Advanced Drug Delivery Reviews 56 (2004) 321 – 334
www.elsevier.com/locate/addr
Impact of solid state properties on developability assessment of
drug candidates
Lian-Feng Huang a, Wei-Qin (Tony) Tong b,*
b
a
Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 1000 Route 202, Raritan, NJ 08869, USA
Pharmaceutical and Analytical Development, Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ 07936, USA
Received 27 June 2003; accepted 6 October 2003
Abstract
Solid state properties including polymorphism, solvate and salt formation can have a profound impact on two of the most
important properties that are essential to the successful development of drug candidates: solubility and stability. To enable
meaningful evaluations of drug candidates for their development risks, often referred to as developability, and provide input to
the molecular design regarding the ‘‘drug-like’’ properties, one must take into account the impact of solid state properties on
solubility and stability. This review examines the importance of solid state properties and their relationship to developability
criteria. Phase appropriate characterization strategies and appropriate salt and crystal form screening and selection processes are
discussed. These strategies and processes should balance the need for speed and throughput of modern discovery with the
quality of data essential to the adequate developability assessment. Specific examples are given to illustrate the importance of
understanding the solid state properties and their impact on developability.
D 2003 Published by Elsevier B.V.
Keywords: Developability; Solubility; Stability; Solid state properties; Polymorphs; Pseudopolymorphs; Solvates; Salts; Crystal form screening
Contents
1.
2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Impacts of solid state properties on solubility, bioavailability and chemical stability
2.1.
Solid state properties, solubility, and dissolution rate . . . . . . . . . . .
2.2.
Solid state properties and bioavailability . . . . . . . . . . . . . . . . .
2.3.
Solid state properties and stability. . . . . . . . . . . . . . . . . . . .
Developability criteria for properties related to solid state properties . . . . . . .
3.1.
Solubility as related to bioavailability . . . . . . . . . . . . . . . . . .
3.2.
Chemical stability . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3.
Solid state properties. . . . . . . . . . . . . . . . . . . . . . . . . .
3.4.
Synthetic process scalability . . . . . . . . . . . . . . . . . . . . . .
* Corresponding author. Tel.: +1-862-778-4795; fax: +1-973-781-4554.
E-mail address: weiqin.tong@pharma.novartis.com (W.-Q. Tong).
0169-409X/$ - see front matter D 2003 Published by Elsevier B.V.
doi:10.1016/j.addr.2003.10.007
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
322
322
323
324
324
324
325
326
327
327
322
L.F. Huang, W.-Q. Tong / Advanced Drug Delivery Reviews 56 (2004) 321–334
4.
Phase appropriate strategies for studying solid state properties. . . . . . . . . . . . . . . .
4.1. Lead identification and lead optimization phases . . . . . . . . . . . . . . . . . .
4.2. Candidate evaluation and selection phase. . . . . . . . . . . . . . . . . . . . . .
5. Salt and crystal form screening and selection processes . . . . . . . . . . . . . . . . . . .
6. Crystallization methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7. Case studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.1. Example A: impact of crystal form on solubility in lead identification and optimization
7.2. Example B: impact of the crystalline form on bioavailability. . . . . . . . . . . . .
7.3. Example C: impact of crystal form on stability . . . . . . . . . . . . . . . . . . .
8. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction
The pharmaceutical industry has faced growing
challenges in recent years as a result of increased
economic and regulatory pressures. With the patents
for blockbuster drugs constantly expiring, pressure to
rebuild drug pipelines is intense. While the advent of
combinatorial chemistry, high-throughput screening
and other drug discovery innovations have resulted
in many more hits and potential development candidates, properties of these candidates are becoming less
favorable for development [1 – 3]. To ensure the
developability of drug candidates, many pharmaceutical companies have established capability for measuring an ensemble of ‘‘drug-like’’ properties, often
referred to as pharmaceutical profiling or developability assessment [1 –4]. This strategy enables project
teams to identify potential development challenges
and ‘‘show stoppers’’, to have the opportunity to take
these ‘‘drug-like’’ properties into account in lead
optimization, and thus to select the best candidates
for advancement.
