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PHARMACOLOGICAL REVIEWS
Copyright 2013 by The American Society for Pharmacology and Experimental Therapeutics
http://dx.doi.org/10.1124/pr.112.005660
Pharmacol Rev 65:315499, January 2013
Address correspondence to: Christopher J. H. Porter, Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical
Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia. E-mail: chris.porter@monash.edu
dx.doi.org/10.1124/pr.111.005660.
315
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319
I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319
A. What Is Low Drug Solubility? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320
B. Determinants of Aqueous Solubility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323
1. Ideal Versus Nonideal Solubility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323
C. Hydrophobic or Lipophilic Drug Candidates? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324
D. Solubility of Electrolytes, Weak Electrolytes, and Nonelectrolytes . . . . . . . . . . . . . . . . . . . . . . . 324
E. Solubility and Dissolution Rate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
F. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326
II. In Vitro Complexities of Working with Poorly Water-Soluble Drugs . . . . . . . . . . . . . . . . . . . . . . . . . 326
A. Drug Precipitation, Adsorption, Binding, and Complexation in In Vitro Assays . . . . . . . . . . 326
B. Changes to Thermodynamic Activity Resulting from Complexation, Binding,
or Solubilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327
III. In Vivo Assessment of Poorly Water-Soluble Compounds. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328
A. Parenteral Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
1. Complexities with Parenteral Administration of Poorly Water-Soluble Drugs . . . . . . . . . 329
2. Parenteral Formulation Approaches for Poorly Water-Soluble Drugs . . . . . . . . . . . . . . . . . 329
B. Oral Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331
1. Formulations to Support Drug Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331
2. Use of Enabling Formulations to Promote Oral Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . 333
3. Preclinical Toxicology Formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333
4. Development of Clinical Formulations for Poorly Water-Soluble Drugs . . . . . . . . . . . . . . . 334
IV. Buffers and Salt Formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334
A. Solution Behavior of Weak Electrolytes and Their Salts. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
1. Ionic Equilibria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
2. pH Solubility Relationships for Weak Electrolytes and Salts of Weak Electrolytes . . . . 335
3. Factors Affecting Salt Formation at pHmax . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337
4. Determinants of Salt Solubility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338
a. pHmax . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338
b. Choice of Counterion to Maximize Salt Solubility. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338
c. The Effect of Common Ions on Salt Solubility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341
d. Effect of Organic Solvents on Salt Solubility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342
B. pH adjustment Strategies for Addressing Low Drug Solubility . . . . . . . . . . . . . . . . . . . . . . . . . . 342
1. Buffered Systems Used in Parenteral Formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342
2. Impact of Cosolubilizers and Electrolytes on pH-Mediated Solubilization . . . . . . . . . . . . . 343
a. pH Adjustment and Cosolvents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343
b. pH Adjustment and Strong Electrolytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344
c. pH Adjustment and Surfactants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344
316
Williams et al.
317
318
Williams et al.
319
AbstractDrugs with low water solubility are predisposed to low and variable oral bioavailability and,
therefore, to variability in clinical response. Despite
significant efforts to design in acceptable developability properties (including aqueous solubility) during lead
optimization, approximately 40% of currently marketed
compounds and most current drug development candidates remain poorly water-soluble. The fact that so many
drug candidates of this type are advanced into development and clinical assessment is testament to an increasingly sophisticated understanding of the approaches
that can be taken to promote apparent solubility in the
gastrointestinal tract and to support drug exposure after
oral administration. Here we provide a detailed commentary on the major challenges to the progression of
a poorly water-soluble lead or development candidate
I. Introduction
High hydrophobicity and intrinsically low water solubility are increasingly common characteristics of hits,
leads, development candidates, and ultimately marketed
drugs. Many hypotheses have been put forward as to
why these trends have emerged, and the true explanation is clearly multifaceted. The application of combinatorial chemistries to generate large chemical libraries
and the common application of high-throughput screening modalities, often in nonaqueous media (or mixedsolvent media), have probably played a role. The desire
for increased potency, coupled with the realization that
receptor binding is mediated, at least in part, by
hydrophobic interactions, further magnifies the likelihood
that drug candidates will have limited aqueous solubility.
Finally, the quest to explore unprecedented drug targets,
some of which are associated with intracellular signaling
pathways, lipid processing architecture, or highly lipophilic endogenous ligands, only amplifies the requirement
320
Williams et al.
Fig. 1. A comparison of the distribution of solubilities for the top 200 oral
drug products in the United States (US), Great Britain (GB), Spain, and
Japan and from the World Health Organization (WHO) Essential Drug
List. Very soluble drugs: over 1000 mg/ml; freely soluble drugs: 1001000
mg/ml; soluble drugs: 33100 mg/ml; sparingly soluble drugs: 1033 mg/ml;
slightly soluble drugs: 110 mg/ml; very slightly soluble drugs: 0.11 mg/ml;
practically insoluble drugs: ,0.1 mg/ml. Adapted from Takagi et al. (2006).
DKA
Cm 2 C0
h
321
Fig. 2. Schematic diagram illustrating the common strategies currently used (and discussed in this review) to address low drug solubility in drug
discovery and development.
DKA
Cm
F5
h
DK
h
where Cs is the solubility (mg/ml) at pH 6.5 (representing the pH of the small intestine); kabs is the rate
constant (h21) for intestinal absorption (which is
related to the permeability); SIWV is the small
intestinal water volume (in milliliters), which is
typically assumed to be ;250 ml (the volume of fluid
assumed to be present in the fasted GI tract after
a glass of water has been drunk when taking
medication orally); and SITT is the small intestinal
transit time (min) of ;270 min (4.5 h). Rearranging
this relationship provides an expression for the
necessary or target solubility for a given dose and kabs
(or permeability) and provides an initial indication as
to whether solubility is likely to limit oral absorption.
This concept is shown graphically in Fig. 3, the data
from which are taken from a seminal review that
shows the theoretical required solubility to provide
good oral absorption for drugs with projected doses
ranging from 0.1 to 10 mg/kg and permeabilities
ranging from low to high. At one end of the spectrum,
highly potent drugs for which the dose is low and the
membrane permeability is high have relatively low
solubility requirements to achieve good oral absorption. At the other extreme, low-potency drugs for which
the dose is high and the permeability is low need
322
Williams et al.
Fig. 3. The relationship between the projected dose and the required
aqueous solubility for low, medium, and high permeability compounds.
Permeability is indicated by the magnitude of the absorption rate
constant (kabs), where low permeability, kabs 5 0.1; medium 5 1.0, high 5
10 h21. From this analysis, moderately permeable compounds (kabs 5
1.0 h21), with projected potencies of 1.0 mg/kg, require aqueous
solubilities of ;52 mg/ml. Adapted from Lipinski (2000).
TABLE 1
Examples of dose, solubility, and volume requirements for a range of poorly water-soluble drugs
Drug
Dose
mg
Piroxicam
Digoxin
Griseofulvin
Chlorthiazide
From Amidon et al. (1995).
20
0.5
500
500
Solubility
mg/ml
0.007
0.024
0.015
0.78
Absorption
ml
2857
21
33,333
636
Low, variable
Good
Low, variable
Reasonable
323
Fig. 5. Three essential steps are required for a solute drug molecule to be
displaced from a solid particle and to enter solution. Step 1: A single
solute molecule is removed from the crystal lattice; energy is required in
this step to overcome solute-solute interactions in the solid state. Step 2:
A void is created within the solvent to accommodate the solute molecule.
Although this step also requires energy, it is likely to be considerably
lower than the energy required in step 1. Step 3: The solute molecule
inserts into the solvent, forming solute-solvent interactions. Simplistically, if the energy released from the solute-solvent interactions (i.e., step
3) is greater than the energy required for steps 1 and 2, solubility is
favored.
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Williams et al.
Vs w21
d1 2 d2 2
2:303RT
325
If we assume sink conditions where the concentration of drug in bulk solution (C) is low relative to the
concentration on the surface of the dissolving solid (Cs),
then this relationship collapses to
dcx D A
Cs
5
h
dt
10
326
Williams et al.
327
328
Williams et al.
a 5 gC
11
become available for compounds with ionizable functional groups. The timing at which these changes occur
during development will impact early preclinical data,
and this needs to be appreciated and factored into
study design and data interpretation.
A. Parenteral Administration
1. Complexities with Parenteral Administration of
Poorly Water-Soluble Drugs. In comparison with the
large number of drugs intended for oral administration,
parenteral formulations constitute a more limited proportion of marketed products. However, the generation
of useful parenteral formulations remains a key component of drug discovery and drug development for almost
all drug molecules (regardless of the intended route of
clinical administration) since data obtained after i.v.
administration is necessary to generate fundamental
pharmacokinetic parameters (volume of distribution,
clearance, half-life, absolute bioavailability) to support
compound optimization and progression, and such data
are also useful to support early stage pharmacodynamic
assessment of drugs intended for acute administration.
Low aqueous solubility significantly complicates the
development of i.v. formulations since, in almost all
cases, simple solution formulations are required. The
following section describes several different approaches
that can be used as i.v. solution formulations, depending
on the physicochemical properties of the drug and the
intended use (e.g., animal or humans). Depending on
the formulation strategy adopted, increases in solubility
of several orders of magnitude are possible. The risks
associated with i.v. administration of poorly watersoluble drugs include, first, the potential for drug
precipitation on administration and, second, the potential for formulation components to cause pain, phlebitis,
inflammation, hemolysis, or unacceptable toxicology.
Precipitation is more likely for formulations where pH
adjustment or cosolvents form the basis for drug solubilization since both are likely to be altered significantly
on dilution (see Sections IV and VI). In contrast, surfactant solubilization, complexation, and i.v. emulsions
are far less sensitive to dilution (see Sections VII, VIII,
and XI). Where dilution-mediated precipitation is
possible, slow administration into large veins, where
the blood flow is higher (and therefore the supply of
plasma proteins and lipoproteins to provide in vivo
binding is higher) is preferred, and this can also reduce
the possibility of pain on injection, hemolysis, and
phlebitis since the irritant component is maximally
diluted. For studies in rats and dogs, this can be
accomplished by implanting a dosing cannula into the
jugular vein (or another large vein) with administration
over a period of 5 to 10 min for rats and up to 30 min or
longer in dogs. In contrast, administration into small
veins in the extremities (where blood flow is much
slower), such as the tail vein in rodent models, and rapid
bolus injection, should be avoided with poorly water-
329
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Williams et al.
TABLE 2
Potential hierarchy of formulation approaches for the development of parenteral formulations for poorly water-soluble drugs
Previously published suggestions for maximum allowable quantities provided in parentheses.a,b,c Further details are provided in individual sections. Note that common
examples are provided, and this is not intended to represent an exhaustive list.
Class
Cosolvents 1 pH adjustment
Surfactants
Complexation agents
Surfactants or complexation agents
1 pH adjustment
Lipid emulsions
Nanomilled drug crystals
Advanced colloids
a
b
c
Examples
Normal saline
5% dextrose
pH 69 for weak acids; common buffers include phosphate, bicarbonate
pH 26 for weak bases; common buffers include citrate, acetate, lactate
Examples:
Propylene glycol (3060%)a (50% 0.5 ml/kg)b
PEG 400 (40100%)a (50% 1 ml/kg)b
Dimethylacetamide (1030%)a
N-Methylpyrrolidone (1020%)a
DMSO (1020%)a (100% 0.1 ml/kg)b
Ethanol (10%)a (20% 0.5 ml/kg)b
Common cosolvent combinations:
Propylene glycol:ethanol:water 40:10:50
PEG 400:ethanol:water 40:10:50
Propylene glycol:ethanol:dimethylacetamide:water 20:10:10:60
As above plus buffered aqueous component
Examples:
Cremophor EL (510%a (10% 0.5 ml/kg, single dose only, potential for anaphylaxis in dogs)b
Tween 80 (510%)a (2% 0.25 ml/kg, potential for anaphylaxis in dogs)b
Pluronic F68 (2050%)a (15% 0.5 ml/kg)b
Hydroxypropyl-b-cyclodextrin (2040%)a
Sulfobutylether-b-cyclodextrin (Captisol) (2040%)a (20% 5 ml/kg)b
As above plus buffered aqueous component
Phospholipid stabilized soybean oil emulsion (1020% lipid) (Intralipid)
Nanocrystals
Liposomes, polymeric or lipid nanoparticles
Concentration range based on rat or mouse and single administration at 10 ml/kg (Li and Zhao, 2007).
Concentration range and maximum dose volume for acute and subchronic doses in rodents (#7 days) (Neervannan, 2006).
Descriptions of toxicological outcomes after specific dose regimens in several species for many common excipients also available in Gad et al. (2006).
polyethylene glycol (PEG 300 or 400), dimethylacetamide (DMA), and DMSO have been used. Combinations of cosolvents provide benefits since cosolvency is
additive, whereas toxicity is often dependent on the
particular solvent.
In many cases, judicious manipulation of solution pH
in combination with cosolvents is sufficient to provide
solubilization and is typically viewed as the first-line
approach. For example, in a review of 317 discovery
compounds, Lee et al., (2003) reported that .90% of
compounds could be formulated using pH and cosolvents and that .60% of these could be formulated
using cosolvent levels of less than 50% v/v.
However, where pH adjustment and cosolvents fail
to provide the required solubility, alternative approaches
must be used. Second-tier approaches include the use of
cyclodextrins, surfactants, and lipid emulsions and,
ultimately, more complex formulations such as liposomes, microemulsions, or nanosuspensions. For
more complex systems, however, the potential effect,
either positive or negative, on systemic clearance and
distribution (and also absorption for non-i.v. parenteral formulations) should be carefully considered.
Surfactants (see Section VII) can also be used to
enhance drug solubility via micellar solubilization.
Surfactants are generally limited to those that are
nonionic because of their more favorable safety profile
and may include polysorbates (e.g., Tween 80), Cremophors (including Cremophor EL and RH40), Solutol
HS-15 (BASF Corporation, Washington, DC), vitamin E
pH adjustment
Cosolvents
Surfactants
Cyclodextrins
Cosolvents
Surfactants
Cyclodextrins
ddd
ddd
331
B. Oral Administration
In contrast to parenteral formulations, the approaches that are commonly used to support the oral
delivery of poorly water-soluble drugs vary significantly depending on the purpose of the in vivo study,
the species in which studies are conducted, the quantity
of material available, and the level of exposure required.
Distinction between the approaches taken at different
stages of the discovery-development continuum is difficult, and different organizations will have different approaches depending on in-house experience and
expertise. Nonetheless, the formulation strategies that
are commonly adopted during discovery and development are summarized as follows.
1. Formulations to Support Drug Discovery. In
proof-of-concept pharmacology studies, the focus is
generally placed on generating sufficient exposure to
allow early indication of the efficacy of a particular
pharmacophore or compound series. At this stage, only
small quantities of compound are usually available,
and control of crystallinity is limited, with early batches
often including a significant proportion of amorphous
material. Before a salt screening program, ionizable
compounds may also be available only as the free acid or
base or potentially as a non-optimal salt form. Under
these circumstances, simple solution formulations are
preferred since they circumvent the complexities of
dissolution and, therefore, obviate any variability in
exposure resulting from differences in solid-state
characteristics. Solution formulations facilitate ease
and reproducibility of administration via oral gavage,
enable ready conduct of single and multiple dose
studies, and support dosing strategies such as cassette
dosing. The approaches taken to develop oral solution
formations are similar to those used for parenteral
formulations, however, the acceptable limits on formulation components are typically wider. A useful order of
potential formulation approaches to achieve simple
oral solution formulations is provided in Table 4. In early
stage proof-of-concept studies, relatively aggressive absorption enabling formulations may be used to overcome
solubility and dissolution rate limitations, depending on
the frequency and length of dosing; however, caution
should be used to ensure that the formulation components
do not confound the efficacy readout, and vehicle controls
are essential.
Oral delivery during lead optimization is typically
focused on prioritizing lead compounds from within
a series with more favorable absorption properties and
on identifying the key structural and physicochemical
factors that contribute to poor oral bioavailability, in
an effort to guide subsequent structural modification.
Understanding the basis for poor oral absorption is
fundamental to designing a strategy to overcome this
limitation. The approaches used for oral formulations
of poorly water-soluble compounds in lead optimization
332
Williams et al.
TABLE 4
Possible hierarchy of formulation approaches for the development of oral solution formulations
Previously published suggestions for maximum allowable quantities of formulation excipients provided in parentheses.a,b,c Exemplar formulationsfor example, cosolvent
combinations, surfactant formulations, and lipid-based formulationsare provided, realizing that they represent a limited snapshot of possible formulations, concentration
ranges, etc. (Further details are provided in the sections of this review that describe each technology.)
Class
Examples
Simple Solutions 6 pH
Cosolvents 6 pH
Surfactants
Complexation agents
Cosolvent/surfactant
combinations
Simple lipid formulations
As Table 2
Propylene glycol (3060%a (80% 2 ml/kg)b
PEG 400 (40100%)a (100% 2 ml/kg)b
DMA (1030%)a
N-Methylpyrrolidone (1020%)a
DMSO (1020%)a (50% 0.5 ml/kg]b
Ethanol [10%]a [50% 0.5 ml/kg]b
Oral cosolvent combinations are common e.g., 75% PEG 400: 25% propylene glycol
As Table 2, but also solid and semisolid surfactants including:
a
D-a-Tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS 1000) (2050%)
Lauroyl macrogol-32 glycerides (Gelucire 44/14) [2050%]a
Caprylocaproyl macrogol-8-glycerides (Labrasol) [4060%]a
As Table 2
PEG-based cosolvent/surfactant combinations, e.g., 55% PEG: 25% propylene glycol: 25% Cremophor EL
Dispersed surfactant/cosolvent combinations, e.g., 50% Cremophor EL: 25% ethanol: 25% propylene glycol 1:1
in water or 20% PEG 400: 10% Cremophor EL: 10% ethanol in water
Lipid solution formulations, e.g., 100% soybean oil, corn oil
Self-emulsifying products, e.g., Labrasol, Labrafil, or Gelucire up to 50% in water
Self-emulsifying preparations, e.g.;
30% long-chain triglyceride (e.g., soybean oil): 30% long-chain diglycerides/monoglycerides
(e.g., Maisine 35-1): 30% Cremophor EL: 10% ethanol, usually dispersed in water, or,
30% medium-chain triglyceride (e.g., Captex): 30% medium-chain diglycerides/monoglycerides
(e.g., Capmul): 30% Cremophor EL: 10% ethanol, usually dispersed in water
a
b
c
Concentration range based on rat or mouse and single administration at 10 ml/kg (Li and Zhao, 2007).
Concentration range and maximum dose volume for acute and subchronic doses in rodents (#7 days) (Neervannan, 2006).
Descriptions of toxicological outcomes after specific dose regimens in several species for many common excipients are also available in Gad et al. (2006).
are therefore usually less complex than those incorporated, for example, during discovery biology, and are
designed to discriminate between compounds in the
absence of enabling formulation effects. Consistency in
formulation is important to distinguish between potential effects resulting from the formulation and intrinsic
differences in structural and physicochemical properties
of the lead.
Simple suspension formulations containing a suspending agent (e.g., cellulose derivatives) along with
a low concentration of surfactant to reduce particle
agglomeration are often used in early bioavailability
studies (see Table 5). These formulations provide little
in the way of assisted dissolution and therefore tend
to discriminate between different compounds. A further advantage is that they can be readily extended
into animal toxicology studies, provided sufficient compound exposure can be achieved. A complexity in the
TABLE 5
Typical suspension formulations
Class
Examples
Simple suspensions
Milled suspensions
Nanosuspensions
333
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Williams et al.
