`Polysorbate 20 0.028%
`
`Polysorbate 80 4%
`Propylene glycol 20%
`
`Cremophor EL 650
`mg/ml
`Alcohol 32.9%
`
`Polyethylene glycol 300
`650 mg/ml
`Ethyl alcohol 30.5% v/v
`Polysorbate 80 8%
`Polyoxyethylated fatty
`acid 7.0%
`
`Generic Name
`
`Trade Name
`
`Routes
`
`Administration
`
`Appx.
`Vehicle
`per Dose
`
`Teniposide
`
`Vumon (Bristol-Myers
`Squibb)
`
`IF
`
`Dilute 1:10 or 1:100
`
`5–9 ml
`
`Phytonadione
`
`Konakion (Roche)
`
`IM only
`
`Direct injection IM
`
`1–2.5 ml
`
`Paclitaxel
`
`Taxol (Bristol-Myers
`Squibb)
`
`Multivitamins
`
`M.V.I.-12 (Astra)
`
`IF
`
`IF
`
`Dilute 1:5 or 1:20
`
`20 ml
`
`Dilute 1:100 or 1:500
`
`5 ml
`
`Chlordiazepoxide HCl
`
`Librium (Roche)
`
`IM only
`
`Direct injection IM
`
`2 ml
`
`Cyclosporine
`
`Sandimmune (Sandoz)
`
`IF
`
`Dilute 1:20–1:100
`
`5 ml
`
`Etoposide
`
`VePesid (Bristol-Myers
`Oncology)
`
`IF
`
`Dilute 1:100
`
`5 ml
`
`Phytonadione
`
`AquaMEPHYTON
`(Merck)
`
`IM, IB
`
`Direct inject IM,
`preferred
`
`1–2.5 ml
`
`PEG40 castor oil 0.115
`ml/ml
`
`Miconazole
`
`Monistat i.v. (Janssen)
`
`IF
`
`Dilute 1:10
`
`20 ml
`
`Direct injection IM
`
`1–2 ml
`
`Direct infusion
`
`20–100 ml
`
`Polysorbate 80 12%
`
`Vitamin A
`
`Polysorbate 80 0.008%
`
`Alteplase
`
`Aquasol A Parenteral
`(Astra)
`
`Activase (Genentech)
`
`Na desoxycholate 0.41%
`
`Amphotericin B
`
`Fungizone (Apothecon)
`
`IM
`
`IF
`
`IF
`
`Polysorbate 20 0.40%
`
`Calcitriol
`
`Polysorbate 80 0.04%
`
`Cefazolin Na
`
`Polysorbate 80 0.004%
`
`Filgrastim
`
`Sodium dodecyl sulfate
`0.18 mg/ml
`
`Aldesleukin
`
`Calcijex (Abbott)
`
`Kefzol (Lilly)
`Ancef (SmithKline
`Beecham)
`
`Neupogen (Amgen)
`
`Proleukin (Cetus
`Oncology)
`
`Polysorbate 80 10%
`
`Cordarone X IV (Sanofi
`Winthrop)a
`IM = intramuscular, IF = intravenous infusion, IB = intravenous direct injection.
`a Drug available outside the United States.
`
`Amiodarone HCl
`
`Dilute 1:50
`
`IB
`IM, IF, IB
`
`Direct injection
`
`Direct injection
`
`3–20 ml
`
`0.5–1 ml
`
`IB
`
`IF
`
`IF
`
`Direct injection
`
`0.25–3 ml
`
`Dilute 1:42
`
`Dilute 1:50
`
`1.2 ml
`
`3–7 ml
`
`amount of cosolvent in the formula (26). They also
`facilitate the study of systems characterized by non(cid:173)
`linear increases in solubility. Optimization techniques in
`pharmaceutical formulation have recently been re(cid:173)
`viewed (32). An example of their use is a simplex search
`for solvent blends producing maximum drug solubility
`(2).
`Acceptable levels of cosolvent in parenteral formula(cid:173)
`tions are not easily defined. A review of currently
`
`marketed parenteral products shows that percentages
`range from 10 to 100% (Table III and IV). Appropriate
`product amounts are often a matter of considering a
`diverse set of factors such as; 1) administration condi(cid:173)
`tions, 2) total dose, 3) target population and 4) duration
`of therapy. Toxicity and adverse clinical effects of
`common cosolvents are summarized (33–34). Recent
`safety assessment reviews of propylene glycol (35) poly(cid:173)
`ethylene glycol (36) and glycerol (37) have been pub-
`
`Vol. 50, No. 5 / September–October 1996
`
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`
`
`TABLE V
`Some Currently Marketed Parenterals Utilizing Complexing
`Agents, Mixed Micelles, or Lipid Systems
`
`Solubilizer
`System
`
`Generic
`Name
`
`Trade Name
`
`investigation (41). Detailed reviews of micelle struc(cid:173)
`tures, characterization techniques, and pharmaceutical
`applications have been published (42, 43).
`The toxicity of surfactants reported in the literature
`prior to 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(cid:173)
`phor EL® (42) have been published. Children and
`newborns may be particularly sensitive to these agents
`and administration to this population is discussed (46).