Scientists must develop products with quality and
in vivo performance in patients that meet the standards of regulatory agencies. These products should
have adequate pharmacokinetic (PK) properties including bioavailability and an acceptable safety profile. They also need to have adequate chemical and
physical stability in their pharmaceutical dosage
forms. The drug substance’s manufacturing process
should be reproducible and it should be produced at a
reasonable cost.
Solubility and chemical stability are two key
contributors to poor bioavailability and other development challenges. They have been the focus of
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
phases .
. . . .
. . . .
. . . .
. . . .
. . . .
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
327
327
328
328
329
331
331
331
332
332
332
332
many high-throughput screening methods developed
in the last few years [1,4 – 6]. Since discovery deals
with large numbers of compounds, small sample size
and short timelines, solid state properties typically
are not studied or considered during Pharmaceutical
profiling. However, solid state properties have a
profound impact on solubility and chemical stability
[7 – 10]. Additionally, poor solid state properties
themselves may present significant development
challenges [10]. A thorough understanding of the
way in which solid state properties influence solubility, stability, and other properties of the drug
substance is critical in the development of profiling
strategies and in the setting of criteria for developability assessment [11].
The objectives of this review are to analyze the
impact of solid state properties on developability
assessment of drug candidates, propose strategies
and processes for studying solid state properties including salt and crystal form screening and selection.
2. Impacts of solid state properties on solubility,
bioavailability and chemical stability
Different lattice energies (and entropies) associated
with physical forms (amorphous, different polymorphs or solvates) give rise to measurable differences in physical properties [8]. When a drug forms a
salt, the particular salt form determines the physicochemical properties [10 – 14]. Some physicochemical
properties that can be affected include melting point,
hygroscopicity, solubility, dissolution rate, stability
(both physical and chemical), refractive index, thermal conductivity, surface activity, density, habit, elec-
L.F. Huang, W.-Q. Tong / Advanced Drug Delivery Reviews 56 (2004) 321–334
323
trostatic, mechanical and optical properties. Biopharmaceutical properties may also be affected.
Table 2
Comparison of apparent solubility of amorphous material (A) and
crystalline material (C)
2.1. Solid state properties, solubility, and dissolution
rate
Solute
Melting
point (jC)
Solubility
ratio (A/C)
Caffeine
Theophylline
Morphine
Hydrochlorthiazide
Sulfamethoxydiazine
Bezimidazole derivatives
238
272
197
273
215
f 300
5
50
270
1.1
1.5
500 – 1000
The concept of solubility implies that the process
of solution (or dissolution) has reached an equilibrium
state such that the solution has become saturated. The
intrinsic solubility of a substance depends on the
particular solid phase (solvate or anhydrate) that is
present [8].
Since lattice energies of physical forms (amorphous, polymorphs or solvates) are responsible for
the difference in solubilities and dissolution rates, the
largest difference in solubility is observed between
amorphous and crystalline materials [9,11,15]. The
solubility difference between different polymorphs is
typically less than 10 times (Table 1) whereas the
difference between amorphous and crystalline material can be up to several hundred times (Table 2).
Based on the thermodynamic theory of solubility
of solvates, the rule applying to solubility behavior is
that solid solvates are always less soluble in the
solvent forming the solvate than the original solid
[8]. Thus, hydrates are less soluble in water than the
corresponding anhydrous solid. Solvates formed from
other solvents, if the solvent is water-miscible, are
more soluble in water than the corresponding nonsolvated form. For example, caffeine hydrate is much
less soluble in water than anhydrous caffeine, but the
hydrate is much more soluble in ethanol than anhydrous caffeine [8].
The most celebrated recent example of the impact
of polymorphs on solubility and dissolution rate is the
Table 1
Comparison of apparent solubility of polymorphs
Solute
Melting
point (jC)
Solubility ratio
(low/high)
Acemetacin
20
70
41
57
30
70
05
10
2.3
4.7
2.0
3.6
3.6
7.4
1.2
1.9
Cycopenthiazide
Mebendazole
Spironolactone
protease inhibitor, ritonavir [16]. A new thermodynamically stable form, Form II, was discovered 2 years
after the launch of product using Form I. The two
crystal forms differ substantially in their physical
properties such as solubility and dissolution rate. Table
3 shows the solubility differences of these two forms.