TABLE 6
Formulation approaches for the development of solid oral formulations
Class
Examples
Traditional tablets,
capsule fills
Particle size
reduction
Lipid-based
formulations
Solid dispersions
salt formation, cocrystals, or nanocrystals fail to provide sufficient exposure, the major routes of progression are the use of lipid-based formulations or solid
dispersions. The choice of approach is dictated largely
by the physicochemical properties of the drug candidate,
where lipid-based formulations lend themselves to
poorly water-soluble, lipophilic drugs (i.e., those with
sufficient solubility in lipids, surfactants, and cosolvents
to allow the target dose to be dissolved in the capsule fill
material), whereas solid dispersions are commonly
explored for drug candidates with insufficient lipophilicity to allow the use of lipid-based formulations.
In conclusion, the general strategies that may be
taken to identify and overcome the challenges of low
water solubility in the drug discovery and development
environment are summarized in the proceeding discussion. The tools that have been suggested as approaches
to overcome the limitations of poor solubility are described
in detail in following sections.
IV. Buffers and Salt Formation
Adjusting solution pH, usually via the use of a buffer,
provides an effective means of increasing the proportion
of a weakly acidic or basic drug that is present in the
ionized form. In turn, increasing ionization increases
polarity and therefore increases drug solubility in polar
(aqueous) solutions. Salt formation results in a similar
endpoint, and in many ways salts of weak acids and
bases are the solid-state equivalent of pH adjustment.
Salts are formed via an ionic interaction between
weakly acidic or basic drugs and an oppositely charged
basic or acidic counterion. When salts are subsequently
allowed to dissolve and dissociate in water, the acidic or
basic counterion from which they were derived causes
a shift in the pH of the solution to provide an
analogous endpoint to that obtained by pH adjustment. Isolation of drugs as a particular salt form also
changes the nature of the crystal lattice, resulting in
differences in dissolution rate from alterations in
solid-state properties compared with the free acid or
free base (Huang and Tong, 2004; Corrigan, 2007).
335
HA 1 H2 O H3 O 1 1 A 2
Ka
BH 1 1 H2 O H3 O 1 1 B
12
A 2 H3 O 1
Ka5
HA
Ka5
H3 O 1 B
BH 1
13
Sulfonic acids
Phosphonates
Carboxylic acids
Imides
Thiols
Sulphonamides
Phenols
Weak acid
Very weak acids
pKa Value
Basic Groups
pKa Value
,1
2
Aliphatic amines
Saturated nitrogen
heterocycles
Pyridines
Anilines
811
911
2.55
811
710
810
810
4.59.5
9.514
Weak base
Very weak base
46
35
4.59.5
0.04.5
336
Williams et al.
h
i
S5S0 1 1 10pKa 2 pH 16
17
BH 1 X 2
solid
Ksp
BH 1 1 X 2
18
19
In region 2 of Fig. 7 (i.e., at the solubility limit), excess solid phase is present as the salt, and the saturated species in solution is largely the ionized form.
At pH values ,pHmax, the total solubility of a weak
base is given by [BH1] plus a small (and decreasing)
quantity of B (free base) (Kramer and Flynn, 1972;
Serajuddin, 2007). The total solubility in region 2 of
Fig. 7 is given by eq. 20. for weak acids (top equation)
and weak bases (bottom equation).
337
Fig. 7. The pH solubility profiles for (A) a weakly basic and (B) a weakly
acidic compound. In region 1, the un-ionized free acid or free base is
present as the solid phase and as the saturation or equilibrium species in
solution. Total solubility is a function of both un-ionized and ionized
species (eq. 16), and at pH values greater than (for a weak acid) and less
than (for a weak base) pKa, solubility increases because of increased
quantities of the ionized species in solution. Solubility is ultimately
limited in the salt plateau region (region 2) by Ksp (eq. 19). In region 2,
the salt is present as the solid phase, and the ionized form is the saturated
or equilibrium species in solution. At pH values greater than (for a weak
acid) and lower than (for a weak base) pHmax, the total solubility decreases
slightly because of a reduction in the quantity of free acid or free base in
solution (eq. 20). Where pH change continues as a result of the further
addition of acidic or basic counterion, salt solubility in region 2 may
decrease much further (dotted line) as a result of the common ion effect.
h
i
H3 O 1
S5A 1 1
5A 2 1 1 10pKa 2 pH
Ka
20
i
h
K a
1
1
pH 2 pKa
S5BH 1 1
5 BH
1 1 10
H3 O 1
2
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Williams et al.
Fig. 8. The effect of (A) pKa, (B) intrinsic drug solubility (S0) and (c) salt solubility (Ksp) on the position of the pHmax of a weak base. Salt formation of
a weak base becomes more attainable (an increase in pHmax) with increasing pKa of the base, an increase in intrinsic solubility, or a decrease in salt
solubility. Adapted from Pudipeddi et al. (2002).
339
pKaa
#26
#6
26
23
22.1
21.34
21.32
21.2
0.17
0.52
0.7
1.271
1.3
1.66
1.92
1.96
2.14
3.02
3.03
3.128
3.18
3.2
3.459
3.55
3.6
3.76
4.19
4.207
4.756
4.9
4.9
a
b
.4
4.9
5.28
Frequency (%)b
Oral
Parenteral
0.3
4.1
56.6
7.5
0.3
0.3
0.6
4.4
0.6
1.0
4.3
53.4
8.2
0.5
0.5
0.5
3.9
0.6
0.3
0.3
6.9
2.5
2.8
1.6
3.4
0.3
0.3
0.3
0.3
0.3
1.9
0.9
0.3
0.9
0.3
0.3
0.5
1.4
Basic
pKaa
;14
;14
12.6
11.4
. 11
10.93
10.93
9.5
9.28
9.0
8.02
5.68
4.46
Frequency (%)
Oral
Parenteral
13.3
65.3
12.0
2.7
1.3
1.0
85.4
2.9
2.7
1.3
1.3
1.0
1.0
4.9
1.0
1.0
1.0
1.0
1.0
0.5
3.4
0.5
3.9
0.5
2.4
0.5
0.5
0.5
0.5
0.5
0.5
5.8
2.9
0.5
0.5
0.5
0.5
Value corresponding to the strongest acid/base moiety only. Values taken from Stahl and Wermuth (2002).
Values taken from Paulekuhn et al. (2007).
22
23
340
Williams et al.
Fig. 9. The pH-solubility profiles for 7-methylsulfinyl-2-xanthonecarboxylic acid and its salts at 25C. Symbols represent experimental data. The
point at which horizontal lines cross the upward solubility curve
represent the pHmax values for respective salts. Solid symbols indicate
that the starting material was the acid, and open symbols indicate that
the starting material was the salt. Adapted from Chowhan (1978).
Fig. 10. The relationship between log Ksp and the melting temperature of
1:1 amine salts of flurbiprofen. Basic counterions were 1) 5 2-amino-2methyl-1,3-propanediol, 2) 5 ammonium, 3) 5 tromethamine, 4) 2-amino2-methylpropanol, 5) 5 tert-butylamine, and 6) 5 adamantanamine.
Adapted from Anderson and Conradi (1985).
341
342
Williams et al.
343
Maleic acid
Tartaric acid
Lactic acid
Citric acid
Acetic acid
1.9, 6.2
2.9, 4.2
3.8
3.1, 4.8, 6.4
4.75
23
2.54
34.5
37
46
Sodium bicarbonate
Sodium phosphate
6.3, 10.3
2.2, 7.2, 12.4
49
68
Buffering Agenta
a
Selected LD50 values (i.v. administration): Acetic acid: 525 mg/kg (mouse), sodium acetate: 1195 mg/kg (mouse), citric acid: 330 mg/kg (rabbit), sodium (mono) citrate: 379
mg/kg (rabbit), trisodium citrate: 143 mg/g (rat).
b
Summarized from Li and Zhao (2007), Lee et al. (2003) and Nema and Brendel (2011).
During parenteral administration, pain on administration is likely when using solutions buffered to high
or low pH. Formulations are therefore typically limited
to a working pH range of 49, although a wider pH
range (29) may be used acutely in a preclinical setting
(Li and Zhao, 2007). Extremes of pH may also lead to
chemical instability, and in these cases, drug stability
should be monitored in the formulation for the
intended period of use (Pasini and Indelicato, 1992;
Islam and Narurkar, 1993; Carstensen, 1995; Zhu
et al., 2002; Chen et al., 2006). Buffer concentrations
normally exceed 0.05 M and are generally less than 0.5
M (Wang and Kowal, 1980; Sinko, 2006). Increasing
buffer capacity does not increase drug solubility but
can prove more effective in maintaining drug in
solution on dilution or with the addition of a formulation additive. High buffer concentrations, however,
increase the risk of pain on injection and in high
volume may alter physiological levels of biologically
important buffer components such as lactate (Nema
and Brendel, 2011). The buffer will also contribute to
the overall ionic strength of the formulation, and high
buffer concentrations can promote salting out of drug
from solution (McDevit and Long, 1952; Raghavan
et al., 1996; Yalkowsky, 1999).
A pH adjustment is a simple and powerful mechanism for solubility adjustment and, as such, is typically
the first approach for solution formulations of ionizable
drugs. For example, naproxen is a weak acid with
a pKa of 4.57 and intrinsic solubility (of the free acid) of
16 mg/ml (Fini et al., 1995). As a comparatively strong
weak acid, the low solubility of naproxen can be increased dramatically in a pH range acceptable for
parenteral administration. Indeed, solution concentrations of ;45 mg/ml might be expected in pH 8
phosphate buffer and ;450 mg/ml in pH 9 sodium
bicarbonate buffer. Under these circumstances, pH
adjustment could be used to deliver a wide range of
doses (Lee et al., 2003). In some cases, and in particular
for weak(er) acids of higher pKa and weak(er) bases with
lower pKa values, pH adjustment alone may be insufficient to allow the administration of an appropriate
344
Williams et al.
pH 2a
pH 1a
mg/ml
Buffer alone
20% Ethanol
20% DMSO
20% PEG 400
40% Propylene glycol
20% Tween 80
0.00003
0.003 (100)
0.002 (66.7)
0.006 (200)
0.017 (567)
1.8 (60 000)
0.024
0.047
0.021
0.028
0.119
1.817
(2.0)
(0.9)
(1.2)
(5.0)
(75.8)
0.210
0.848
0.511
0.702
1.114
2.948
(4.0)
(2.4)
(3.3)
(5.3)
(14.0)
345
346
Williams et al.
associated with precipitation may take 24 h to materialize) and largely qualitative unless efforts are made to
quantitate precipitation by monitoring, for example, an
increase in temperature at the site of administration
(Ward and Yalkowsky, 1993; Johnson et al., 2003).
Alternatively, in vitro precipitation models may be used
(Yalkowsky et al., 1983, 1998; Li et al., 1998b; Dai,
2010). Briefly, simple serial dilutions of the formulation
are generated with a variety of solutions, including
water, saline, dextrose 5%, human plasma, tris buffer,
or Sorensens phosphate buffer (SPB) (Reed and Yalkowsky, 1985; Yalkowsky et al., 1998) and evidence of
drug precipitation detected visually or spectrophotometrically following filtration (or another appropriate separation means) of the solutions. Similarly, the dropwise
addition method may be used where small aliquots of
formulation are slowly introduced (approximately every
30 s) into a static or continuously stirred dilution
medium (El-Sayed and Repta, 1983; Li et al., 1998b).
The latter method has the advantage of revealing the
minimum volume ratio of formulation-to-dilution medium that promotes precipitation. Dynamic precipitation methods are designed to mimic better the effects in
vivo via the addition of formulation to a circulating
medium (normally pumped through plastic tubing using
a peristaltic pump) (Yalkowsky et al., 1983, 1998;
Johnson et al., 2003). A major advantage of this
approach is that the effect of injection rate on the
likelihood of drug precipitation can be assessed (Li et al.,
1998b), and although dynamic tests are more complex
than static in vitro tests, they have been shown to better
correlate with in vivo bioavailability data (Cox et al.,
1991; Dai, 2010).
The duration of an in vitro precipitation test is
important since drug precipitation may not be immediate and may occur at varying rates and extents,
depending on the formulation and the nature of the
dilution medium. Li and Zhao (2007) proposed that 35
min is a sufficient to assess the likelihood of drug
precipitation during static serial dilution tests as an
administered formulation is likely to have been
significantly diluted in this time after circulation with
the blood. Also, in many cases, the administered drug
will bind to components of human plasma (e.g., albumin
and lipoproteins); therefore, in vitro precipitation
methods that use simple solutions and buffers may
overestimate the extent of drug precipitation (Cox
et al., 1991). The use of more complex dilution media
(i.e., containing plasma proteins) may serve to alleviate
these differences, although conscious omission of these
materials provides a more conservative estimate of
precipitation potential.
4. Buffer Systems in Nonparenteral Formulations.
Solution formulations intended forfor example, oral,
ocular, or nasal administrationalso commonly use
buffers. Similar to parenteral formulations, buffers
may be used in these systems to alter pH such that
347
348
Williams et al.
349
Fig. 13. Effect of dissolution media pH on the dissolution rate of (A) haloperidol free base and (B) hydrochloride and (C) mesylate salt forms, and (D)
the pH at the surface of a solid as a function of bulk pH of the dissolution media. Dissolution values are expressed as means (n 5 6). Dashed lines are
used for pH 7.01 as only data during the first 30 min of dissolution was provided. Adapted from Li et al. (2005b).
350
Williams et al.
351
Fig. 14. The dissolution and precipitation of salts in the fasted stomach and during transit into the more neutral small intestine. (A) Dissolution of
a salt of a weak acid in the acidic stomach is promoted by the self-buffering effect of salts. Drug in solution in the stomach may enter the intestine and
be absorbed, or it may convert to the un-ionized free acid in the stomach, typically resulting in supersaturation and increasing the risk of precipitation.
Precipitated free acid may exist as fine particles (either amorphous or crystalline) or may form a layer of poorly soluble free acid around the salt
particle, inhibiting further gastric dissolution. On gastric emptying, dissolution of precipitated free acid is subsequently promoted by the higher pH in
the intestine. Incomplete dissolution of the salt of a weak acid in the stomach leads to gastric emptying of undissolved salt and the expectation of
improved dissolution in the higher pH environment of the small intestine. (B) Dissolution of the salt of a weak base in the stomach is favored by the low
pH environment. Drug in solution subsequently enters the intestine, where the increase in pH commonly leads to transient supersaturation as the
degree of ionization (and therefore drug solubility) is decreased. Depending on the rate of absorption, supersaturated drug may be absorbed or
precipitate (in either the amorphous or crystalline form). Precipitated free base may form discrete particles or coat incompletely dissolved salt particles,
inhibiting further dissolution. Redissolution is possible, however, as drug is absorbed and sink conditions return. Incomplete dissolution of the salt of
a weak base in the stomach results in gastric emptying of the undissolved salt, the dissolution of which is slow in the small intestine but assisted by the
self-buffering effect of the salt. Salt 5 light shaded purple, free acid/base 5 dark shaded purple.
352
Williams et al.
Fig. 15. The effect of acidity or basicity of weak acids and weak bases on the relationship between pHmax and physiologic pH, and therefore, the
likelihood of in situ salt-un-ionized drug conversion. In situ conversion from the more soluble salt to the less soluble free acid or free base is expected
where physiologic pH is lower (for weak acids) or higher (weak bases) than pHmax. For salts of typical weak bases (pKa ;9) under gastric and most
intestinal conditions, conversion to the free base is relatively unlikely. For weaker bases, however (pKa ;6), the likelihood of conversion increases,
especially under intestinal pH. For weak acids, conversion is more likely since GI pH values are largely acidic. For typical weak acids (pKa ;4), the
potential for conversion to the free acid is evident under gastric conditions and potentially in the small intestine (depending on pHmax). For even
weaker acids (pKa ;7) conversion under most physiologic conditions is likely. Note the difference between pHmax and pKa has been arbitrarily shown
here as ;2.5 pH units to allow simple illustration but will vary for differing salts.
353
354
Williams et al.
exposure in vivo and facilitate more confident progression through pharmacokinetic and toxicokinetic
studies. However, selecting the optimal salt is not
straightforward, as many of the properties that dictate
the potential in vivo performance of a salt (e.g., Ksp, the
potential for in situ conversions to a less soluble salt,
the formation of hydrates, self-association properties,
and so forth) cannot be predicted using the fundamental solubility principles of the ionized form (i.e., via the
Henderson-Hasselbalch equation, eq. 14). The large
number of potential counterions (Table 8) also precludes
the synthesis and detailed evaluation of all potential
salt forms. A more efficient approach, therefore, is to
develop experimental methodologies that rapidly screen
potential salt forms that meet predetermined criterion.
Shanker et al. (1994) described one of the first screening
protocols to search for the most promising salt forms for
new chemical entities, and several companies subsequently adopted similar screening approaches, with
each company setting its own selection criterion. The
successes of salt screening methodologies have spawned
an era of automation and the creation of specialty
companies dedicated to salt and polymorph screening.
The development of small-scale characterization
techniques that require low (milligram) quantities of
raw material (Shanker et al., 1994; Tong and Zografi,
1999; Bastin et al., 2000; Morissette et al., 2004) and
the availability of high-throughput screening methods
for multiple physical forms now enable physicochemical profiling of salt forms to be a routine process that is
undertaken earlier in drug development (Kerns, 2001;
Kerns and Di, 2003). One such example suggests that
as little as 100 mg of drug material may be sufficient to
complete pharmaceutical salt profiling (Balbach and
Korn, 2004).
1. Salt Formation Feasibility. A simple but effective
indicator of the potential for salt formation is the
presence of a 2-unit difference in pKa between the drug
and the oppositely charged counterion (Tong and
Whitesell, 1998; Pudipeddi et al., 2002; Black et al.,
2007). This stems from the realization that the wider
the difference in acidity and basicity between the drug
TABLE 11
Criteria of salt formers in classes 1, 2, and 3
Classa
Example
Criteria
Acids
2
3
Bases
L-Arginine,
Diethylamine, tromethamine,
Piperazine, ethylenediamine
calcium, lysine,
magnesium, sodium, potassium
355
356
Williams et al.
a preferred salt form remains a priority when attempting to address the problems of low solubility of
a potential drug candidate.
V. Optimization of Crystal Habit: Polymorphism
and Cocrystal Formation
Crystal engineering is traditionally defined as the
deliberate design and control of molecular packing
within a crystal structure with the intention of
generating a solid that shows a particular and desirable characteristic (Desiraju, 2001, 2010). Since the
solid-state properties of a drug will influence a range of
different drug properties, including solubility, the level
of interest in crystal engineering strategies has increased dramatically over recent years (Desiraju, 2001;
Datta and Grant, 2004; Blagden et al., 2007).
In the broadest sense, crystal engineering may
encompass any manipulation that results in altered
crystal packing, including both traditional approaches,
such as the isolation of different salts (Peterson et al.,
2010), solvates (Blagden et al., 2007), or polymorphs,
and more recent approaches, such as cocrystal formation (Aakeroy and Salmon, 2005). In each of these
approaches, a change to solid-state properties is likely
to affect solubility and may be advantageous in
overcoming solubility limitations that stem from the
strength of the crystal lattice. In the case of salt
formation, however, changes to solubility reflect both
changes to the crystal lattice and coincident changes to
pH and ionization (and where changes to pH and
ionization provide the primary beneficial effects). Salt
formation is therefore addressed in a separate section
(see Section IV).
Here the discussion of crystal engineering strategies
is limited to polymorphism and cocrystal formation
(i.e., approaches that alter the crystal habit). A
somewhat broader use of the term crystal engineering
has also emerged (Biradha et al., 2011) to describe
strategies that include not only deliberate manipulation of the crystal lattice but also manipulation of
crystallization conditions to isolate drug crystals of
a particular size and shape (Nokhodchi et al., 2003;
Blagden et al., 2007). The latter strategy, however, is
arguably better described as particle (rather than
crystal) engineering since it is the physical properties
of the particle that are changed rather than the crystal
form (see Section IX). Indeed, the same polymorphic
form can form particles with widely differing characteristics (Nokhodchi et al., 2003; Iacocca et al., 2010).