`
`D. Use of Complexing Agents
`
`Complexation of water insoluble drugs usually in(cid:173)
`volves the incorporation of the drug within the inner
`core of the complexing agent so that the outer hydro-
`philic groups of the complexing agent interacts with
`water rendering the complex soluble.
`An example of successful application of this technol(cid:173)
`ogy is Amphocil®, a lipid complex formed between
`amphotericin B and sodium cholesteryl sulfate, a natu(cid:173)
`rally occurring cholesterol metabolite (47). In solution,
`the complex is postulated to be a stable disc-like
`structure that remains intact in the systemic circulation.
`Comparative studies in animals with micelle solubilized
`amphotericin B (Fungizone®) have shown a significant
`reduction in systemic toxicity as a result of altered
`systemic distribution and elimination characteristics (48).
`Naturally occurring cyclodextrins, particularly ß-cyclo¬
`dextrin, are able to complex water insoluble drugs and
`render them soluble in water. However, ß-cyclodextrin
`have been associated with renal toxicity upon parenteral
`administration. The toxicity has been attributed the low
`aqueous solubility of ß-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 preparation
`and successful use of chemically modified cyclodextrins
`such as 2-hydroxypropyl-ß-cyclodextrin in solubilizing
`and even stabilizing various proteins and peptides.
`An example where the drug was not incorporated
`within some kind of matrix, but combined with an
`additive to obtain basically a soluble salt complex
`involved 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 reported to be
`enhanced by the water soluble vitamins nicotinamide,
`ascorbic acid or pyridoxine HCl (32). A cage-like struc(cid:173)
`ture formed by the vitamins around molecules of metro(cid:173)
`nidazole was postulated.
`
`E. Emulsion Systems
`
`If a molecule has sufficient lipid solubility, emulsions
`may be employed. Typical emulsions contain triglyceride-
`rich vegetable oils and lecithin and may also contain
`nonionic surface active agents as emulsifying agents.
`Insoluble drugs may be incorporated into commercial
`fat emulsions or through emulsification of the oil-
`solubilized drug. The former is usually not successful
`
`Complexing Agents
`Hydrolyze
`gelatin 0.7%
`Ethylenediamine
`
`Corticotropin
`
`Aminophylline
`
`Amphotericin B
`
`Amphotericin B
`
`Diazepam
`
`Vitamin K
`
`DMPG and
`DMPC lipid
`complex
`Na cholesteryl
`sulfate, col(cid:173)
`loidal disper(cid:173)
`sion
`Mixed Micelles
`Glycocholic acid-
`lecithin
`Glycocholic acid-
`lecithin
`Emulsions or Liposomes
`Lipid emulsion
`Diazepam
`
`Athcar (Rhone-
`Poulenc Rorer)
`Aminophylline
`(Abbott, Elkins-
`Sinn, American
`Regent)
`Alelcet (The Lipo(cid:173)
`some Co.)a
`
`Amphocil (Lipo(cid:173)
`some Tech(cid:173)
`nology)
`
`Valium MM
`(Roche)a
`Konakion/120
`(Roche)a
`
`Lipid emulsion
`Lipid emulsion
`
`Propofol
`Perfluorodecalin
`
`Liposome
`
`Amphotericin B
`
`Dizac (Ohmeda)
`Diazemuls
`(Dumex)a
`Diprivan (Zeneca)
`Fluosol-DA (Alpha
`Therapeutics)
`AmBisome
`(Vestar)a
`IM = intramuscular, IF = intravenous infusion. IB = intravenous
`direct injection.
`a Drug available outside the United States.
`
`lished. Local toxicity of several cosolvent vehicles in
`animals is summarized in Table VI.
`
`C. Use of Surface Active Agents
`
`Surface active agents are usually incorporated into
`parenterals to provide one of several desirable proper(cid:173)
`ties; 1) increase drug solubility through micellization, 2)
`to prevent drug precipitation upon dilution (38), 3)
`improve the stability of a drug in solution by incorpora(cid:173)
`tion of the drug into a micellar structure (39), and 4) in
`protein formulations, prevent aggregation due to liquid/
`air or liquid/solid interfacial interactions.
`Table IV provides examples of FDA-approved paren(cid:173)
`teral products containing surface active agents. While
`many different types of surfactants exist (40), only an
`extreme few have precedence for use in parenteral
`products. For example, for stabilization of proteins
`against problems of aggregation, only polyoxyethylene
`sorbitan monooleate (polysorbate 80) is an FDA-
`approved surfactant (18). Other surfactants which have
`been used in parenteral products are poloxamer 188
`(polyoxyethylene-polyoxypropylene copolymer), polysor(cid:173)
`bate 20 and 40 (polyoxyethylene-polyoxypropylene (poly(cid:173)
`oxyethylene sorbitan monofatty acid esters), Cremophor
`EL® and Emulphor EL 719® (polyethoxylated fatty acid
`esters and oils). Which surfactant is most effective as a
`solubilizer or stabilizer is often a matter of empirical
`
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`because drugs influence the stability of these commer(cid:173)
`cial emulsions (53).
`Emulsion formulas have shown advantages over high
`cosolvent levels by reducing local venous irritation (54).
`While emulsion