The marketed formulation, a semisolid formulation,
consisted of a nearly saturated solution of Form I.
Since Form II was much less soluble in the solvents
used for the formulation, it was supersaturated with
respect to Form II. This finally forced the manufacturer
to recall the original formulation from the market [17].
Many compounds have ionizable groups and thus
can form salts with proper counter ions. Changing the
salt forms varies the solubility, dissolution rate, which
in turn affects its bioavailability, PK profile, and even
toxicity [12].
Various solubilization techniques have been
employed to enhance the solubility of compounds
[9,18]. Salt formation will have a significant impact
on solubility when these techniques are used. For
example, a salt frequently will exhibit a lower complexation binding constant with cyclodextrins than a
free base. However, since the solubilities of salts
typically are higher, the salt may still have greater
solubility in cyclodextrin solutions than the free base.
Significantly different solubilities also can be expected
Table 3
Solubility profile of ritonavir in various hydroalcoholic solvent
systems at 5 jC
Solubility
(mg/ml)
Ethanol/water
Form I
Form II
100/1
90
19
95/5
188
41
90/10
234
60
85/15
294
61
80/20
236
45
75/25
170
30
324
L.F. Huang, W.-Q. Tong / Advanced Drug Delivery Reviews 56 (2004) 321–334
for salts in solutions containing surfactants or in semipolar non-aqueous solvents [19].
For a more in-depth review of the effect of polymorphism and solvates on solubility and dissolution
rates, see the recent review by Brittain and Grant [20].
2.2. Solid state properties and bioavailability
The absorption rates of many poorly water soluble
compounds depend upon the rate of drug dissolution.
Because of the effect of solid state forms on solubility
and dissolution rate, the use of amorphous, different
polymorphs or solvates would be expected to affect
the bioavailability. For a compound that has borderline bioavailability of approximately 20% from an
amorphous or a metastable crystalline form, a change
to a less soluble, more thermodynamically stable form
may result in unacceptable bioavailability [21]. Other
PK parameters such as Cmax and Tmax may also be
affected by polymorphic changes. Typically, poor
bioavailability (<20%) can result in dose-to-dose
variations, more variable drug levels, poorly controlled pharmacological effects, poorly controlled toxic effects, and increased cost [22].
The effect of polymorphs on the bioavailability of
chroamphenicol palmitate suspension is a classic
example [23]. Chroamphenicol palmitate exists in
four crystal forms. Form B gave much higher blood
levels than Form A after oral dosing of the suspension
formulations. A particular suspension formulation
even exhibited an unsatisfactory therapeutic effect.
This was attributed to the fact that this particular
formulation contained too much Form A rather than
Form B. Some additional examples of the effect of
polymorph on bioavailability include phenylbutazone
[24] and amobarbital [25].
The impact of salt forms on bioavailability is very
well documented and reviewed [12,13]. Bighley et al.
provided a systematic compilation of various drug
salts and their effects on PK and bioavailability [13].
Typically maximizing the bioavailability potential via
salt formation is considered the most practical approach in enhancing bioavailability.
reaction rates are typically the greatest in the liquid
or solution states and least in crystalline state, with
intermediate rates occurring in the amorphous state.
For example, NCEX is a PPAR-dual agonist for the
treatment of type II diabetes [26]. It exists in two
monotropically related crystal forms, Forms I and II,
with melting points of 160 and 140 jC, respectively.
After 4 weeks storage at 40 jC/75% RH, Form I
shows 0.3% total degradation compared to 6% for
Form II and 20% for the amorphous material.
Salt formation will also impact a compound’s
chemical stability. Some factors that may contribute
to the stability difference between a salt and its
unionized form or between different salts include
different microenvironmental pH and different molecular arrangements in a particular crystal lattice. For
example, the hydrochloride salt of the GG818 showed
much improved light stability compared to the free
base [27]. It is suspected that the light labile functional
group(s) in the crystal lattice of the hydrochloride salt
may either be less accessible to light compared to that
of the free base or have different ‘‘microenvironments’’ in the crystal lattice and hence, have differing
photochemical stability.
For more detail discussions on the impact of solid
state properties on stability, refer to the two recent
excellent reviews by Yoshioka and Stella [28] and
Guillory and Poust [29].