The potential for a drug to form one or more
crystalline solids that differ only by the molecular
arrangement of drug molecules in the crystal lattice is
referred to as polymorphism, and different crystalline
forms of the same compound are described as polymorphs. Materials lacking crystalline character are
said to be amorphous. Since they differ in crystal habit,
357
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Williams et al.
molecules in an orientation that is constant throughout the crystal lattice. The nature and strength of the
intermolecular interactions that form between drug
molecules within the unit cell and between adjacent
cells are determined by the chemical properties of the
drug molecule and their orientation within the unit cell.
Molecular interactions within a crystal lattice are
either attractive or repulsive and include relatively
weak van der Waals forces, p-p stacking, and
electrostatic interactions (0.522 kJ per mol), stronger
hydrogen bond interactions (530 kJ per mol), and much
stronger (;150 kJ per mol) ionic interactions. The
summation of the energies from all intermolecular
interactions determines the total packing energy of
a crystal or the crystal lattice energy. Since stronger
intermolecular interactions minimize the molecular
energy (and mobility) of the molecules within the
crystal, the higher the lattice energy, the greater the
stability (and lower the solubility) of the crystal (Datta
and Grant, 2004; Lohani and Grant, 2006). The most
stable crystal form therefore allows the largest number
of molecular interactions with adjacent molecules.
Accordingly, a crystal lattice in which the orientation
of the drug molecule does not permit the maximum
number of interactions with adjacent molecules is
unstable, or metastable, and over time or after exposure
to heat or moisture, molecules within the crystal lattice
will reorientate (relax) to adopt a more thermodynamically stable conformation. It is important to recognize
the potential confusion that can occur between reference
to unstable polymorphs as high-energy solids (where
the reference to high energy refers to thermodynamic
instability) and the realization that the crystal lattice
energy of these systems is, in fact, low compared with
the thermodynamically stable crystal form.
Polymorphism is the term most frequently used to
describe the ability of an organic molecule to exist in
more than one crystalline form (i.e., polymorph) (see
Fig. 16), and it has been estimated that approximately
80% of pharmaceutical compounds show more than one
polymorph (Grunenberg et al., 1996; Datta and Grant,
2004; Lohani and Grant, 2006). In addition to true
polymorphs, where different crystal packing arrangements result entirely from differences in packing
Fig. 16. Schematic diagram illustrating common solid-state arrangements of drug molecules in the crystalline state and the amorphous form. Drug
polymorphs vary only in the molecular organization of individual drug molecules in the crystalline state. Solvates and hydrates (often referred to as
pseudopolymorphs) are molecular complexes of drug and molecules of water (in the case of hydrates) or other solvent molecules (in the case of solvates)
that form intermolecular interactions with the drug and become incorporated within the crystalline lattice. Cocrystals are also molecular complexes,
consisting of drug and a cocrystal former (coformer), which interact primarily via hydrogen bonds. Popular definitions of cocrystals in the
pharmaceutical literature state that the coformer must be solid at room temperature, distinguishing cocrystals from solvates and clathrates. Salts are
in many ways analogous to cocrystals but differ by virtue of an electrostatic interaction that forms between a charged drug molecule and an
oppositively charged counterion.
359
360
Williams et al.
361
A a Bb A a 1 Bb
25
K sp 5Aa Bb
26
362
Williams et al.
363
K 11 5
AB AB
5
AB K sp
27
28
29
Fig. 20. The relationship between cocrystal solubility and the solubility
of the coformer. Drugs used were caffeine, theophylline, and carbamazepine. Open symbols are solubilities determined in water, closed symbols
in organic solvents. Adapted from Good and Rodriguez-Hornedo (2009).
364
Williams et al.
Fig. 21. Theoretical pH solubility profiles of various ionizable and nonionizable compounds and their cocrystals. (A) carbamazepine-succinic acid, (B)
carbamazepine-4-aminobenzoic acid hydrate, (C) itraconazole-L-tartaric acid, and (D) gabapentin-3-hydroxybenzoic acid. The plots show that even for
nonionizable drugs [i.e., (A) and (B)], pH can affect the solubility of the cocrystal via effects on the solubility of the coformer. Adapted from Bethune
et al. (2009).
365
366
Williams et al.
TABLE 13
Cocrystal references describing effects on in vitro dissolution rate and in vivo bioavailability
Drug
Coformer(s)
Maleic acid
Saccharin
Saccharin
Aspirin
p-Aminobenzoic
acid (PABA)
Urea
Isonicotinamide
Caffeine
Theophylline
Theobromine
367
Fig. 22. Comparison of CFPC and its glutaric acid cocrystal during (A)
intrinsic dissolution testing in pure water (37C with USP paddles at 100
rpm) and in (B) beagle dog oral pharmacokinetic testing (dosed at 50 mg/
kg). Values are expressed as means [n 5 3 in (A) and n 5 6 in (B)] 6 SD.
CFPC is 2-[4-(4-chloro-2-fluorophenoxy)-phenyl]pyrimidine-4-carboxamide. Adapted from McNamara et al. (2006).
368
Williams et al.
TABLE 14
Commonly used pharmaceutical cosolvents in parenteral drug delivery: recommended concentrations in preclinical testing and maximum
concentrations observed in clinical use
Cosolvent
Glycerol
Propylene glycol
Recommended Range
for Preclinical Usea
3060%
Frequency of Use in
Commercial Formulationsb
17
32
40% in Valium
Ethanol
10%
40100%
1020%
10 30%
40% in Lanoxin
68% in Luminal
60% in Alkeran
100% in alprostadil
injection USP
49% in Taxol
80% in Prograf
42% in Vumon
50% in methacarbamol
67% in Busulfex
33% in Busulfex
34
% w/v, on the basis of single dosing 10 ml/kg to a mouse or rat. Li and Zhao (2007). See text for additional details.
Values obtained from Nema and Brendel (2011), Strickley (2004), and Bouqet and Wagner (2012).
369
also contains PEG 400 but with glycerin, citric acid, and
a small amount of water; amprenavir capsules and oral
solution (Agenerase; GlaxoSmithKline), which contain
PEG 400, propylene glycol, TPGS, sodium chloride,
sodium citrate, and citric acid.
C. Solubilization by Cosolvents
1. Cosolvent Effects on Solubility Parameters.
Cosolvents increase the aqueous solubility of poorly
water-soluble drugs by disrupting the intermolecular
hydrogen bonding networks that are present in
aqueous systems. This leads to a decrease in the
polarity of the solvent and the creation of an environment with physicochemical properties that are more
similar to that of the solute (e.g., drug). Simplistically,
this results in an increase in drug solubility according
to the general principle of like dissolves like.
More accurately, the effect of cosolvents on drug
solubility may be assessed using the solubility parameter approach. The role of solubility parameters in
ideal and nonideal solubility was discussed in Section
I.B.1 of this review. In brief, differences between the
solubility parameters of solute (drug) and solvent
provide an indication of the differences in intermolecular forces in the solute (i.e., solute-solute interactions)
and solvent (i.e., solvent-solvent interactions) and in
turn provide an indication of how close the properties
of the solution are to an ideal solution (eq. 8).
In an ideal solution, intermolecular forces between
solute-solute and solvent-solvent molecules are equal,
and under these conditions, solubility is essentially
maximal (and solvent independent). However, the
large differences between intermolecular bonds in
water and most poorly water-soluble solutes dictate
that almost all aqueous solutions are nonideal. Deviations from ideality result in a decrease in solubility,
and the magnitude of the deviation from ideality is
captured by the activity coefficient (g) (eq. 7), which in
turn is a function of the difference in the solubility
parameters of solute and solvent (eq. 8).
The solubility parameter (d) may be determined
experimentally by measuring the energy required to
vaporize (Ev) a solute or solvent of molar volume Vm
where
r
30
d5 DEv
Vm
370
Williams et al.
TABLE 15
Examples of cosolvents widely used in parenteral drug delivery and corresponding descriptors of their relative polarity
Solubility Parametera (d)
Cosolvent
Dielectric Constanta ()
cal/cm3
Water
Glycerol
Ethylene glycol
Propylene glycol
Ethanol
DMSO
PEG 400
DMA
Dioxane
Interfacial Tensiona
Log Kowa
dynes/cm
23.4
16.5
14.6
12.6
12.7
12.0
11.3
10.8
9.9
81.0
42.5
37.7
37.7
24.3
46.7
13.6
37.8
2.2
72.0
64.9
48.8
37.1
22.2
38.0
46.0a, 11.7b
35.7
33.6
24.00
22.60
21.93
21.40
20.31
21.09
21.30
20.66
20.42
dt 5
q
d2d 1 d2p 1 d2h
31
32
33
371
34
TABLE 16
Rank order in drug solubilization obtained in various water/cosolvent
binary mixtures
Drug
Fig. 23. Log-linear solubility relationship for a series of alkyl p-aminobenzoates in propylene glycol-water mixtures. A decreasing slope reflects
decreasing log P values for the various solutes. Alkyl chain lengths on the
drug were ethyl (C2), butyl (C4), hexyl (C6), octyl, (C8), dodecyl (C12).
Adapted from Yalkowsky et al. (1972).
NSC-639829, pH 1 (ionized)
(Jain et al., 2001)
Carbendazim (Ni et al.,
2002)
N-Epoxymethyl-1,8naphthalimide
(Dong et al., 2008)
PG-300995 (Ran et al.,
2005)
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Williams et al.
373
Fig. 24. Solubilization of NSC-639829 by ethanol, propylene glycol, DMSO, and PEG 400 at pH 1, 2, and 7. DMSO, dimethyl sulfoxide; PEG,
polyethylene glycol. Adapted from Jain et al. (2001).
ethanol solutions is higher in the presence of hydroxypropyl-b-cyclodextrin and that as little as 0.2%
cosolvent (which is insufficient to solubilize a significant
amount of drug via cosolvency alone) increases drug
solubility in the presence of the cyclodextrin (Li et al.,
1999d; He et al., 2003). Consistent with these data, the
currently marketed Sporanox IV solution (itraconazole;
Janssen Pharmaceuticals, Titusville, NJ) contains 40%
hydroxypropyl-b-cyclodextrin and 2.5% propylene glycol (Strickley, 2004) (see also Section VIII.D.2).
4. Cosolvents and Strong Electrolytes. Strong electrolytes such as sodium chloride increase solution
polarity, and this acts to oppose the decrease in polarity stimulated by addition of cosolvent. Consequently, the addition of salts to cosolvent systems is
generally avoided as it will decrease drug solubility
(Yalkowsky, 1999).
374
Williams et al.
375
376
Williams et al.
TABLE 17
Cosolvent regimens well tolerated in various animals
Summarized in this table are the data obtained in a number of in vivo studies performed by four separate organizations between 1991 and 2006 and summarized in Gad
et al. (2006). In each study, a vehicle control group was evaluated, with the results summarized in this table.
Cosolvent
DMSO
Ethanol
Glycerol
PEG 300
PEG 400
PG
Species
Duration of Study
Route of Administration
Dose
Dog
Rat
Rat
Rat
Guinea pig
Mouse
Rabbit
Primate
Dog
Dog
Rat
Mouse
Mouse
Mouse
Mouse
Rat
Rat
Guinea pig
Mouse
Mouse
Mouse
Rabbit
Guinea pig
Mouse
Rabbit
Guinea pig
Mouse
Mouse
Rat
Rat
Rat
Rat
Minipig
Rat
Rat
Minipig
Mouse
Mouse
Dog
1 mo
1 mo
1 mo
1 mo
1 mo
1 mo
1 mo
Efficacity
1 mo
3 mo
1 wk
6 mo
1 mo
Acute
13 wk
1 mo
1 mo
1 mo
Acute
1 mo
1 mo
ADME test
1 mo
1 mo
1 mo
1 mo
1 mo
1 mo
1 mo
104 wk
2 wk
1 mo
1 mo
26 wk
1 mo
1 mo
1 mo
i.v.
i.v.
i.p.
Oral
i.v.
Oral
s.c.
Oral
Oral
Oral
Oral
Oral
Oral
i.p.
Cutaneous
Oral
s.c.
Oral
i.v.
s.c.
i.p.
i.v.
i.v.
Oral
Oral
Oral
Oral
i.p.
Oral
i.v.
Cutaneous
Cutaneous
Cutaneous
Oral
s.c.
Cutaneous
Oral
i.p.
Oral
1.25 ml/kg
200 mg/kg
5 ml/kg
5 ml/kg
0.1 mg/kg
5 ml/kg
1 ml/kg
3 ml/kg/day
5 ml/kg (7.5% solution)
5 ml/kg (5.0% solution)
10 ml/kg (10% solution)
2.5 g/day
2.5 ml/day (5% solution)
5 ml/kg (5% solution)
100 ml/animal/day (70% solution)
1000 mg/kg
10 mg/kg
500 mg/kg
100 mg/kg
10 mg/kg
10 mg/kg
10 mg/kg
1 ml/kg
10 ml/kg/day
500 mg/kg
1000 mg/kg
10 ml/kg/day
500 mg/kg
5 ml/kg
0.5 ml/kg
5 ml/kg (35% solution)
2.5 ml/kg
2.5 ml/kg
2.5 ml/kg
2.5 ml/kg
2.5 ml/kg
10 ml/kg (50% solution)
2.5 ml/kg (40% solution)
2.5 ml/kg
ADME, absorption, disposition, metabolism, and elimination; PG, propylene glycol; mo, month; wk, week.
combination approaches that include surfactant, cosolvent, and lipid. Such formulations are usually described under the generic heading of lipid-based
formulations, regardless of the quantity of traditional lipid incorporated. Notable examples of formulations of this type include amprenavir (Agenerase;
GlaxoSmithKline), cyclosporine (Neoral; Novartis
Pharmaceuticals), and ritonavir (Norvir SEC; Abbott
Laboratories). These systems are described in more
detail in Section XI of this review. Surfactants are also
commonly used to stabilize nanosuspension formulations and are therefore an important constituent of
formulations described in Section IX. Finally, surfactants may be used to improve wetting of hydrophobic
materials in simple solid dosage forms and to stabilize
traditional suspension-based formulations. The interested reader is directed to the following reviews for
further details (Nielloud and Marti-Mestres, 2000;
Tadros, 2005).
The emphasis of the current section is on the use of
surfactants in parenteral formulations. In comparison
with oral delivery (where most surfactants are not
377
TABLE 18
Examples of nonionic surfactants commonly used as solubilizing agents in parenteral drug delivery
Primary Hydrophilic
Component
General Class
Span
Sorbitan
Tween
Polyethoxylated sorbitan
(polysorbate)
Cremophora
Polyoxylglycerides
Tocols
Brij
Poloxamers
Polyoxyethylene
b
Polyoxyethylene
Polyethylene glycol
Polyoxyethylene
Ethylene
oxide units
Propylene
oxide units
153
27
8
74
23
23
43
43
Poloxamer
Poloxamer
Poloxamer
Poloxamer
188
184
331
335
(Pluronic
(Pluronic
(Pluronic
(Pluronic
F68)
L64)
L101)
P105
Cloud Point
C
LS
76
73
80
65
LS
93
72
LS
LS
64
;40
.100
.100
.100
58
15
91
378
Williams et al.
TABLE 19
Commonly used surfactants: published recommendations for concentrations in preclinical testing and maximum concentrations observed in clinical
parenteral products
Surfactant
Cremophor EL
Recommended
Range for
Preclinical Usea
(oral and i.v.)
510%
Frequency of Use in
Commercial Formulationsb
Concentrations Used in
Some Commercial
Preconcentratesc
65% (Sandimmune)d
51% (Taxol)d
Cremophor RH 40
Cremophor RH 60
Tween 20
Tween 80
Solutol HS-15
a
510%
510%
2050%
1
1
22
72
50% (Vumon)
50% (Valstar)
7%f
20% (Prograf)
2.4%f
100% (Taxotere)d
50% (Panitol)g
% w/v on the basis of single 10 ml/kg excipient dose to a mouse or rat, from Li and Zhao (2007).
From Nema and Brendel (2011).
From Strickley (2004).
d
Significant evidence of local/systemic adverse reactions.
e
From Gelderblom et al. (2001).
f
It was not possible to identify the product.
g
Licensed for use in Mexico.
b
c
379
formulations where dilution leads to a nonlinear decrease in drug solubility and, typically, drug precipitation. The molar solubilization capacity k is frequently
used to quantify surfactant solubilization and is
defined as the mole ratio of micellar solubilized drug
(SM) to the concentration of micellar surfactant (Cmic)
(Yalkowsky, 1999):
Stot 2 S0
S
5 M
35
k5
Cmic
Csurf 2 CMC
where S0 is the intrinsic solubility of the drug, Stot is
the total concentration of drug in solution (solubilized
plus free), and Csurf is the total surfactant concentration. The determination of k provides a rapid, effective
means of comparing the solubilization efficiency of
various surfactants for a particular drug. It does not,
however, account for potential differences in the intrinsic drug solubility. The micelle-water partition
coefficient (KM) is therefore a more appropriate index
for comparing total solubilization for different drugs:
KM 5
Stot 2 S0
SM
5
S0
S0
36
380
Williams et al.
partition coefficient (log P) of a solubilized drug resulted in a corresponding increase in KM (AlvarezNunez and Yalkowsky, 2000) (Fig. 27) and led to the
suggestion that micellar solubilization is likely to be of
most potential benefit for drugs with log P values . 3.
The exceptions to this suggestion include drugs with
high potency that require relatively low levels of solubilization and drugs where interaction at the micellar
interface is the prevalent mechanism of solubilization.
3. Effect of Surfactant Type and Structure on Drug
Solubilization. Increasing the length of the hydrophobic region of an ionic or nonionic surfactant leads
to a decrease in the water solubility of surfactant
monomers, in turn leading to a decrease in the CMC
(Hall and Pethica, 1967; Attwood and Florence, 1983;
Chandler, 2005). Micelle formation from surfactants
with larger hydrophobic chains also typically results in
an increase in the volume of the micelle core (El-Eini
et al., 1976; Lindman et al., 1980; Ong and Manoukian,
1988; Hurter et al., 1993; Wanka et al., 1994; Chen
et al., 1998; Tsui et al., 2010). Together, these trends
predict an improvement in micellar drug solubilization
with surfactants of increasing alkyl chain length. The
effect of surfactant alkyl chain length has been observed in many solubilization studies using Tween,
Brij, and Pluronic surfactants (Ismail et al., 1970;
Samaha and Cadalla, 1987; Ong and Manoukian, 1988;
Kozlov et al., 2000; Ahmed, 2001; Tommasini et al.,
2004; Kovacs et al., 2009).
Other reports suggest that the impact of surfactant
chain length on drug solubilization is significant only
when the drug is highly nonpolar and has a high
affinity for the micelle core (Alvarez-Nunez and
Yalkowsky, 2000). For example, indomethacin solubilization is similar in Tween 20 or Tween 80 micelles,
381
382
Williams et al.
Fig. 29. Experimentally determined total aqueous flavopiridol solubilities (mM) in Tween 20 solutions at different pH values. Adapted from Li
et al. (1999b).
37
383
38
384
Williams et al.
TABLE 20
Selected oral and parenteral toxicity of some commonly used
nonionic surfactants
Surfactant
Brij 35
Tween 20
Tween 40
Tween 60
Tween 80
Labrasol
Labrafil
Cremophor EL
Cremophor RH40
Cremophor RH 60
Poloxamer 188
(Krzyzaniak and Yalkowsky, 1998). The typical experimental design used was described in Section VI.F.2,
and studies of this type have revealed that increasing
the chain length of nonionic surfactants appears to
promote surfactant toxicity against red blood cells
(Ernst and Arditti, 1980), although this toxicity increase is not maintained above a chain length of
approximately 14 carbons (Schott, 1973; Ferguson
and Prottey, 1976). The nature of the hydrophobic
portion of a surfactant may also impact on cell penetration, and in this regard, triglycerides are bulkier
than monoalkyl materials and, therefore, may reduce
surfactant cell interaction. Nonionic surfactants of
equivalent/similar hydrophobic character have also
been shown to exhibit wide differences in lytic effects,
implicating a role for the hydrophilic component in
dictating toxicity differences (Zaslavsky et al., 1978;
Tragner and Csordas, 1987). For example, nonionic
surfactants comprising hydrophilic segments made up
of polyoxyethylene (e.g., Brij and Solutol HS-15)
exhibit significantly less cellular toxicity compared
with a range of sugar-based surfactants (Shalel et al.,
2002; Soderlind et al., 2003), and the toxicity toward
an epithelial cell line of a series of commonly used
surfactants with similar C18 chain-length lipophilic
regions and only small differences in surface activity
(CMC values were similar) varied more than 100-fold
in the following rank order: Simulsol 4000 (least toxic)
, Cremophor EL , Tween 80 , Tween 20 , Solutol
HS-15 , TPGS 1500 (Maupas et al., 2011). It was
further proposed that this rank order reflected variation in the size of the hydrophilic group, with bulkier
polyoxyethylene chains providing a greater steric
385
386
Williams et al.
evidence of higher plasma concentrations in comparison with the other formulations, suggesting that
changes to drug clearance are possible, although in
this case, changes were specific to Cremophor EL
rather than Tween 80 (Gelderblom et al., 2001). van
Zuylen et al. (2001) have shown a similar increase in
paclitaxel concentrations after coadministration with
Cremophor EL and suggested that the mechanism
of enhanced exposure reflected the low volume of
distribution of Cremophor EL (;blood volume) and
subsequent entrapment of paclitaxel in surfactant
micelles in the plasma (van Zuylen et al., 2001). It is
not clear why this effect was not observed with Tween
80 (Fig. 31), although Tween 80 is cleared more quickly
than Cremophor (ten Tije et al., 2003) and Cremophor
EL has been suggested to impact on excretory processes such as P-glycoprotein (P-gp) efflux (see Section
XI). The existence of Cremophor micelles in the blood
after administration of Taxol may also lead to altered
pharmacokinetics for simultaneously administered
drugs (ten Tije et al., 2003) and, therefore, the
potential for drug interactions. Further descriptions
of the effect of Cremophor EL on the pharmacokinetics
of paclitaxel and other drugs are found in the following
references: Gelderblom et al. (2001), ten Tije et al.
(2003), and Buggins et al. (2007).
Beyond simple physicochemical mechanisms of solubilization (and therefore changes to pharmacokinetics
presumably via differences in free concentration), it
is increasingly apparent that surfactants (including
Cremophor) can affect the activity of metabolic cytochrome P450 enzymes and excretory drug transporters, thereby potentially changing clearance and
distribution processes directly (Bittner et al., 2003;
Wandel et al., 2003; Bravo Gonzlez et al., 2004;
Christiansen et al., 2011). For example, several drugs,
including many cytotoxic agents, are substrates for
efflux transporters such as P-gp, breast cancer resistance protein (BCRP), and multidrug resistance proteins (MRP1 and MRP2) (Schinkel et al., 1996; Borst
and Elferink, 2002; Leonard et al., 2003). Upregulation
of these transporters is evident in many tumor types,
leading to the phenomenon of multidrug resistance.
P-gp expression at the luminal side of the blood-brain
barrier (BBB) is also believed to limit drug access to
the brain and, therefore, the cytotoxity of some anticancer drugs that are P-gp substrates (van Asperen
et al., 1996; Kemper et al., 2003). Cremophor EL has
been reported to inhibit P-gp and may therefore
reverse the implications of this MDR phenotype
(Friche et al., 1990b; Schuurhuis et al., 1990; Woodcock
et al., 1990). Similar P-gp inhibition has been shown in
several cancer cell lines using Tween 80 (Friche et al.,
1990b), Solutol HS-15 (Coon et al., 1991), TPGS
(Dintaman and Silverman, 1999; Bogman et al.,
2003), and Pluronic surfactants (Yang et al., 2007).
Cremophor EL, Tween 20, Span 20, Brij 30, and
387
in conjunction with solubilization approaches, including cosolvency, pH adjustment, and lipid-based delivery systems. However, realizing the potential for
surfactant-induced hypersensitivity after parenteral
administration (e.g., Cremophor EL in commercial
paclitaxel formulations) and the possibility of surfactant effects on free concentration and transporter/
metabolic enzyme activity, care must be taken to
interpret correctly the pharmacokinetic and pharmacodynamic data obtained in the presence of surfactants
(especially after parenteral administration).
VIII. Cyclodextrins
A. Rationale for the Use of Cyclodextrins in the
Solubilization of Poorly Water-Soluble Drugs
Cyclodextrins (CDs) are macrocyclic oligosaccharides
consisting of a hydrophilic outer exterior and a hydrophobic inner cavity (Fig. 32). Drug molecules are
able to form dynamic inclusion complexes within this
cavity, and the higher solubility of the drug-CD complex relative to the solubility of drug alone increases
apparent solubility, often over several orders of magnitude. As a result, there has been widespread interest
in the use of CDs to address low solubility in both oral
and parenteral drug products (Loftsson and Brewster,
1996; Rajewski and Stella, 1996; Stella and Rajewski,
1997; Uekama et al., 1998; Davis and Brewster, 2004;
Brewster and Loftsson, 2007; Loftsson and Duchne,
2007). Examples of marketed formulations that use CD
complexation are listed in Table 21 and include oral
solid dosage forms (e.g., Omebeta, Betafarm) and liquid
dosage forms for both oral (Sporanox Oral Solution;
Janssen Pharmaceuticals) and parenteral (e.g., Vfend,
Pfizer) routes of administration.
Common CDs include those formed by six, seven, or
eight saccharide monomers, and these are classified as
a, b, or g CD, respectively. The most widely used CDs
in pharmaceutical preparations are based on b-CD
(i.e., CDs containing seven sugar moieties) (Fig. 32).
The broad utility of b-CD stems from the good
alignment between b-CD cavity size and the aromatic
scaffolds commonly encountered in poorly water-soluble
drugs. Since the upper limit of the solubility of a drugCD complex is that of the CD alone, the relatively poor
water solubility of unmodified CDs limits their widespread utility. Modified CDs, such as hydroxypropylb-CD (HP-b-CD) and sulfobutylether-b-CD (SBE-b-CD)
(Table 22), have therefore been introduced, the solubility of both being significantly higher than that of the
unmodified material and typically in excess of 0.5 g/ml
(see Table 22). The higher solubility of chemically
modified CDs also reduces the nephrotoxicity previously
associated with poorly water-soluble CDs (Brewster
et al., 1989; Thompson, 1997; Stella and He, 2008). This
improved toxicological profile of the modified CDs has
enhanced interest in the use of CDs in parenteral
388
Williams et al.
Fig. 32. The (A) chemical structure and (B) geometric configuration of a b-cyclodextrin ring. Adapted from Uekama et al. (2004).
with altered drug pharmacokinetics after i.v. administration of a drug-CD complex (Charman et al., 2006),
although this appears to be the exception rather than
the rule and only likely for drug molecules with CD
binding constants in excess of 1 105 M21 (Stella and
He, 2008).
The nature of the drug-CD complex dictates that
solubilization with CDs is molecularly specific and
driven by the relative fit of the drug molecule (or
a portion of the molecule) within the CD cavity. CD
approaches are therefore less generic than solubility
enhancement strategies such as micellar solubilization.
Nonetheless, CDs solubilize a wide variety of structurally distinct drug molecules, both neutral and ionized,
and may be used with other solubilization strategies,
such as pH adjustment.
Solid drug-CD complexes may also be isolated by, for
example, freeze-drying drug-CD solutions. Parenteral
drug-CD formulations that can be reconstituted before
use and oral formulations containing solid CD-drug
complexes are therefore possible. In such formulations,
rates of in vitro dissolution of the drug-CD complex
may be dramatically increased compared with uncomplexed drug due to the significant increases in
apparent solubility of the drug-CD complex. The
generation of an altered solid form of the drug also
provides additional mechanisms of dissolution enhancement via changes to solid-state properties.
TABLE 21
Commercially available cyclodextrin-containing formulations
Drug/Product
Route of Administration
HP-b-CD
HP-b-CD
SBE-b-CD
SBE-b-CD
b-CD
b-CD
a-CD
b-CD
389
Common Name
Aqueous Solubility
(mg/ml) (25C)
Alfadex
Betadex
Gammadex
Cavasol W6 HP (Wacker, Germany)
Cavasol W7 HP (Wacker, Germany)
Capitsol (CyDex Pharmaceuticals, USAd)
Cavasol W7 M (Wacker, Germany)
Ensuiko Sugar Refining Co. (Japan)
2/972
2/1135
2/1297
0.65/1199
0.65/1400
0.9/2163
1.8/1312
0.14/1459
14.5
1.85
23.2
.500
.600
.600
.600
.500
CD cavity. Changes in entropy (DS) are usually moderate and either negative or slightly positive Komiyama
and Bender, 1978; Harrison and Eftink, 1982; Inoue
et al., 1993). In contrast, the association of two nonpolar molecules in solution (or, for example, amphiphiles during micelle formation) is more commonly
associated with an increase in entropy as structured
water molecules are redistributed into free solution
(Frank and Evans, 1945). The more moderate changes
in entropy during drug-CD complexation have been
suggested to reflect a loss of rotational freedom on
complex formation that offsets the gain in entropy
during water redistribution. The free energy of complexation is therefore driven by the negative enthalpy
term rather than by an increase in entropy and provides an example of enthalpy-entropy compensation
(Inoue et al., 1993; Rekharsky and Inoue, 2000; Omar
et al., 2007; di Cagno et al., 2011). Ionic substituents
located on the exterior segment of some CDs, for
example, SBE-b-CD, may also interact with the drug
via ion-dipole interactions or via an ion pair if the
drug is oppositely charged. Drug interactions external
to the cavity may also play a role in dictating the
stoichiometry of drug-CD complexation (Okimoto
et al., 1996).
Drug binding affinity to a CD is described by the
equilibrium binding constant (K), also referred to as
the stability constant. The binding constant provides
a measure of the solubilizing potential of a particular
CD toward the drug of interest. For a 1:1 complex of
drug-CD, the binding constant K is defined by eq. 39,
where [Df] and [CDf] are the concentration of the free
drug and CD, respectively, and [D:CD] is the concentration of the formed complex:
K1:1
Df 1 CDf D : CD
K 1:1 5
D : CD
Df CDf
39
390
Williams et al.
40
K 1:1 S0
CDT
1 1 K 1:1 S0
41
K 1:1 S0
CDT 5 mCDT 1 S0
1 1 K 1:1 S0
42
K 1:1 S0
1 1 K 1:1 S0
43
m
S0 2 m
44
Other commonly used methods to determine drugCD binding constants include NMR spectroscopy, UV
spectroscopy, circular dichroism, potentiometry, microcalorimetry, freezing-point depression, HPLC/TLC,
membrane permeation techniques, and capillary electrophoresis. Spectroscopic techniques (e.g., NMR) have
proved useful in discerning drug-CD complex stoichiometry (Bettinetti et al., 1991; Piel et al., 1998; Miyake
et al., 1999b; Ribeiro et al., 2005a; di Cagno et al.,
2011). Provided the environmental factors likely to
affect solubility (e.g., pH and temperature) are tightly
controlled, different methods may generate highly
consistent results (Kurkov et al., 2011). However, in
some cases, higher-order complexes identified during
phase solubility studies have not been able to be verified by NMR experiments or UV spectroscopy. These
discrepancies may be attributed to the more dilute
conditions used in the NMR/UV spectroscopy studies,
in which there is a reduced likelihood of forming
higher-order complexes in comparison with the higher
concentration conditions in phase-solubility experiments (Loftsson et al., 2002; Magnusdottir et al.,
2002; Loftsson et al., 2005).
Phase-solubility profiles are classified according to
their shape (Higuchi and Connons, 1964), and vary
depending on the solubility and stoichiometry of the
complex (Fig. 33). Two main solubility profiles are
evident and are described as either A-type or B-type.
B-type profiles typically lead to limited increases in
drug solubility and are more commonly (but not exclusively) associated with nonsubstituted CDs (Szejtli,
1994; Brewster and Loftsson, 2007). BS-type profiles are
reflective of situations where complexation initially results in an increase in drug solubility, but the maximum
solubility of the complex in solution is soon reached (the
plateau phase in Fig. 33B). Further increases in CD
concentration result in precipitation of the complex,
391
392
Williams et al.
45
46
47
393
394
Williams et al.
48
49
Fig. 35. Total experimental aqueous flavopiridol solubilities in hydroxypropyl-b-cyclodextrin (HP-b-CD) solutions at different pH values.
Adapted from Li et al. (1998a).
395
396
Williams et al.
(Jarho et al., 1998). Water-soluble polymers (at low concentrations), therefore, offer a potentially synergistic
benefit for CD-mediated drug solubilization.
The mechanism by which water-soluble polymers
enhance drug solubilization in the presence of CDs is
not fully understood (polymers typically have little
intrinsic effect on drug solubility), although it has been
suggested that the polymers interact directly with the
drug-CD complex to form a ternary drug-CD-polymer
structures with enhanced solubilization capacity (Loftsson et al., 1994; Loftsson and Brewster, 1996; Messner
et al., 2010). In support of this contention, solid-state
analysis of vinpocetine-CD-polymer ternary complexes
reveals evidence of hydrogen bond interactions between the polymer and the drug-CD complex (Ribeiro
et al., 2003b). However, other interactions (such as van
der Waals or ion-dipole interactions) cannot be discounted (Ribeiro et al., 2005a). Indeed, Valero et al.
(2003) suggest that PVP is able to form ion-dipole interactions with naproxen sodium while the drug is
enclosed within the hydrophobic cavity of HP-b-CD, and
simultaneously to form hydrogen bonds with the CD.
Interestingly, in the latter example, the addition of PVP
did not enhance CD solubilization of naproxen, and
Smith et al. (2005) report that PVP is unable to enhance
the solubilization of carbamazepine by SBE-b-CD.
Enhancement of CD solubilization via the addition of
water-soluble polymers is therefore not universal.
Polymers may also stabilize drug-CD aggregates and
reduce the potential for deaggregation on dilution or
agitation (Loftsson et al., 2002; Messner et al., 2011b).
Thus, 0.5% carboxymethyl cellulose (a negatively
charged polymer) stabilizes hydrocortisoneHP-b-CD
aggregates (Messner et al., 2011a), although in this
case, the addition of 5% of a neutral (HPMC) or positively charged (hexadimethrine bromide) additive had
little effect on aggregate stability (Messner et al.,
2011a).
2. Cyclodextrins and Cosolvents. Cosolvents such as
short-chain alcohols (e.g., ethanol), low-molecularweight polyethylene glycols, and propylene glycol are
often used to enhance drug solubility (see Section VI)
and may also be used in combination with CDs.
However, cosolvent molecules compete with drug
molecules for the CD hydrophobic cavity and also
promote the solubility of the noncomplexed drug in free
solution (Loftsson et al., 1993). As such, drug-CD
binding may be reduced (van Stam et al., 1996; Miyake
et al., 1999b; Evans et al., 2000; Partyka et al., 2001).
Nonetheless, combinations of CDs with cosolvents may
lead to net increases in drug solubilization compared
with cosolvent or CD alone (Reer and Muller, 1993;
Yalkowsky, 1999; Li et al., 1999d; Nandi et al., 2003).
Consistent with this suggestion, the marketed itraconazole formulations (Sporanox IV and Oral Solution)
contain both CD and propylene glycol. Similarly, the
solubility of fluasterone in a 20% HP-b-CD solution is
397
398
Williams et al.
urine. The elimination half-lives of HP-b-CD and SBEb-CD are less than 2 h in humans (;114 min and ;84
min for HP-b-CD and SBE-b-CD, respectively), with
complete elimination within 6 to 12 h (Zhou et al.,
1998; Stella and He, 2008). The rate of clearance of
administered CDs may be lower under conditions of reduced glomerular filtration in patients suffering from
renal insufficiency (Irie and Uekama, 1997), potentially
leading to accumulation after repeated administration
(Stella and He, 2008). More detailed information on
maximum possible doses for commonly used CDs is
available in reviews by Brewster and Loftsson (2007)
and Stella and He (2008).
F. In Vivo Utility of Drug-Cyclodextrin Complexes
in Oral (Nonparenteral) Formulations
i.v. administration to dogs compared with a commercially available propylene glycolbased formulation
(Amidate, Abbott Laboratories) (McIntosh et al.,
2004). The potential for hemolysis after administration
of HP-b-CD and SBE-b-CD, therefore, appears to be
no greater than, and likely less than, many other
solubilization strategies.
The renal toxicity of CDs is highly linked to CD
solubility. Thus, i.v. administration of the relatively
poorly water-soluble b-CD to rats at ;0.9 g/kg dose
leads to significant renal toxicity and some irritation at
the site of administration (Frank et al., 1976; Irie and
Uekama, 1997; Thompson, 1997). The renal toxicity of
natural CDs follows the rank order b-CD (most toxic) .
a-CD . g-CD (Thompson, 1997), a trend consistent
with solubility where g-CD (most soluble) . a-CD .
b-CD (Irie and Uekama, 1997). The low aqueous solubility and subsequent nephrotoxicity of b-CD preclude
use in parenteral formulations. In contrast, modified
CDs are more soluble in water, show lower renal
toxicities, and are usually eliminated unchanged in the
Fig. 39. Cinnarizine plasma concentration in dogs after oral administration of 25 mg cinnarizine in either sulfobutylether-b-cyclodextrin
(SBE-b-CD) or hydroxypropyl-b-cyclodextrin (HP-b-CD) solutions, a cinnarizine aqueous suspension (pH 4.5), or capsules containing cinnarizine
with and without SBE-b-CD. Values are expressed as means (n 5 4) 6
SEM. Adapted from Jarvinen et al. (1995).
399
400
Williams et al.
Fig. 40. (A) Release profiles of ketoprofen in 900 ml of 0.1 N HCl and 0.1
N HCl containing either 25mg of sulfobutylether-b-cyclodextrin (SBEb-CD) or 25 mg of b-cyclodextrin (b-CD). (B) Effect of hot-melt extrusion
processing with either SBE-b-CD or b-CD on ketoprofen release in 900 ml
of 0.1 N HCl. Experiments carried out at 37 6 0.5C USP apparatus 2, 50
rpm. Values are expressed as means (n 5 6) 6 SD. Adapted from Fukuda
et al. (2008).
of the amorphous form and stabilize the supersaturated solutions that form on dissolution. Supersaturation stabilization likely reflects increases in apparent
drug solubility in the presence of CD and a reduction in
the degree of supersaturation relative to the solubility
of the stable crystal form. Alternatively, and in a
manner analogous to the use of polymers in solid
dispersions or lipid-based formulations (Brewster
et al., 2002; Chowdary and Srinivas, 2006; Cappello
et al., 2007; Lee et al., 2009; Warren et al., 2010; Anby
et al., 2012), CDs may stabilize supersaturation by
slowing/inhibiting nucleation or crystal growth (Brewster
et al., 2008a).