3. Developability criteria for properties related to
solid state properties
Since solid state properties do not directly impact
pKa, lipophilicity and permeability, these properties,
although considered important parts of developability
considerations, are not the subjects of this review.
When designing pharmaceutical profiling strategies and setting developability criteria, it is important
to consider the following fundamental questions:
.
.
2.3. Solid state properties and stability
.
For most pharmaceutical degradation reactions,
because of the importance of molecular mobility,
What kind of properties constitutes ‘‘show
stoppers’’?
What data are needed to support developability
assessment?
Is the quality of the data generated from any
particular screening good enough for the intended
decision-making?
L.F. Huang, W.-Q. Tong / Advanced Drug Delivery Reviews 56 (2004) 321–334
The following sections will address these questions
for each developability criteria related to solid state
properties.
It is very possible that compounds with most
favorable pharmaceutical profiles are not chosen due
to other considerations; however, results of the pharmaceutical profiles can help identify development
risks early, thus providing the opportunity for early
initiation of development efforts to reduce delays.
3.1. Solubility as related to bioavailability
What kind of solubility property will constitute a
‘‘show stopper’’? The answer to this question is not
necessarily straightforward. First of all, solubility
requirement for a drug candidate is dose dependent.
Lipinski [1] noted that solubility is not likely to limit
fraction absorbed for an oral administered drug with a
dose of 1 mg/kg, if the solubility is greater than 65 ug/
ml, but it is likely to limit absorption if the solubility
is less than 10 ug/ml. These estimates are based on the
concept of maximum absorbable dose (MAD) [30,31].
MAD is a conceptual tool which estimates the maximum amount of drug that can be absorbed during the
time drug stays in the intestine as a solution. It is
defined as:
MAD ðmgÞ ¼ S ðmg=mlÞ Ka ðper minÞ
SIWV ðmlÞ SITT ðminÞ
where S is solubility at pH 6.5 reflecting typical small
intestine condition. Ka is transintestinal absorption
rate constant determined by a rat intestinal perfusion
experiment. SIWV is small intestinal water volume
available for drug solubilization, generally accepted to
be 250 ml. SITT is small intestinal transit time,
typically around 270 min. A more simplified and
conservative approach is adopted by the FDA to
define a biopharmaceutical classification system
(BCS) [32]. This system defines low solubility compounds as those whose aqueous solubility in 250 ml
of pH 1 – 7.5 aqueous solution is less than the amount
contained in the tablet or capsule with the highest
dosage prescribed.
Secondly, it is important to realize that a compound
with solubility and dissolution rate as the rate-limiting
step of absorption does not mean that it is not
developable. The compounds that can be classified
325
as soluble by the BCS are only a small portion of
compounds under development [2]. Typically, through
various solubilization efforts such as salt formation,
particle size reduction, and use of amorphous material
and other non-traditional formulations such as lipidbased self-emulsifying systems, dissolution rate can
be enhanced to give acceptable product performance
for many compounds with poor solubility [9,17].
However, the risk proportionally increases as the
difference between the solubility and the solubility
required to dissolve the dose in 250 ml of pH 1 –7.5
solution increases. Additionally, using non-conventional formulations such as soft-gel capsule and amorphous materials obviously carries additional risks and
these risk factors need to be considered as the integral
part of developability assessment.
For poorly water soluble compounds, a proper
design PK study can provide valuable information
that is critical for the development risk assessment
regarding the solubility as related to bioavailability.
Different formulations will give different indications
regarding the ability to formulate. Table 5 summarizes
the four tier formulation approaches and their formulation development implication. For example, if some
compounds are giving reasonable PK results from a
suspension formulation, it indicates that developing a
traditional solid dosage form (tablet and capsule) may
be feasible. On the other hand, if a poorly soluble
compound is showing poor bioavailability even from
solution formulations, developing a traditional solid
dosage form may be very challenging.
The requirement for solubility is typically more
demanding for toxicological studies. It is possible
that a compound’s solubility is so low, further increasing in doses may fail to further increase blood
level (AUC). If the achievable difference in the
toxicological coverage and the projected human
doses is too small (3– 10 times depending on the
potential toxicity and bioavailability), the compound
may not be developable.