401
natural and chemically modified CDs has been extensively reviewed elsewhere (Irie and Uekama, 1997;
Thompson, 1997; Uekama et al., 1998; Stella and He,
2008), and in general, CDs are less toxic after oral
administration compared with i.v. administration since
oral bioavailability of CDs is low; natural a-CDs and
b-CDs are not substrates for salivary and pancreatic
amylases and are also resistant to acid hydrolysis in
the stomach. Conversely, g-CD is rapidly digested into
glucose and maltose by amylases in the GI tract (De
Bie et al., 1998). All CD varieties may be subject to
fermentation by microflora present in the large intestine (Flourie et al., 1993), although chemical substitution is thought to reduce the extent of breakdown
(Irie and Uekama, 1997).
The high molecular weight (usually .1000 Da) and
hydrophilicity of CDs limits membrane permeability;
therefore, absorption after oral administration is low
(Irie and Uekama, 1997; Stella and He, 2008). Indeed,
less than 1% of an orally administered dose of HPb-CD is absorbed in rats (Stevens, 1999), and similarly
low (0.53.3%) absorption of HP-b-CD has been reported in humans (Thompson, 1997; Brewster and
Loftsson, 2007). Much less oral safety data are available for SBE-bCD; however, absorption is likely to be
low (consistent with HP-b-CD), with most ingested CD
excreted via the feces (Thompson, 1997). Predictably,
more lipophilic CD derivatives, including randomly
methylated (RM) and dimethylated (DM) bCD derivatives, are absorbed to a greater extent, although oral
bioavailabilities remain relatively low. For example, in
rats, ;10% of DM-bCD (Szatmari and Vargay, 1988;
Thompson, 1997) and ;12% of RM-bCD (Antlsperger
and Schmid, 1996) are bioavailable after oral administration.
Cyclodextrins have been shown to complex with bile
salts that are present in the intestinal lumen (Tan and
Lindenbaum, 1991; Holm et al., 2011). Rats repeatedly
dosed orally with 5 g/kg HP-b-CD developed pancreatic
hypertrophy (and later, pancreatic neoplasia), and this
was attributed to bile salt-CD complexation in the
intestine and increased fecal excretion of bile salts, in
turn promoting the release of cholecystokinin, a peptide
with known mitogenic properties in rats (Gould and
Scott, 2005). However, as cholecystokinin shows no
mitogenic effects in humans and other species, the
effects of HP-b-CD on the pancreas may be specific to
the rat (Gould and Scott, 2005).
Similar to parenterally administered CDs, those that
enter the systemic circulation via the GI tract are
largely excreted through the kidneys. The combination
of low absorption and the relatively low systemic
toxicity of HP-b-CD and SBE-b-CD dictates that large
quantities may be tolerated after oral administration,
with doses of up to 8 g per day of HP-b-CD used in the
clinic (Gould and Scott, 2005; Loftsson and Brewster,
2010). No marketed products for oral administration at
402
Williams et al.
403
Fig. 41. The change in surface area obtained when solid particles exist in
the micron-size range (microparticle) and the nanometer-size range
(nanoparticles). Both microparticles and nanoparticles can be prepared
from top-down and bottom-up techniques. Adapted from Merisko-Liversidge and Liversidge (2008).
404
Williams et al.
TABLE 23
List of currently marketed medicines and those under development that contain nanosized drug
Drug
Brand Name
Technology
Rapamycin
Aprepitant
Fenofibrate
Megestrol
Fenofibrate
Paliperidone palmitate
Thymectacina
Rapamune (Wyeth)
Emend (Merck)
Tricor 145 (Abbott)
MegaceES (Par Pharmaceutical Companies)
Triglide (Sciele Pharma Inc)
Invega Sustenna (Janssen Pharmaceuticals)
Theralux (Celmed)
NanoCrystal
NanoCrystal
NanoCrystal
NanoCrystal
DissoCubes
NanoCrystal
NanoCrystal
Oral, tablet
Oral, capsule
Oral, tablet
Oral, liquid solution
Oral, tablet
i.v., sustained release injection
i.v.
significant (Fig. 41) and may lead to large improvements in dissolution rate compared with both unmodified drug powders and micronized drug. Indeed, in
some cases, dissolution is sufficiently fast as to be
practically instantaneous [e.g., .80% release within 2
min has been reported for nanocrystals of ibuprofen
(Plakkot et al., 2011) and indomethacin (Liu et al.,
2011; Niwa et al., 2011a)]. Figure 42 provides a recent
illustration of the effect of particle size reduction on
the dissolution of suspensions of itraconazole. Here,
micronization (to 5.5 mm) leads to a 2- to 3-fold increase
in dissolution rate, whereas further particle size
reduction to produce nanoscale particulates (350700
nm) elicits additional 3- to 5-fold increases in dissolution rate compared with the micronized product (and
therefore an overall ;14-fold increase in dissolution
compared with nonmicronized drug) (Sun et al., 2011).
Although increases in surface area are widely
acknowledged as the primary driver of increased dissolution for microparticulates and nanoparticulates, it
is also apparent that the improvements in dissolution
velocity may exceed that predicted simply on the basis
of available surface area. Under these circumstances,
changes to drug solubility (Cs), to the thickness of the
diffusional layer (h), and to particle shape may also
Cs
2sVm
5
C 2:303RTrr
50
405
406
Williams et al.
1=2
L
hH 5k 1=2
V
51
as this attenuates the increase in free energy associated with the creation of new particle surface and
prevents nanocrystal aggregation. Stabilizers are usually added before milling initiation, however, recent
studies suggest that the dynamic addition of stabilizers
during milling may further facilitate the milling process (Bhakay et al., 2011).
The NanoCrystal technology platform (Elan Drug
Technologies, Dublin, Ireland) is the most well developed pearl-milling method for particle size reduction, although it is available only through a contractual
agreement with Elan (recently merged with Alkermes,
Dublin, Ireland). This technology utilizes a patented
milling medium (PollyMill) consisting of small (,1
mm) highly cross-linked polystyrene beads (or
pearls), the design of which facilitates the grinding
process by maximizing the number of bead-drug
particle contact points (Merisko-Liversidge and Liversidge, 2011). The NanoCrystal technology is scaleable from small-scale milligram batches (with
application in early preclinical studies) to largescale batches (5001000 kg) that can be progressed
to clinical use and marketing. Marketed products that
use the NanoCrystal technology platform cover
a range of applications and are listed in Table 23.
Although the NanoCrystal technology has dominated pearl milling applications for some time, alternative pearl mill technologies have been developed de
novo (e.g., Dyno-Mill; Willy A. Bachofen, Basel,
Switzerland) (Jinno et al., 2006, 2008), and yet others
have been developed in-house based on modifying
existing milling equipment (Nekkanti et al., 2009;
Juhnke et al., 2010; Niwa et al., 2011b; Plakkot et al.,
2011). These new methods have not yet been used to
support the manufacture of a marketed product.
Early descriptions of pearl milling suggested that
long milling times (several days) may be required to
produce nanosized particles (Merisko-Liversidge et al.,
1996; Muller et al., 2001; Hu et al., 2004a). However, it
is apparent from the more recent literature that nanoscale particles may be achieved for some compounds
after milling for much shorter periods of minutes or
hours (Fig. 43) (Merisko-Liversidge and Liversidge,
2011). Longer milling times are likely required only
when low milling speeds are used or during the milling
of crystals that do not easily fragment (i.e., very hard
or very soft crystals). One concern surrounding the use
of pearl milling is the potential erosion of the milling
media leading to contamination of the final product.
The milling media must therefore be shown to withstand the milling process to avoid potential erosion and
product contamination (Merisko-Liversidge et al., 2003).
PolyMill, the milling medium used in the NanoCrystal
platform, is said to be entirely resistant to the milling
process (Merisko-Liversidge and Liversidge, 2011),
although final formulations for parenteral delivery are
routinely assessed for possible impurities.
407
Fig. 43. Particle size reduction during milling. The particle size reduction of naproxen is shown in the processing chamber of the media mill. With
increased milling time, the particle size distribution profile using laser light diffraction decreases dramatically (i.e., shifts to the left) and narrows. The
particle size distribution curves are as follows: (A) the initial particle size of naproxen before processing, (B) 15 min postprocessing, (C) 30 min
postprocessing, and (d) 60 min postprocessing in a media mill. The time required to process a poorly water-soluble compound is dependent on
properties of the molecule, properties of the chosen stabilizer systems, and various processing parameters. For naproxen stabilized with povidone,
a residence time of 60 min provides a nanosuspension with a mean particle size diameter (DMEAN) of 200 nm. Adapted from Merisko-Liversidge and
Liversidge (2011).
Most drug powders are applicable to dry- and wetmilling techniques. However, those with low glass transition or melting temperatures (typically below 100C)
show a tendency to deform plastically under stress
(rather than fracture) and are therefore at greater risk
408
Williams et al.
409
Fig. 44. Engineering breakable crystals with a combination of microprecipitation and homogenization. Crystal morphology of raw drug material is
modified to facilitate breakage into smaller nanoparticles. (A) Crystals of starting raw material are too large and hard to run efficiently through
a homogenizer. (B) The raw material is solubilized, filter sterilized, and precipitated to yield crystals of needle-like morphology, which are easily broken
during homogenization. (C) Homogenization yields nanoparticles suitable for parenteral injections. Reprinted by permission from Macmillan
Publishers Ltd: Nat Rev Drug Discov (3:785796), copyright (2004).
possible but may be eliminated by subsequent spraydrying; however, this may also (unintentionally)
yield amorphous drug particles (Rasenack and
Muller, 2002).
Supercritical fluids (SCFs) may be used as an
alternative to organic solvents in a number of pharmaceutical applications, including controlled crystallization. SCFs are typically gases at room temperature
and pressure, but they exist at temperature and
pressures above a critical point in a phase that is
neither gaseous nor liquid but shares properties of
both. SCFs therefore have the solvent properties of
liquids but behave in many other respects like gases
(Palakodaty and York, 1999; Pasquali et al., 2006).
SCFs are of particular interest to particle synthesis
methods as it is possible to fine-tune their solvent
properties via small changes in pressure and temperature (Phillips and Stella, 1993). The gaseous properties of SCFs also afford rapid and efficient mixing
(Chan and Kwok, 2011). Carbon dioxide (CO2) is the
most widely used SCF for pharmaceutical applications
because of its moderate (and therefore practical)
critical temperature (304.2 K, 31.1C) and pressure
(7.38 MPa; 1070 psi). Supercritical CO2 is also nontoxic, nonflammable, inexpensive, and can be recycled
during supercritical techniques (Bahrami and Ranjbarian, 2007).
SCFs have been used for a number of years as
a means of microparticle isolation via the rapid expansion of supercritical solution (RESS) process (Phillips and Stella, 1993; Rasenack and Muller, 2004;
Bahrami and Ranjbarian, 2007). In RESS, a drugcontaining SCF is heated and passed through a nozzle
into a precipitation chamber. Passage through the
nozzle results in a drop in pressure, supersaturation,
and ultimately drug crystallization (Phillips and
Stella, 1993; Pasquali et al., 2006). Although RESS is
410
Williams et al.
411
412
Williams et al.
TABLE 24
Selected particle size manipulation references describing effect on in vitro dissolution and in vivo performance
Median or Mean Particle Size
and Stabilizer/Dispersants Used
220 nm
HPC and docusate sodium
Suspension
260 nm
HPC and docusate sodium
D-Mannitol
Wet-milled tablet
169 nm
PVP K-15
292 nm
PVP K-30 and SLS
D-Mannitol
Suspension
280 nm
HPMC 1500 cPs and
PVP K-30, SDS
270 nm
HPMC (6 cPs), PVP K-30
and SLS
394 nm/393 nm/986 nm
Pluronic F68/Pluronic
F127/Tween 80
Particle size not described
Pluronic F108/Tween 80
and Soybean lecithin
Suspension
Spray-dried
suspension
Suspension
and spray-dried
suspension
Freeze-dried
nanosuspension
Suspension
316 nm
Pluronic F127
and SLS
Freeze-dried
nanosuspension
515 nm
Lecithin, poloxamer
188, HPMC and PVP.
D-Mannitol
580 nm
Pluronic F68
Freeze-dried
nanosuspension
compressed into
tablets
Freeze-dried
nanosuspension
in gelatin capsules
727 nm
SDS
Cefpodoxime proxetil
(Gao et al., 2010b)
Spironolactone (Langguth
et al., 2005)
245 nm
Poloxamer 188, HPMC
E3-LV and glycerol
400 nm
Dioctyl sulfosuccinate
Freeze-dried
nanosuspension
compressed into
tablets.
Spray-dried
nanosuspension
Revaprazan hydrochloride
(Li et al., 2011c)
562 nm
Poloxamer 188
Freeze-dried
nanosuspension
Spray-dried
suspension
Deacety mycoepoxydiene
(Wang et al., 2011a)
Diclofenac (Lai et al., 2009)
Bottom-up
Itraconazole (Mou
et al., 2011)
Suspension
Dissolution/Bioavailability Enhancement
413
Itraconazole (Sathigari
et al., 2011)
560820 nm (depending on
RESS conditions).
300 nm (RESSAS using
PVP solutions)
7.8 mm (RESSAS using
Tween 80 solutions)
940 nm (via SAS)
820 nm (via SAS followed
by mixing drug with
fast-flo lactose, 6% drug
loading)
860 nm (via SAS in Pluronic
F127 solution and mixing
drug with fast-flo lactose,
50% drug loading)
Dissolution/Bioavailability Enhancement
Harvested
particles
Harvested
particles
Cmax, maximal drug concentration; SLS, sodium lauryl sulfate; SAS, supercritical antisolvent; RESS, rapid expansion of supercritical solution; RESSAS, rapid expansion of
supercritical solution into aqueous solution; Tmax, time of maximal concentration.
414
Williams et al.
2010b; Gao et al., 2011c), and in some cases, nanosuspensions are better tolerated than cosolvent formulations (Gao et al., 2011c; Brazeau et al., 2011).
Further evidence for the favorable safety profile of
nanosuspensions may be drawn from the development
of several nanosuspension formulations for use in the
clinic, although, as described already, these are yet to
reach the market.
To avoid phlebitis and potentially more serious systemic side effects such as hypersensitivity and pulmonary embolism, nanosuspensions for i.v. use require
particles with diameters of less than 300400 nm
(Jacobs et al., 2000; Muller et al., 2001; Li and Zhao,
2007). A risk of local irritation remains, however, if
nanoparticles aggregate on contact with blood (Aramwit et al., 2006), and the i.v. compatibility of a nanosuspension should be assessed in a manner analogous
to that commonly used for buffered/cosolvent/micellar
formulations (see Sections IV, VI, and VII; and Yalkowsky
et al., 1998). A number of studies have also linked the
i.v. use of particulate formulations with hemodynamic
effects, including a reduction in arterial blood pressure
(Slack et al., 1981; Douglas et al., 1987; de Garavilla
et al., 1998; Sigfridsson et al., 2011a). Reducing the
rate of administration or use of histamine premedication may reduce the severity of these and other adverse
effects associated with parenteral use of nanosuspensions (de Garavilla et al., 1996, 1998; Aramwit et al.,
2006).
The reduced particle size of nanosuspension formulations provides the opportunity for parenteral formulations
to dissolve sufficiently rapidly in situ that the pharmacokinetic profiles of a formulated drug are indistinguishable from administration in a cosolvent or
cyclodextrin formulation. Indeed, many studies have
observed similar pharmacokinetics after administration
of a nanosuspension formulation compared with other
parenteral formulations (Fig. 48) (Clement et al., 1992;
Viernstein and Stumpf, 1992; Gassmann et al., 1994;
Sigfridsson et al., 2007). However, there is also a
significant body of evidence that has described differences in drug pharmacokinetics after i.v. administration of nanoparticle formulations. These are usually
manifest as a marked reduction in Cmax and an increase in mean residence times after nanoparticle
administration, presumably reflecting the incomplete
initial dissolution and altered distribution and elimination profiles of particulate drug as opposed to drug in
solution (White et al., 2003; Rabinow et al., 2007; Wang
et al., 2010b; Zakir et al., 2011; Gao et al., 2011c). For
example, the apparent plasma half-life of an itraconazole-cyclodextrin solution formulation (Sporanox) is
approximately 5 h after i.v. administration to rats but
increased to 15 h after administration of a crystalline
nanosuspension (Fig. 49) (Rabinow et al., 2007). The
nanosuspension was also associated with a reduction
in Cmax (Fig. 49), although at an equivalent dose, it
showed superior antifungal properties (Rabinow et al.,
2007). Perhaps unsurprisingly, effects on pharmacokinetics are highly dependent on the particle size of the
nanosuspension (Gao et al., 2008; Wang et al., 2010b),
and amorphous (rather than crystalline) nanosuspensions appeared to show smaller reductions in Cmax
Fig. 48. The mean plasma levels of AZ68 versus time after i.v.
administration of AZ68 in a PEG 400:DMA:water (1:1:1) solution, as an
amorphous nanosuspension, and as a crystalline nanosuspension to rats.
The administered dose was 5 mmol/kg in all cases. Values are expressed
as means (n 5 3). PEG, polyethylene glycol; DMA, dimethylacetamide.
Adapted from Sigfridsson et al. (2007).
415
416
Williams et al.
Carrier
HPMC
HPMC
HPMC
HPMC
HPMC
HPC/HPMC
HPMCAS
HPMCAS
PEG
PVP
PVP
PVPVA
PVPVA
417
Here we describe the various solid dispersion subtypes and the mechanisms of drug release that underpin solid dispersion utility. Common methods of
manufacture are also briefly described. Finally, the
manner in which polymers may be used to maintain
the stability of the amorphous state in solid dispersions
over prolonged storage periods is discussed.
A. Classification of Solid Dispersions
Solid dispersions can be classified according to the
molecular arrangement of the drug within the carrier
matrix and the properties of the carrier. In simple
terms, drug may be 1) partially dissolved with excess
drug suspended in the crystalline state, 2) partially
dissolved with excess drug suspended in the amorphous
state, or 3) completely dissolved (i.e., molecularly
dispersed). The solid dispersion matrix may be either
crystalline or amorphous. As such, there are six major
types of solid dispersions (although mixtures of amorphous and crystalline particles are also possible). These
are described in Table 26, and each arrangement is
shown schematically in Fig. 50 (van Drooge et al., 2006).
Solid dispersions containing amorphous drug particles
or molecularly dispersed drug are usually described as
amorphous solid dispersions and those based on an
amorphous carrier as glasses. Where drug is present as
a molecular dispersion, formulations are described as a
solid solution (where the carrier is crystalline) or a glass
solution (where the carrier is amorphous). Depending on
the drug loading in the solid dispersion relative to drug
solubility in the carrier, solid or glass solutions may be
supersaturated (see Section X.G.5).
The different classes of solid dispersion are described
in the following sections, and systems where the
carrier is crystalline (i.e., types 13 in Table 26) are
discussed first. The simplest of these systems comprise
crystalline drug suspended in a crystalline carrier and
are commonly referred to as eutectic mixtures. Eutectic
mixtures are combinations of crystalline components
(drug and a carrier) that are miscible in the molten
liquid state but show little or no miscibility in the solid
state (Sekiguchi and Obi, 1961; Chiou and Riegelman.,
1970). A eutectic system has a single chemical composition that becomes a solid at a lower temperature
than any other composition made with the same components. This unique composition is known as the
eutectic composition and the temperature as the eutectic temperature. Below this eutectic temperature, a
mixture of drug and carrier simultaneously crystallize
to form an intimate mixture of fine crystalline drug
particles within a crystalline carrier matrix. At all
other drug-carrier compositions (i.e., noneutectics), one
component preferentially solidifies during cooling until
the remaining concentrations in the liquid phase reach
the eutectic composition, at which point the remaining
drug and carrier (in the liquid phase) simultaneously
crystallize.
418
Williams et al.
TABLE 26
Classification of solid dispersion subtypes according to the physical form of the drug and the carrier
Type
1
2
3
4
5
6
a
Solid Dispersion
Drug
Carrier
Total No.
of Phases
Eutectic mixture
Solid amorphous
suspension
Solid solutiona
Crystalline particles
Amorphous particles
Crystalline
Crystalline
2
2
Stable
Unstable; crystallization risk
Molecularly dispersed
Crystalline
Glass suspension
Glass amorphous
suspension
Glass solution
Crystalline particles
Amorphous particles
Amorphous
Amorphous
2
2
Molecularly dispersed
Amorphous
May include continuous/discontinuous and substitutional/interstitial; see Leuner and Dressman (2000).
and Van den Mooter, 2009). Discontinuous solid solutions are therefore the more relevant pharmaceutical
system (Chiou and Riegelman., 1971). In regions of the
phase diagram where drug and carrier are miscible
(i.e., where solid solutions are formed), drug is mixed
within the carrier at a molecular level, and drug in this
form exhibits the maximum attainable surface area for
hydration (right hand panel; Fig. 50). The rate of drug
release from solid solutions is faster than that from
equivalent multiphase systems containing suspended
solid drug particles, regardless of whether the suspended material is amorphous (e.g., type 2) or crystalline (e.g., type 1).
Solid dispersions containing drug dispersed in an
amorphous carrier (i.e., types 46) may be classified
in a similar fashion to those where the carrier is
crystalline, although in this case the solid dispersions
are commonly referred to as glasses to reflect the noncrystalline character of the carrier. Thus, type 4 systems, or glass suspensions, are analogous to eutectics
and contain crystalline drug suspended in an amorphous carrier; type 5 systems, or amorphous glass
suspensions, are related but contain amorphous drug
particles suspended in an amorphous drug carrier; type
6 solid dispersions or glass solutions are analogous to
solid solutions and contain a molecular dispersion of
drug in an amorphous carrier. The use of the term
Fig. 50. Schematic depicting the three different molecular arrangements of drug molecules within a solid dispersion. The panels illustrate the major
arrangement of drug in each solid dispersion subtype (Table 26). In types 13, the carrier is crystalline; in types 46, the carrier is amorphous. Note
that some molecularly dispersed drug will be present in each type (reflecting the solid solubility of the drug).
419
420
Williams et al.
an increase in the dissolution rate resulting from a decrease in the size of dissolving drug particles is evident.
The use of highly water-soluble carrier materials
also promotes rapid influx of hydration media into
the solid dispersion matrix, resulting in an increase
in wetting. To take advantage of this effect, 1stgeneration solid dispersions used low-molecularweight, highly water-soluble carriers such as urea
(Goldberg et al., 1966a,c), aliphatic short-chain carboxylic acids such as citric and succinic acid (Goldberg
et al., 1966b; Summers and Enever, 1976), and sugars
such as sucrose, trehalose, sorbitol, and mannitol
(Allen et al., 1978; Arias et al., 1995; Okonogi et al.,
1997; Valizadeh et al., 2004). In one of the earliest
studies, Sekiguchi and Obi (1961) described an increase in the rate of dissolution of sulfathiazole when
the drug was fused with urea and then crash-cooled to
form a solid dispersion (when compared with a physical
mixture of drug and urea). The improvement in dissolution rate was attributed to the rapid dissolution of
the eutectic and liberation of drug in the form of a
microcrystalline dispersion and was ultimately shown
to improve oral absorption in human subjects.
A growing awareness of the potential benefits associated with the use of polymeric or surfactant-based
solid dispersions and the relatively high melting temperatures of many sugars (which complicates solid
dispersion manufacture via melting/fusion techniques)
(Leuner and Dressman, 2000) have resulted in a general decline in the use of 1st-generation carriers.
Second-generation polymeric carriersincluding PVP,
PEG, polymethacrylates, and HPMC (and its derivatives)
and 3rd-generation carriers including self-emulsifying
and surfactant-based excipients are now considerably
more common (Serajuddin, 1999; Vasconcelos et al.,
2007).
Polyethylene glycol (PEG) was the first widely explored 2nd-generation polymeric excipient and formed
the basis for the first commercial solid dispersion product (Gris-PEG, Pedinol Pharmacal Inc., Farmingdale,
NY). PEG has a low melting temperature (the melting
point of PEG 20 000 is between 60 and 63C) and can
be readily fused with drug by quench-cooling a melt
or via hot-melt extrusion (Craig, 1990; Leuner and
Dressman, 2000). PEG-based solid dispersions enhance
the dissolution of many low solubility compounds (Law
et al., 1992, 2001; Saers and Craig, 1992; Save and
Venkitachalam, 1992; Lloyd et al., 1997; Van den
Mooter et al., 1998; Verheyen et al., 2002; Valizadeh
et al., 2004; Baird and Taylor, 2011), however, benefits
over and above simple physical mixtures of drug and
polymer are not always apparent. For example, PEG
6000based solid dispersions increase the dissolution
rate of diazepam and temazepam compared with
crystalline drug, however, the rate of dissolution is
no better than that of equivalent PEG-drug physical
mixtures (Verheyen et al., 2002). Similarly, physical
421
energy difference between amorphous and crystalline drug and reduce the solubility advantage compared with theoretical predictions (Murdande et al.,
2010a,b).
Despite the potential for errors in the estimation of
solubility, significant solubility advantages remain for
noncrystalline drug, and these are manifest through
increases in dissolution rate and, ultimately, oral
bioavailability. This solubility advantage is the basis
for much of the utility of amorphous solid dispersions.
3. Maintenance of Supersaturation after Drug
Dissolution. Drug dissolution from dosage forms containing high-energy polymorphs or amorphous solids
typically leads to the attainment of drug concentrations in solution that are supersaturated with respect
to the saturated solubility of the stable crystal form.
The attainment of supersaturation is beneficial in
providing a greater concentration of dissolved drug and
in generating drug solutions with increased thermodynamic activity. The induction of supersaturation in
solution has been referred to as a concentration
spring and may occur under many conditions, including dissolution of amorphous drug, but also the
dispersion or digestion of lipid-based dosage forms,
the dissolution of salts of weak acids or bases, and after
the gastric emptying of basic drugs that are soluble in
acidic gastric fluid, but less soluble in the intestine
(Fig. 51) (Guzmn et al., 2004; Kostewicz et al., 2004;
Brouwers et al., 2009; Warren et al., 2010; Porter et al.,
2011; Shono et al., 2011; Anby et al., 2012).
Supersaturated solutions provide an advantage with
respect to drug absorption but are unstable and at risk
of precipitation. The rate of drug precipitation from
supersaturated solutions can be markedly slowed by
the presence of materials (including polymers) that inhibit crystal nucleation or slow crystal growth (Vandecruys et al., 2007; Brouwers et al., 2009; Warren et al.,
2010). Consistent with the spring analogy for supersaturation induction, the reduction in the rate of drug
precipitation from supersaturated solutions has been
referred to as a parachute and the combined mechanism of supersaturation generation and precipitation
inhibition as a spring and parachute (Guzmn et al.,
2004, 2007) (Fig. 51).
The potential for the polymers that are used to
fabricate solid dispersions also to inhibit drug precipitation from supersaturated solutions post dissolution is illustrated in Fig. 52A. In this example, three
tacrolimus solid dispersions were manufactured using
different carrier polymers. In each case, the formulations led to consistent (and rapid) initial rates of
dissolution (Yamashita et al., 2003). However significant differences in the ability of the polymers to maintain supersaturation were subsequently evident. HPMC
prevented recrystallization more effectively compared
with PVP and PEG 6000, and HPMC-based solid dispersions were later shown to provide for a 10-fold
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Williams et al.
increase in Cmax and AUC in dogs compared with administration of crystalline drug (Fig. 52B) (Yamashita
et al., 2003). HPMC plays a similar role in enhancing
the bioavailability of the poorly water-soluble weak base
itraconazole after oral administration of the Sporanox
formulation. In this case, drug dissolution under acidic
conditions reflective of the gastric environment is unsurprisingly rapid, but it is widely believed that the
robust bioavailability (;55%) of itraconazole after administration of Sporanox is due, at least in part, to the
ability of HPMC to prevent drug precipitation as dissolved drug leaves the acidic stomach and enters the
less favorable solubilizing conditions (for a weak base)
in the intestine (Jung et al., 1999; Six et al., 2005;
Augustijns and Brewster, 2012).
Similar behavior with respect to the capacity for
polymers to stabilize supersaturated drug has been
attributed to HPMCAS-based solid dispersions (Friesen
et al., 2008; Kennedy et al., 2008; Konno et al., 2008;
Curatolo et al., 2009; Murdande et al., 2011a). HPMCAS
is unusual compared with many of the most commonly
used polymers in oral formulations in that it shows
some degree of amphiphilicity, with hydrophobic
domains available for interaction with poorly watersoluble drugs and hydrophilic domains available
423
maximize the performance of the formulation (Augustijns and Brewster, 2012). Support for this contention
is provided by the data described by Six et al. (2005),
where slower rates of itraconazole release from HPMC
solid dispersions led to better in vivo performance in
human subjects compared with solid dispersions prepared using Eudragit E100 or mixtures of Eudragit
E100 and PVPVA 64 that showed faster in vitro rates
of dissolution. Solid dispersions of itraconazole prepared using enteric polymers (Eudragit L100-55 and
Carbopol 947P) to reduce drug release in the stomach
also showed enhanced performance compared with
HPMC (Miller et al., 2008; DiNunzio et al., 2010a).
Specifically, the enteric polymers reduced the quantity
of the dose that was solubilized in the acidic gastric
content and, therefore, reduced the solubilized bolus
that was introduced into the higher pH environment of
the intestine on gastric emptying. This in turn lowered
the degree of supersaturation that was invoked by the
increase in pH in the small intestine and the drop in
itraconazole solubility (Miller et al., 2008; DiNunzio
et al., 2010a). Subsequent bioavailability studies using
an itraconazole-Eudragit L100-55 enteric solid dispersion and a conventional HPMC solid dispersion in rats
revealed that the enteric matrix resulted in prolonged
and improved exposure (although the results were
highly variable) (Miller et al., 2008). Similarly,
although the release of a sparingly soluble glycogen
phosphorylase inhibitor was faster from solid dispersions formed with cellulose acetate phthalate (CAP)
compared with HPMCAS, the highly supersaturated
drug solutions that resulted from dissolution of the
CAP formulation could not be maintained, and the
slower releasing HPMCAS solid dispersion showed
improved overall performance (Crew et al., 2007).
b. Mechanisms by which Polymers Maintain Supersaturation in Solution. Precipitation from a supersaturated solution follows two critical steps: the formation
of particle nuclei and subsequent particle growth
(Macie and Grant, 1986; Gebauer et al., 2008; Lindfors
et al., 2008). Nucleation and particle/crystal growth in
solution is in large part controlled by the same drivers
of phase-separation or crystallization that occur in the
solid state. These include decreases in molecular
mobility (mediated via changes in viscosity and molecular interactions between drug and carrier) and direct
inhibition of nucleation and crystal growth (see Section
X.F). However, differences in the nature of the matrix
in which precipitation or crystallization occurs (i.e., in
solution or within the polymer) result in important
differences in assessment and stabilization.
One example of a means of reducing the potential for
precipitation from solution is via an increase in drug
solubility in solution as this will reduce the level of
supersaturation and the thermodynamic drivers of
drug precipitation. Supersaturation stabilization via
an increase in solubilization is largely applicable to
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Williams et al.
425
subsequently removed, filtered, or centrifuged and dissolved drug concentrations determined by UV spectrophotometry (Vandecruys et al., 2007; Curatolo et al.,
2009). Continuous monitoring of turbidity via nephelometry can also be used to track precipitation in real
time (Warren et al., 2010). The receptor medium used
is usually water or a buffered solution, although more
complex screening methods may be performed using
biorelevant media such as simulated gastric or intestinal fluids. Bevernage and coworkers recently compared
the ability of polymeric excipients to prevent precipitation from supersaturated solutions using simple
buffers, simulated intestinal fluids (fasted/fed), and
aspirated human intestinal fluid. In this case, the
capacity of the polymer to reduce precipitation was
diminished when studies were run in aspirated intestinal fluid (Bevernage et al., 2011).
Of the carriers that are commonly used in the
manufacture of solid dispersions, HPMC has been
shown to inhibit precipitation for a number of different
compounds and is arguably the least compound-specific
precipitation inhibitor (Warren et al., 2010). Nonetheless, precipitation inhibition by HPMC remains variable. For example, in an examination of the ability
of HPMC to inhibit drug precipitation from supersaturated solutions of a series of 24 compounds, precipitation inhibition was evident for only 12 compounds,
whereas for 12 others, little evidence of stabilization
was apparent (Vandecruys et al., 2007). Variability in
the ability of polymers to inhibit precipitation has also
been shown with polymers, including PVP and HPMCAS,
where under some circumstances precipitation inhibition may be highly effective (some evidence for the
benefits of HPMCAS are shown in Fig. 53), but under
other conditions, effects may be limited (Warren et al.,
2010).
Difficulties have also emerged in translating the
data obtained from screening methods using polymer
solutions to successful precipitation inhibition during
the dissolution of a manufactured dosage form. For
example, vitamin E TPGS 1000 (D-a-tocopheryl polyethylene glycol succinate) and PVPVA-64 effectively
inhibit the precipitation of itraconazole from supersaturated solutions in vitro using solvent-shift methods
(Janssens et al., 2008). In contrast, dissolution tests
conducted using solid dispersion formulations containing the same components resulted in drug recrystallization from supersaturated solutions after ;1 h. The
authors attributed the lack of inhibition of precipitation during the dissolution tests to the presence of seed
crystals in the solid dispersion matrix. Contradictory
results have also been reported for Eudragit 4155F and
PVP (Abu-Diak et al., 2011). In the latter case, PVP
maintained the stability of supersaturated solutions of
celecoxib formed via solvent shift more effectively than
Eudragit 4155F, whereas the reverse was true on
examination of drug dissolution patterns from solid
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Williams et al.
dispersions containing the same polymers. The improved performance of Eudragit 4155F in the dissolution experiments was ascribed to superior solubilization
and wetting properties (Abu-Diak et al., 2011).
The variability observed in the performance of
polymeric precipitation inhibitors (PPI) currently precludes a priori selection of appropriate inhibitors
without experimental testing and is compounded by
a lack of understanding of the mechanisms by which
PPIs act (Warren et al., 2010). This is further complicated by the realization that the most effective
polymers must enhance dissolution and maintain
supersaturation in solution and simultaneously maintain drug stability in the solid state in the formulation.
Screening for polymer carriers on the basis of their
ability to support supersaturation should therefore be
used as only one indicator of an appropriate carrier
(Yamashita et al., 2011).
C. Recent Examples of Bioavailability Enhancement
Using Solid Dispersions
Solid dispersions containing drug in the amorphous
form (i.e., types 2 and 3 and types 5 and 6, Fig. 50)
commonly result in faster rates of drug dissolution
compared with crystalline drug, drug-carrier physical
mixtures, and solid dispersions containing drug in the
crystalline form (i.e., types 1 and 4, Fig. 50). Most
recent investigations of the utility of solid dispersion
formulations have therefore focused on the development
of formulations containing drug in the amorphous form
(Newman et al., 2012). Law et al. (2004) have described
PEG 8000based solid dispersions containing amorphous ritonavir and provide evidence of significantly
faster dissolution rates compared with simple physical
mixtures (Fig. 54A) and marked increases in oral
bioavailability in beagle dogs compared with crystalline drug (Fig. 54B). Increases in drug load, however,
led to phase-separation of drug within the crystalline
PEG carrier, giving rise to decreased dissolution rates
and in vivo exposure (Law et al., 2004). Amorphous
solid dispersions have also been explored as a potential
formulation strategy for AMG 517, a poorly soluble
vanilloid receptor-1 antagonist (Kennedy et al., 2008).
Originally formulated as a drug suspension in 10%
Pluronic F108 (OraPlus), AMG 517 showed good oral
bioavailability during preclinical evaluation, although
it was later revealed that this was due to AMG 517
forming a cocrystal with sorbic acid, the preservative in
OraPlus (Bak et al., 2008) (see Section V.B.5). Unfortunately, the OraPlus formulation was unable to
achieve sufficient exposure using higher AMG 517
doses intended for human clinical trials (Kennedy
et al., 2008). Solid dispersions were therefore prepared
by spray-drying solutions of drug and HPMC E5 (a low
viscosity grade of HPMC) or HPMCAS, both approaches resulting in isolation of amorphous drug.
Although improvements in dissolution were evident for
Fig. 54. (A) In vitro dissolution in 0.1 N HCl of physical mixture (PM)
containing crystalline ritonavirPEG at 10:90 and amorphous ritonavir
in PEG solid dispersions (SD) at various drug:polymer ratios. Dissolution
was determined using the USP I method (50 rpm, 37C). Values are
expressed as means (n $ 2). (B) plasma concentrationtime profiles of
ritonavir after a single oral dose of ritonavir formulations to beagle dogs.
Ritonavir was administered in the crystalline form or as the amorphous
form in PEG solid dispersions at various drug:polymer ratios. Values are
expressed as means (n 5 7). Adapted from Law et al. (2004).
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Williams et al.
The critical processes that occur during carriercontrolled drug release have been described in detail
by Craig (2002). In situations where polymer dissolution is fast, drug is in contact with the polymer only
transiently and is liberated into the bulk medium as
a fine molecular dispersion. Increasing carrier viscosity
leads to slower drug release, and an inverse relationship between drug release rate and carrier viscosity
has been described for solid dispersions based on PEG
(Dubois and Ford, 1985; Craig and Newton, 1992;
Shah et al., 1995), PVP (Bansal et al., 2007), HPMC
(Karavas et al., 2001, 2007; Tajarobi et al., 2011) and
Eudragit (Miller et al., 2008; DiNunzio et al., 2010b;
Abu-Diak et al., 2011) High-molecular-weight PVP and
HPMC provide additional barriers to dissolution via
the formation of viscous gels that restrict the rate of
water ingress and egress from the matrix (Leuner and
Dressman, 2000; Karavas et al., 2001, 2007). This is to
some extent analogous to carrier-dependent release of
drug from hydrophilic matrix tablets, albeit in the
latter case, the rate of drug release is intended to occur
much more slowly.
In addition to increases in dissolution, polymeric
carriers require properties that enable the stabilization of the high-energy amorphous form. The ideal
polymer properties for amorphous stabilization (highmolecular-weight, high-viscosity, nonhygroscopic) are
largely contradictory to those that promote rapid release. Polymer selection is therefore a tradeoff between
properties, including release rate and amorphous drug
stabilization (Janssens and Van den Mooter, 2009).
Drug-release profiles also change with increasing
drug-carrier ratio, and several studies have shown a
reduction in drug dissolution rate from solid dispersion
with increasing drug-carrier ratios (Corrigan, 1986;
Veiga et al., 1993; Kapsi and Ayres, 2001; Verreck
et al., 2003b; Law et al., 2004; Karavas et al., 2005;
Janssens et al., 2008; Konno et al., 2008; Lakshman
et al., 2008; Abu-Diak et al., 2011; Alonzo et al., 2011;
Dontireddy and Crean, 2011; Ghosh et al., 2011; Han
et al., 2011; Khan et al., 2011) with one example reproduced in Fig. 55 (Simonelli et al., 1976). The decrease in dissolution is usually attributed to a
reduction in the quantity of drug in the molecularly
dispersed form since increasing drug load reduces the
intermolecular distance between drug molecules and
the quantity of stabilizing polymer, both of which favor
phase separation of amorphous/crystalline particulate
drug in the carrier (Vasanthavada et al., 2005; Qian
et al., 2010a).
At high drug-carrier ratios, the reduction in the
relative quantity of polymer present may also lead to
a decrease in drug wetting and the potential for
incongruent release of drug and carrier, with the latter
resulting in the formation of a carrier-depleted, drugrich solid phase that is at increasing risk of phase
separation or crystallization (Higuchi et al., 1965a;
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Williams et al.
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Williams et al.
433
52
Fig. 57. Plot of glass transition temperature (Tg) versus weight percent
of PVP for indomethacin-PVP coprecipitates. The symbols represent data
points, and the solid line represents the fit to the Gordon-Taylor equation
(eq. 52). Adapted from Yoshioka et al. (1995).
r 1 Tg1
r 2 Tg2
53
434
Williams et al.
435
molecular mobility gave a better indication of crystallization tendency. Others have also suggested that
increases in configurational entropy may be used to
provide an indication of increased stability of amorphous materials (Zhou et al., 2008; Graeser et al., 2009;
Baird and Taylor, 2012). In contrast, Johari and
Shanker (2010) question the use of thermodynamic
descriptors (such as heat capacity and melting enthalpy) to predict the kinetic stability of amorphous
solids. This is described in more detail in Section X.G.3.
1. Drug-Polymer Intermolecular Association. Drugpolymer interactions, such as hydrogen bonding, decrease the ease of recrystallization by reducing drug
mobility and by limiting the drug-drug molecular interactions that precede nucleation and crystallization
(Khougaz and Clas, 2000; Weuts et al., 2003; Miyazaki
et al., 2006; Bhugra and Pikal, 2008). Hydrogen bonds
between indomethacin and PVP, for example, limit
indomethacin crystallization by preventing the formation of drug-drug dimers through adjacent carboxylic acid groupsan interaction likely to be the initial
step in indomethacin crystallization (Taylor and
Zografi, 1997). Suppression of indomethacin crystallization in the presence of PVP has also been reported
at polymer levels (5%) that are too low to have a
significant impact on Tg, suggesting other mechanisms of stabilization (Yoshioka et al., 1995; Matsumoto and Zografi, 1999). PVP hydrogen bonds with
many drug compounds in solid dispersions, and these
provide the opportunity for increases in physical
stability (Van den Mooter et al., 1998; Matsumoto and
Zografi, 1999; Tantishaiyakul et al., 1999; Damian
et al., 2002; Weuts et al., 2003; Jun et al., 2005; Shinde
et al., 2008; Lima et al., 2011). PVP has two functional
groups (5N- and C5O) with the capacity to accept
hydrogen bonds, although steric hindrance around the
nitrogen generally favors intermolecular hydrogen
bonding via the carbonyl group (Van den Mooter et al.,
1998). Drug-polymer hydrogen bonding has also been
shown for several other drug-polymer combinations, for
example, carbamazepine-PEG 4000/6000 (Doshi et al.,
1997), benzidazole-PEG 6000 (Lima et al., 2011),
cefuroxime-HPMC (Jun et al., 2005), and NVS981HPMC phthalate (Ghosh et al., 2011). The absence of
a drug-polymer intermolecular interaction within
a solid dispersion, however, does not necessarily
preclude the ability of a polymer to stabilize the
amorphous form (Van den Mooter et al., 2001; Caron
et al., 2010). The extent to which drug and polymer
interact also determines the level of mixing and,
therefore, miscibility. The importance of miscibility to
stability in solid dispersions is described in more
detail in Section X.G.5.
2. Inhibition of Crystal Nucleation. The potential
for polymers to stabilize amorphous solid dispersions
via direct inhibition of nucleation is well described
(Konno and Taylor, 2006; Marsac et al., 2006b; Caron
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Williams et al.
2 DGa 1 DGp
kT
54
437
DHrelax
DH
55
59
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Williams et al.
Tg
Tm
60
439
greater crystallization tendenciesa property attributed to the ease of formation of crystal nuclei during
cooling of drug melts. Class I compounds (i.e., those
least likely to form amorphous material) included
tolfenamic acid, griseofulvin, carbamazepine, and tolbutamide. Class II included acetaminophen, celecoxib,
nifedipine, and cinnarizine; class III (i.e., those with
a higher glass-forming potential and most stable in the
amorphous form) included fenofibrate, felodipine, itraconazole, ritonavir, and indomethacin (Baird et al.,
2010). Mahlin et al. (2011) used in silico techniques to
predict glass-forming potential based on molecular
structure, and consistent with the data described by
Baird et al. (2010), suggest that larger molecules with
larger numbers of rotational bonds and limited molecular symmetry show good glass-forming potential.
4. Limitations to the Use of Thermal Analysis to
Estimate Molecular Mobility. Although estimations
of molecular relaxation using changes in heat capacity
remain common, in large part because of the wide
availability of thermal analytical techniques, Johari
and Shanker (2010) have highlighted a number of
potential shortcomings of correlating measured or
calculated thermodynamic quantities (such as heat
capacity of a glass) with the molecular mobility of an
amorphous pharmaceutical to estimate differences in
stability. In these studies, relaxation dynamics in
acetaminophen glasses were instead obtained using
dielectic relaxation spectroscopy (Johari et al., 2005)
and the data compared with previous studies using
calorimetry (Zhou et al., 2002). In short, the data
obtained using thermal analysis appeared to underestimate relaxation. The authors suggest that this
finding reflected errors in estimation of configurational
entropy from specific heat data since entropy originating from nonconfigurational sources may contribute
significantly to heat-capacity changes on varying
temperature but does not appear to have a role in
structural relaxation (Johari et al., 2005). Dielectric
relaxation spectroscopy may therefore represent a more
accurate means of assessment of molecular mobility,
although some limitations for pharmaceutical applications are apparent (Craig, 1992). Specifically, in their
most preferred configuration, dielectric spectroscopy
measurements are conducted using a sealed cell in
which the sample is melted (Alie et al., 2004; Johari
et al., 2005; Adrjanowicz et al., 2010a; Dantuluri et al.,
2011). In contrast, pharmaceutical scientists are
usually interested in monitoring stability over the
projected pharmaceutical shelf-life and in samples that
have been subjected to different humidity and temperature conditions. This requires the use of a parallel
plate method (Adrjanowicz et al., 2010a; Grzybowska
et al., 2010); however, this may introduce additional
experimental error, including the entrapment of
varying amounts of air and moisture (the dielectric
constants of air and water are markedly different from
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Williams et al.
predictive of miscibility at lower (storage) temperatures (Qi and Craig, 2010; Qian et al., 2010a,b; Baird
and Taylor, 2012). Similarly, the lack of crystalline
peaks in x-ray diffraction data (i.e., the presence of the
characteristic amorphous halo) provides evidence of
amorphous content but little additional information as
to miscibility of the amorphous drug with the polymer
(i.e., the degree of molecular dispersion).
The limitations of DSC and XRPD in assessing solid
dispersion physical stability were recently highlighted
by Qian et al. (2010b), who used hot-melt extrusion to
prepare PVPVA solid dispersions of an unnamed experimental compound, using either a low (50 rpm) or
high (225 rpm) extruder screw speed. On initial assessment, batches produced using either method had
a single and equivalent Tg (88C). XRPD assessments
were also similar, and both methods of characterization
suggested that variation in screw speed had little effect
on the properties of the solid dispersion. In contrast,
repeat testing after 2 months revealed that crystallization had occurred in the batch produced using the slower
screw speed, whereas the batch prepared using the high
screw speed was stable. Confocal Raman microscopy
was subsequently used to chemically map samples of the
two solid dispersions. Significant differences in homogeneity were obtained (Fig. 59), with the least stable solid
dispersion (left) showing regions rich in amorphous drug
(red areas in Fig. 59). These data provide a good
example of the potential advantage of characterization
methods beyond conventional DSC and XRPD, in
particular, spatially specific spectroscopic methods, to
assess the homogeneity of mixing in amorphous solid
dispersions (Breitenbach et al., 1999; Qian et al., 2010b).
Fig. 59. Representative compositional Raman images of two experimental solid dispersions prepared by hot melt extrusion (HME 1 and HME 2,
respectively). The red regions depict higher local concentration of drug in the formulation (an undisclosed compound). The size of each Raman map is
800 mm 800 mm and 1600 (40 40). Raman spectra were collected to construct each image. HME 1 5 slow extruder screw speed (50 rpm); HME 2 5
fast extruder screw speed (225 rpm). Reprinted from Qian F, Huang J, Zhu Q, Haddadin R, Gawel J, Garmise R, and Hussain M (2010b) Is a distinctive
single Tg a reliable indicator for the homogeneity of amorphous solid dispersion? Int J Pharm 395:232235, with permission from Elsevier.
The Flory-Huggins equation for mixing of two polymers (eq. 62) (Flory, 1953) is shown below and is an
extension of the Gibbs free-energy change on mixing
(eq. 61):
DGmix 5 RT
f
fB
lnfA 1
lnfB 1 x fA fB 62
rA
rB
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Fig. 60. Nanometer homogeneity in various drug-polymer mixtures is shown with phase maps recorded with tapping-mode atomic-force microscopy on
fracture surfaces of the blank excipients (upper panels, AE) and corresponding combinations with a neurokinin 1 (NK1) receptor antagonist (middle
panels, FJ) and also with an inhibitor of cholesterylester transfer protein (CETP) (bottom panels, KO). The numbers visible in the image rows (FJ
and KO) refer to the number of imaged regions across the sample showing comparable surface morphology to that illustrated in the images above
relative to the total number of regions imaged. The scale bar is 1 mm in length. Reprinted from Lauer et al. (2011), Copyright 2011, with permission
from Springer.
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Williams et al.
Fig. 61. Schematic depicting (A) the effect of increasing fA (the volume
fraction of component (A) on the free energy of mixing (Gmix) at
a constant temperature, (B) miscibility boundaries as a function of
temperature and increasing fA. The green curve in (A) is calculated using
the Flory-Huggins interaction parameter x and eq. 62. The free-energy
minima are highlighted by the letter x. Taking the first derivative of eq.
62 and setting Gmix equal to zero allow the phase boundary curve in (B)
to be derived, and by taking the second derivative of eq. 62, it is possible
to derive the spinodal curve. The second derivative is equal to zero at the
spinodal points on the green curve in (A) (i.e., the letter y). Mixtures that
lie above the phase boundary are miscible and stable. Mixtures that lie
inside the phase boundary line but outside the spinodal curve are
metastable. Mixtures that lie inside the spinodal curve (the spinodal
region) are unstable.
predictions of high miscibility, at risk of phase separation. The limitations of the Flory-Huggins model
in this example were ascribed to an inability to account
for specific saturable interactions (e.g., drug-polymer
H-bonds) and the fact that the interaction parameter
was based on mixing data at high temperatures (i.e.,
near the melting temperature of the drug) where miscibility was favored (eq. 62) (Paudel et al., 2010).
Since attractive intermolecular interactions between
drug and polymer provide a driver for enhanced miscibility, several spectroscopic techniques, including infrared, Raman, and NMR spectroscopy, have been used
to probe the presence of drug-polymer interactions in
solid dispersions (Taylor and Zografi, 1997; Van den
Mooter et al., 1998; Tantishaiyakul et al., 1999; Khougaz
and Clas, 2000; Konno and Taylor, 2006; Marsac et al.,
2006a; Rumondor et al., 2009a). The absence of drug
polymer interactions, however, does not always preclude miscibility, and Eudragit E100 and itraconazole,
for example, are partially miscible but show no evidence of intermolecular bonding (Janssens et al., 2010).
443
Fig. 62. Scheme depicting a simplified version of events that occur on increasing drug loading in solid dispersions in relation to physical stability.
Individual drug molecules are depicted by the yellow triangles and are present in a carrier matrix (green). Increasing drug concentrations in the solid
dispersion provides additional utility through higher potential drug doses but is accompanied by additional stability concerns. Solid dispersions
containing drug above the crystalline solubility are thermodynamically unstable and may separate to form multiphase systems via nucleation and
particle growth. Above the amorphous solubility (miscibility limit), solid dispersions initially phase separate by two different mechanisms. Within the
metastable region (i.e., between the miscibility curve and the spinodal curve; see also Figure 61B), separation occurs via nucleation and growth.
However, in the unstable region (i.e., below the spinodal curve), solid dispersions spontaneously phase-separate. In the event of spontaneous phase
separation, crystallization is expected to occur rapidly as concentrations of stabilizing polymer surrounding the drug molecules are low. The positions of
the solubility limits (crystalline and amorphous) are carrier dependent for a particular drug, and phase separation may occur below the amorphous
solubility (miscibility limit) if heterogeneous mixtures are prepared during manufacture or during storage.
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Williams et al.
more likely to crystallize compared with solid dispersions where drug is present in a molecularly dispersed
form (i.e., type 3 or type 6 systems) that has increased
kinetic stability as a result of intimate contact with the
polymer (Six et al., 2004; Marsac et al., 2006b;
Rumondor and Taylor, 2010). Solid dispersions with
lower drug-polymer ratios and those with high drugpolymer miscibility therefore show better physical
stability at ambient temperatures (Chan and Kazarian,
2004; Van Drooge et al., 2004; Weuts et al., 2005;
Friesen et al., 2008; Qian et al., 2010a). These solid
dispersions are also more physically stable at elevated
temperature and in the presence of moisture (Van
Drooge et al., 2004; Vasanthavada et al., 2004;
Rumondor and Taylor, 2010). Water or other solvents
(that may be carried over from manufacturing) reduce
miscibility by promoting molecular interactions between solvent and drug or polymer and, therefore,
reduce the number of possible drug-polymer intermolecular interactions. The plasticizing properties of solvents also encourage phase-separation in situations
where drug loads exceed the miscibility limit through
increased molecular mobility in the system. Rumondor
and Taylor (2010) further propose that moisture affects
the route of drug recrystallization, either by promoting
phase-separation, and therefore crystallization from
heterogeneous dispersions containing amorphous drug
clusters, or by promoting spontaneous crystallization
from homogeneous dispersions (see Fig. 62). The latter
route of crystallization and crystal growth is likely to
be slower given the higher surrounding concentrations
of stabilizing polymer.
Finally, the processes depicted in Fig. 62 assume
initial preparation of homogeneous solid dispersions.
Where the method of manufacture does not provide for
adequate mixing, drug and polymer phase-separation
may occur below the miscibility limit. Under conditions
of poor mixing, regions exist that are drug rich and
polymer poor, and the (local) level of drug in these
regions is likely to be in excess of the miscibility limit.
This scenario leads to localized phase separation and
drug crystallization, which may ultimately trigger
more widespread (global) crystallization.
H. Summary
Solid dispersion formulations comprise drug physically dispersed within an inert and usually highly
water-soluble carrier, often a high molecular weight
polymer. Drug may exist in the carrier in multiple
physical forms and may be dissolved, partially dissolved with excess drug suspended in the crystalline
state, partially dissolved with excess drug in the
amorphous state, or partially dissolved with excess
drug present as a mixture of crystalline and amorphous states. The inert carrier matrix may also be
present in either crystalline or amorphous forms. Academic researchers and industrial investigators have
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Williams et al.
digestion products, such as DG and FA, and the mechanical mixing that occurs in the stomach (Nordskog
et al., 2001) facilitates the formation of a coarse lipid
emulsion (droplet size ,50 mm) that increases the surface area of exposure for further digestion.
Entry of this coarse emulsion (chyme) into the
duodenum via the pylorus subsequently triggers
a series of events that lead to the chemical digestion
and physical solubilization of dietary lipids and
ultimately to highly efficient lipid absorption, mostly
from the upper small intestine (Nordskog et al., 2001;
Mu and Hoy, 2004). Thus, the presence of TG digestion
products in the duodenum stimulates cholecystokinin
release, gallbladder contraction, and bile and pancreatic enzyme secretion into the duodenum (Nordskog
et al., 2001; Mu and Hoy, 2004). Undigested lipid in the
lower small intestine can also activate an ileal brake
that reduces small intestine motility and thus
increases the time available for further digestion and
absorption. In the duodenum, pancreatic lipase binds
to the surface of chyme and continues the digestion of
TG and DG to monoglyceride (MG) and free FA (Lowe,
1997). In the presence of bile salts, co-lipase is required
to promote anchoring of lipase to the lipid droplet
interface (Lowe, 1997). Other dietary lipids are also
hydrolyzed in the duodenum. For example, phosphatidylcholine is digested by pancreatic phospholipase
(PLA-2) to yield lysophosphatidylcholine (LPC) and
free FA (Borgstrom et al., 1957; van den Bosch et al.,
1965; Arnesjo and Grubb, 1971) and cholesterol ester,
which accounts for 1015% of dietary cholesterol (with
the remainder present as free cholesterol) (Nordskog
et al., 2001), is hydrolyzed by cholesterol esterase.
Cholesterol esterase also has additional activity toward TG and PLs (Lombardo et al., 1980).
Solubilization of lipids occurs simultaneously with
chemical digestion. Bile componentsincluding bile
salts, PL, and cholesterolare released into the
duodenum in the form of micelles after gallbladder
contraction. Bile components facilitate further emulsification of chyme, leading to a reduction in lipid droplet
size and an increase in the surface area available for
lipase-mediated hydrolysis. Although the products of
lipid digestion are somewhat more water-soluble than
their glyceride precursors, they nonetheless have poor
bulk water solubility and as such accumulate on the
surface of digesting lipid droplets. As they are hydrated
at the oil-water interface, these polar oils swell to form
liquid crystal structures ranging from lamellar to cubic
and hexagonal phase structures. The phase behavior is
complex and a function of the types and quantities of
lipids and lipid digestion products present and the
concentration of bile salts, phospholipids, and other
dietary/formulation components (Patton and Carey,
1979; Hernell et al., 1990; Staggers et al., 1990;
Kossena et al., 2003; Fatouros et al., 2007a,b). In
general, lipolytic products (FA, MG, DG) detach from
447
448
Williams et al.
449
Fig. 63. Schematic of the mechanisms by which poorly water-soluble drugs are absorbed from lipid-based formulations (LBF), including illustration of
the mechanisms by which LBF promote the absorption or bioavailability of poorly water-soluble drugs. (1) Avoidance of the need for traditional drug
dissolution by presenting the drug as a monomolecular dispersion (solution) in the LBF. (2) Formation of a dispersed emulsion within the stomach in
which the drug remains solubilized after capsule rupture. (3) Stimulation of bile secretion, bile salt, and phospholipid micelle release into the intestinal
lumen and thus an increase in intestinal concentrations of biliary-derived solubilizers. (4) Combination of biliary secretions with lipid digestion
products in the small intestine lumen to form colloidal speciesincluding emulsion droplets, vesicles, and mixed micellesthat have high
solubilization capacities for poorly water-soluble drugs. Note that the release of pancreatic lipase
and co-lipase
from the gallbladder facilitates
digestion of formulation lipids and thus the formation of more polar digestion products that assist in vesicle and mixed micelle formation. (5) Promotion
of mass transport across the unstirred water layer (UWL) via transport within intestinal mixed micelles. (6) Enhanced drug permeability across the
enterocyte apical membrane where formulation components may alter passive permeability or reduce efflux. (7) Transport across the enterocyte via
interaction with cytosolic lipid-binding proteins. (8) Highly lipophilic drugs (typically log D . 5, long-chain TG solubility . 50 mg/g) have the potential
for association with developing lipoproteins in the enterocyte and uptake into the intestinal lymph rather than the mesenteric blood capillaries, and
therefore transport to the systemic circulation via a route that avoids passage through the liver and first-pass hepatic metabolism. (9) Protection from
enterocyte-based drug metabolism, either directly via excipient effects on enzyme activity or indirectly where lipoprotein association within the
enterocyte occurs.
450
Williams et al.
that is present, limiting transfer into micellar components until all remaining lipid is digested (Sek et al.,
2002; Kaukonen et al., 2004a; Day et al., 2010). As
expected, drugs with higher affinities for bile salt and
phospholipid mixed micelles equilibrate into the
colloidal lipid phase more effectively (Christensen
et al., 2004).
Solubilization is further influenced by the mass and
type of lipid administered in the formulation, and, in
general, administration of a higher lipid mass provides
greater support for drug solubilization. This reflects
the ability of larger quantities of lipid to maximize the
release of bile salt (Kossena et al., 2007) and also the
ability of larger quantities of lipid digestion products to
more effectively swell endogenous bile salt micelles,
thereby increasing solubilization capacity. Effective
differentiation of the ability of different lipids to most
effectively promote drug solubilization in the GI tract
remains a goal of many research programs, including
ours; however, it is apparent that the inclusion of, for
example, glycerides based on medium-chain (MC) or
long-chain (LC) FA leads to quite different colloidal
behavior and, therefore, differences in drug solubilization. For example, Kossena et al. (2003, 2004) examined phase behavior and drug solubilization on
dilution of MC and LC FA and monoglyceride (MG)
(reflecting common digestion products) in simulated
endogenous intestinal fluid (SEIF: 4 mM BS, 1 mM PL,
and 0.25 mM cholesterol). At high concentrations of
lipid, reflective of conditions likely to exist on the
surface of a digesting oil droplet, liquid crystalline
phases dominated with a lamellar phase evident in MC
FA and MG systems and a more viscous cubic phase
formed in the long-chain FA and MG systems. Further
dilution resulted in the production of large vesicles and
the coexistence of mixed micelles and unilamellar
vesicles at concentrations likely to reflect the environment adjacent to the absorptive surface of the enterocyte.
The MC systems were vesicle rich and had higher
solubilization capacities at high FA and MG concentrations compared with the LC systems; however, the
solubilization capacity of the MC system was rapidly
lost on dilution. In contrast, the LC systems retained
solubilization capacity through greater levels of dilution, coincident with the persistence of vesicular
species at greater dilutions. Therefore, LC lipids appear to support more robustly drug solubilization at
high dilution.
It is also apparent that the properties of formulationderived lipids change significantly on digestion. Indeed, differential solubilization properties may become
apparent only on digestion. For example, drug solubility in MC lipids is usually higher (on a milligram per
gram basis) than in LC lipids, providing advantages in
drug solubility in the formulation and therefore the
potential for the administration of higher drug doses in
the same mass of formulation. On digestion, however,
451
452
Williams et al.
nbL
nbs
Csaq
63
where nbs and nbL are the mole numbers of surfactant and
lipid in the membrane bilayer, respectively, and Csaq is
aqueous surfactant concentration (Heerklotz, 2008). In
general, Kr is proportional to the log P of the surfactant
and approximates 1/CMC. Thus, more lipophilic surfactants have lower CMCs and partition more readily into
membranes. However, deviations from this relationship
are possible, for example, where the surfactant is
charged and forms electrostatic interactions with the
membrane or where the surfactant induces bilayer or
monolayer curvature strain in the membrane.
453
454
Williams et al.
TABLE 27
Summary of studies investigating the impact of lipid formulation components on drug efflux by major intestinal efflux transporters [P-glycoprotein
(P-gp), breast cancer resistance protein (BCRP), and multidrug resistance protein-2 (MRP-2)]
Solubilizer
Brij 30
Brij 35
Cremophor EL
Cremophor RH40
Transporter
Concentration
20200 mM
50100 mM
30120 mM
In vitro ,2% (w/v)
3050 mM
In vitro 50100 mM
In vivo 600 mg, 3 daily
50100 mM
CRL-1605 copolymer
132 mg/kg
Gelucire 44/14
P-glycoprotein (Sachs-Barrable
et al., 2007; Yamagata et al.,
2007a)
BCRP (Yamagata et al., 2007a)
0.050.5% (w/v)
Labrasol
115 mM
20200 mM in vitro.
200 mM in situ
100200 mM
020%
Pluronic F68
02%, 07050 mM
0.00022% (w/v)
100 mM
Pluronic F108
Pluronic L81
100 mM
40100 mM
100 mM
Effects
455
Pluronic P85
Transporter
Concentration
0220 mM
100 mM
In vitro 120 mM
In vivo 100500 mg/kg
Pluronic PE8100
and Pluronic
PE6100
Poloxamer 188
Propylene glycol
P-glycoprotein (Bogman
et al., 2003)
0.00022% (w/v)
0.00022% (w/v)
P-glycoprotein (Bogman
et al., 2005)
P-glycoprotein (Yamagata
et al., 2007a)
BCRP (Yamagata et al.,
2007a)
P-glycoprotein (Bogman et al., 2003;
Lo, 2003; Shono et al., 2004)
Solutol HS
Span 20
Span 80
TPGS
Effects
456
Williams et al.
TABLE 27Continued
Solubilizer
Tween 80
Tween 80
Transporter
Concentration
100-250 mM
In vitro 01 mM
0.00022% (w/v)
50100 mM
0.00022% (w/v)
Imwitor 742
0.050.5% (w/v)
Miglyol
0.050.5% (w/v)
1-monoolein and
1-monostearin
Peceol (glycerol
monooleate)
0.00022% (w/v)
Phospholipid
liposomes
FaSSIF
03 mM
Effects
457
458
Williams et al.
459
Fig. 64. Schematic of lymphatic drug transport. After oral administration, most drugs (D) are taken up into and pass across the enterocyte, access the
lamina propria and are then taken up into blood capillaries that converge into the portal vein and pass through the liver before accessing the systemic
circulation. In contrast, highly lipophilic (log D . 5) and lipid-soluble [triglyceride (TG) solubility .50 mg/g] drugs may associate with lipid absorption
pathways, and in particular with lipoproteins (LPs) that are formed after resynthesis of lipid digestion products such as fatty acids (FA) and
monoglycerides (MG) to TG. After exocytosis from the enterocyte, drug-lipoprotein complexes are taken up specifically into the intestinal lymphatics,
which converge to form the thoracic lymph duct. Thoracic lymph empties directly into the systemic circulation and, as such, transport via the lymphatic
system avoids passage through the liver and the potential for first-pass hepatic metabolism.
460
Williams et al.
461
462
Williams et al.
and MC triglycerides typically exhibit greater oxidative stability than LC triglycerides (as a result of the
presence of fewer unsaturated fatty acid chains). The
choice of emulsifier is driven by toxicity, the need for
all components in parenteral formulations to be
metabolized or excreted, the potential for effective
emulsion stabilization, and the need for stability
during sterilization. Natural lecithin, from either
animal (egg yolk) or vegetable (soybean) origin, has
been used as an emulsifier in almost all marketed
products. Lecithin-stabilized emulsions require highpressure colloid milling to facilitate emulsification, but
the resulting oil-in-water dispersions are remarkably
stable owing to strong adsorption of the lecithin at the
oil-water interface. The aqueous phase of parenteral
emulsions contains ionic or osmotic agents, antioxidants,
buffers, and preservatives (Floyd, 1999; Hippalgaonkar
et al., 2010). Oils exert no osmotic effects, so isotonic
adjustment (to 280300 mosm/kg) is typically achieved
via the addition of glycerol, sorbitol, or xylitol to commercial preparations. Buffering agents are generally not
used as they may catalyze hydrolysis of TG and PL and
reduce emulsion stability. A small amount of sodium
hydroxide is often added to adjust to a slightly alkaline
pH (;8.0) as emulsion pH decreases on sterilization and
storage because of the small amounts of hydrolysis of TG
and PL to free FA.
Parenteral emulsions are typically formulated by
dissolving drug in the oil phase before emulsification
with the aqueous phase (i.e., de novo emulsion formation) or via the addition of drug to preprepared
commercial parenteral emulsions. The latter approach
is a relatively simple way to prepare poorly watersoluble drugs for i.v. administration in preclinical
studies. In this case, the drug is predissolved in a cosolvent and slowly added to a commercial lipid emulsion under conditions of agitation (e.g., ultrasonication
or homogenization). The de novo method is more
commonly used for clinical formulations, but drug
may also be incorporated into preprepared i.v. emulsions with the aid of a cosolvent, via direct incorporation of drugs, which are liquid at room temperature
(e.g., propofol), or via direct incorporation of nanomilled drug powders or nanocrystals followed by
homogenization. De novo preparation is achieved by
first dissolving (usually with heating) all water-soluble
and oil-soluble ingredients in the aqueous or lipid
phase, respectively. Emulsifiers are then added to
either the oil or aqueous phase. The lipid phase is
mixed with the aqueous phase under controlled conditions (temperature, agitation, rate of addition) to form
a coarse emulsion (droplet size ,20 mm). The droplet
size of the coarse emulsion is subsequently reduced (to
a maximum mean droplet size ,500 nm) via homogenization or microfluidization. The emulsion is ultimately filtered to remove any large particulates.
Sterilization is achieved through aseptic preparation
463
464
Williams et al.
or stearoyl polyoxylglycerides) either alone or in combination with a solid carrier may be solubilized in organic
solvent and spray dried to remove the solvent (Chauhan
et al., 2005). Alternatively, oil-in-water emulsions may
be spray dried to prepare dry emulsions. Medium-chain
triglycerides and oleyl polyoxylglycerides have been
used as the lipophilic phase in dried emulsions of this
type (Christensen et al., 2001; Dollo et al., 2003;
Hansen et al., 2004; Jang et al., 2006; Yi et al., 2008;
Oh et al., 2011; Kang et al., 2012). To generate
adsorbed solid LBF, liquid lipid formulations such as
SEDDS are simply adsorbed to a carrier (e.g., calcium
silicate, magnesium aluminometasilicate, silicon dioxide, or carbon nanotube) under mixing to form a freeflowing powder (Ito et al., 2005; Patil and Paradkar,
2006; Abdalla et al., 2008; Agarwal et al., 2009; Tan
et al., 2009; Dixit and Nagarsenker, 2010; Wang et al.,
2010c; Tan et al., 2011; Van Speybroeck et al., 2012).
Solid or semisolid lipids (e.g., polyoxylglycerides,
lecithin, partial glycerides, polysorbates) (Seo et al.,
2003; Shimpi et al., 2005; Vilhelmsen et al., 2005) have
also been used to create solid SEDDS via traditional
melt granulation, effectively forming an emulsifiable
solid dispersion (see Section X). Melt granulation may
be used further to adsorb semisolid self-emulsifying
systems onto solid carriers (Gupta et al., 2001, 2002).
In contrast, melt extrusion techniques force molten
lipid-based formulations through a die under controlled conditions to produce a product that subsequently solidifies to form extrudates of uniform
shape and density. Lipid-based excipients, such as
sucrose monopalmitate (Surfhope D-1616; Halim Biotech, Singapore, Singapore), lauroyl polyoxylglycerides
(Gelucire 44/14), and polysorbate 80 (Tween 80) have
also been included as additives in traditional melt
extrusion formulations (e.g., those containing microcrystalline cellulose) to enhance the dissolution of poorly
water-soluble drugs (Hulsmann et al., 2000; Serratoni
et al., 2007). More complex extrusion techniques have
described the specific introduction of lipidic excipients
(such as Gelucire 44/14) into the core of sustained
release formulation matrices (Mehuys et al., 2004,
2005; Windbergs et al., 2010).
Solid lipid nanoparticles (SLNs, which possess a solid
core) or nanostructured lipid carriers (NLCs, which
possess a liquid core) may be produced by highpressure homogenization (Mller et al., 2000; Mehnert
and Mader, 2001; Hu et al., 2004c; Puri et al., 2009;
Bunjes, 2010). SLNs typically consist of a solid matrix
of high melting lipids such as glyceryl dibehenate
(Compritol 888 ATO; Gattefoss) and surfactants such
as poloxamer 188 (Pluronic F68) or Tween 80. NLCs
generally contain a liquid lipid excipient such as MC
triglycerides in addition to the components of SLNs.
Supercritical fluidbased methods have also been used
to generate SLNs where the drug and lipidic excipients
are dissolved in a supercritical fluid, followed by
465
TABLE 28
Typical composition of LFCS types I, II, IIIA, IIIB, and IV lipid-based formulations and their solubilization capacity for drug before and after dispersion
and digestion in the gastrointestinal tract
Increasing Hydrophilic Content
Typical
Composition
(% w/w)
Triglycerides or
mixed
glycerides
Water-insoluble
surfactants
(HLB ,12)
Water-soluble
surfactants
(HLB .12)
Hydrophilic
cosolvents
Solvent capacity
prior to
dispersion
Solubilization
capacity upon
dispersion
Impact of
digestion on
solubilization
capacity and
absorption
Type I
Type II
Type IIIA
Type IIIB
100
4080
4080
,20
2060
Type IV
020
2040
2050
3080
040
2050
050
Generally . type II
Type III formulations include lipids, hydrophilic surfactants (HLB . 12), and cosolvents and self-emulsify
very effectively to form emulsions with small particle
sizes (usually ,250 nm). Type III LBF have therefore
been described as self-microemulsifying drug delivery
systems (SMEDDS) (based on thermodynamic expectations of the dispersion) or self-nanoemulsifying drug
delivery systems (SNEDDS) (based on particle size).
Type III formulations contain long- or medium-chain
glycerides, high HLB surfactants (e.g., Cremophor EL,
Cremophor RH40, Tween 80, Gelucire), and cosolvents.
There is a somewhat arbitrary division between type
IIIA and IIIB formulations to distinguish those that
contain greater quantities of hydrophilic components
(type IIIB). Key considerations to formulation design
include protection against drug precipitation on dispersion and digestion of the formulation. In vitro
testing of the potential for precipitation on dispersion
and digestion is therefore crucial to development and
assessment (see Sections XI.C.1 and XI.C.2). Most
currently marketed LBF are type III formulations.
Type IV formulations were more recently added to the
LFCS (Pouton, 2006) and comprise mixtures of surfactant and cosolvent in the absence of traditional lipids.
The attraction of type IV formulations is the high
solvent capacity of cosolvents and surfactant compared
with lipids, which usually permits higher drug loading
in type IV formulations compared with types I, II, and
466
Williams et al.
TABLE 29
Excipients commonly used in oral lipid-based formulations
Excipient Class
Medium-chain triglycerides
Long-chain triglycerides
Medium- and/or long-chain monoglycerides,
diglycerides, or mixed glyceridesa
Low HLB surfactants (HLB ,8)a
Water-insoluble, lipophilic surfactants (HLB 8-12)
Water-soluble surfactants (HLB . 12)
Cosolvents
Lipid-soluble antioxidants
Polymeric precipitation inhibitors (PPIs)
Examples
467
of a series of esterification products and a lack of explicit molecular characterization of the product. Potential batch-to-batch variation in surfactant properties
is therefore particularly evident for surfactants of this
type where variations in the quantities of each product
are likely as a function of batch.
e. Capsule Compatibility. Compatibility of LBF
with hard and soft gelatin capsules was reviewed in
detail by Cole et al. (2008). In general, low-molecularweight polar molecules such as cosolvents (e.g., propylene glycol), surfactants, and water are most likely to
interact with capsule shells, although differences are
evident between hard and soft gelatin capsules. Newer
capsule materials such as hydroxypropyl methylcellulose hard gelatin capsules and plant polysaccharidebased soft gel capsules provide additional options with
468
Williams et al.
TABLE 30
Factors affecting the choice of excipients for lipid-based formulations
Solvent capacity
Miscibility
Regulatory issues: irritancy, toxicity, knowledge, and experience
Morphology at room temperature (i.e., melting temperature)
Self-dispersibility and role in promoting self-dispersion of the
formulation
Digestibility,and fate of digested products
Capsule compatibility
Purity, chemical stability
Cost of goods
TABLE 31
Comparative properties of glyceride lipids in oral lipidbased formulations
Triglycerides vs. monoglycerides, diglycerides, or mixed glycerides
Partial glycerides are often better solvents than triglycerides
(unless the drug is highly lipophilic), and their increased
amphiphilicity typically results in improved emulsification
properties.
Addition of mixed glycerides to combinations of triglyceride and
surfactants typically improves miscibility.
Glyceride lipids comprising long-chain vs. medium-chain fatty acids
LC glycerides usually have lower solvent capacity and emulsify
less readily than MC glycerides.
LBF based on LC glycerides are often more effective at
maintaining solubilization capacity on dispersion and digestion.
LC glyceride more effectively promote lymphatic transport of highly
lipophilic drugs compared with MC glycerides.
LC lipids are typically less stable to oxidation.
Unsaturated glycerides vs. saturated glycerides
Glycerides comprising unsaturated fatty acids usually exhibit
increased solvent capacity.
Unsaturated lipids are less stable to oxidation.
Unsaturated glycerides more effectively promote lymphatic
transport of highly lipophilic drugs compared with saturated
lipids.
Saturated glycerides have higher melting points and are commonly
solid at room temperature.
469
Fig. 66. Experimental setup for an in vitro digestion experiment. (A) Lipid formulations are introduced into a temperature-controlled reaction vessel
(37C), which contains media consisting of buffer and bile salt and phospholipid concentrations designed to simulate fasted or fed intestinal conditions.
The contents of the reaction vessel are stirred throughout experiments. Either at the time of introduction of the formulation or after a period of
dispersion (to enable assessment of drug precipitation upon dispersion), a source of pancreatic enzyme(s) is added to the system to initiate the process
of lipid digestion. Digestion of glycerides liberates FAs, which causes a transient drop in pH. The pH is maintained at a setpoint (B) by the addition of
NaOH via an autoburette coupled to a pH-stat meter controller. Maintenance of constant pH is important to mimic in vivo conditions and to enable
digestion to continue. The rate of NaOH addition is recorded via the computer. This enables the calculation of the extent of digestion as digestion of
a molecule of triglyceride liberates a molecule of monoglyceride and 2 free FAs and OH ions react with H ions from liberated free FA in a 1:1
stoichiometric ratio (assuming complete ionization). (C). Samples can be taken throughout the digestion process, digestion stopped via the addition of
the lipase inhibitor 4-bromophenylboronic acid (BPBA), and samples centrifuged to obtain three separate phases: an undigested oil phase, an aqueous
phase, and a pellet phase. Precipitated drug is present in the pellet phase, whereas drug solubilized in micellar structures within the aqueous phase is
believed to represent drug that is available for absorption. Adapted from Porter et al. (2007).
470
Williams et al.
Fig. 67. (A) Percent of drug mass contained within the aqueous phase (gray area of bars) and pellet phase (white area of bars). (B) Final aqueous phase
concentration of danazol after the addition of 250 mg of medium-chain (MC) or long-chain (LC) SEDDS formulation containing 15 mg/g danazol to an in
vitro digestion apparatus followed by dispersion for 30 min in nondigesting conditions or dispersion for 10 min followed by addition of pancreatin to
stimulate digestion for 30 min. Samples were ultracentrifuged to obtain an aqueous phase and pellet phase to probe for drug precipitation. (C) and (D)
Plasma concentration versus time profiles for danazol after oral administration of 15 mg of danazol to beagle dogs. Values are expressed as means (n 5
4) 6 SEM. (C) Profiles after fasted administration of lipidic solutions containing 5 mg/g of danazol in 3 g of MC-SEDDS, LC-SEDDS, or LC triglyceride
(soybean oil) solution. (D) Profiles following fasted or postprandial administration of a dry micronized powder form of danazol. The MC SEDDS
formulation consisted of the following ratios of components: danazol (5 mg), Captex 355 (360 mg), Capmul MCM (180 mg), Cremophor EL (360 mg), and
absolute ethanol (100 mg). The LC SEDDS formulation consisted of the following ratios of components: danazol (5 mg), soybean oil (300 mg), Maisine
35-1 (300 mg), Cremophor EL (300 mg) and absolute ethanol (100 mg). Adapted from (Porter et al., 2004a).
471
472
Williams et al.
473
474
Williams et al.
475
476
Williams et al.
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