Among the high throughput assays for solubility
that have been reported are turbidimetry [1], nephalometry [5] and direct UV [6]. Solubilities from these
methods are typically called ‘‘kinetic’’ solubilities.
The key issues with ‘‘kinetic’’ solubility results are
that they may be time-dependent and are most likely
to change as the solid state properties of the residuals
in the solubility samples change. Since these ‘‘kinet-
326
L.F. Huang, W.-Q. Tong / Advanced Drug Delivery Reviews 56 (2004) 321–334
Table 4
Comparison of solubility data from three different methods
Compound
Benzthiazide
Progesterone
Butylparaben
Betamethasone
Oxyphenbutanzone
Phenyl salicylate
Propylparaben
Solubility (ug/ml)
From
solid by
HPLC
From DMSO
solution by
HPLC
From
nephelometry
11
6
139
63
>500
16
273
20
15
88
>196
<1
<1
89
27
20
97
>196
40
>107
>89
ic’’ solubility methods do not take into account the
contribution of the crystalline lattice energy to solubility, whether to see a good correlation with the
equilibrium method or not is really compound specific. For compounds that are not soluble due to high
crystallinity, it is obvious that a ‘‘kinetic’’ solubility
will most likely differ significantly from an equilibrium solubility. On the other hand, for compounds that
are not soluble in water due to high lipiphilicity, the
difference between the ‘‘kinetic’’ solubility and equilibrium solubility may be smaller. Table 4 compared
solubility data from three different methods [5]. The
significance in differences in solubility results by
different methods is obvious and difficult to predict.
Since the ‘‘kinetic’’ solubility is not an intrinsic
property of drug molecules, it is obviously not suitable for structure properties relationship. Since the
solubility difference caused by polymorphs is typically much smaller, it may be feasible to build a
relatively good structure property relationship if equilibrium solubility results from crystalline materials are
used. With the advancement in automation, the
throughput of measurement equilibrium solubility
may not necessarily be a bottleneck in supporting
lead optimization [4,33].
3.2. Chemical stability
For any assay to provide reliable results, compounds need to have adequate chemical stability. For
compounds to be bioavailable, they need to have
adequate stability in the gastric and intestinal fluid.
For compounds to be successfully formulated into
products, they need to be stable for the shelf-life of the
products. These stability requirements have different
meanings and different scales, thus require different
studies and criteria.
High-throughput screening of the solution stability
may be easily accomplished, but the impact of the
solution stability issues on the developability of
dosage forms requires additional studies including
studying the effect of solid state properties on stability. It may be ideal to screen away all the compounds
with any solution stability problems. However, there
are many formulation approaches available that can be
applied by the formulation scientists to overcome
chemical stability problems [28,29]. Additionally,
formulations that overcome certain stability challenges may provide additional intellectual protection
and life cycle management opportunities. However, if
a compound is chemically unstable as the crystalline
material, the challenge to develop an oral dosage form
will be very significant. If the compound is stable as
crystalline material but not stable as amorphous material, the risk may not be as high but controlling the
amorphous content in drug substance manufacturing
and formulation process may become a significant
challenge. Early selection of salt and crystal form
including considerations for excipient compatibility
and the impact of various processing parameters is
Table 5
Tier formulation approach for PK studies and its implication for
formulatability
Tier # Formulation
Formulatability implication
1
. Conventional dosage forms
2
Suspension
(crystallinity
and particle
size monitored)
pH-adjusted
solution
(capsule and tablet)
. Conventional dosage forms
with salts
. Most likely the best case for
3
4
solubilization via a salt option
. Non-conventional dosage forms
Non-aqueous
solvents
such as soft-gelatin capsule
(e.g. PEG400 and PG)
. Non-conventional dosage forms
Self-emulsifying
lipid based systems/
such as soft-gelatin capsule
microemulsions
. May reduce bioavailability at
low doses for drugs with
solubility limited absorption
(drug partitioning into micelle
resulting in lower concentration
of the ‘‘free’’ drug)
L.F. Huang, W.-Q. Tong / Advanced Drug Delivery Reviews 56 (2004) 321–334
crucial to the key decision-making in assessing
developability.
3.3. Solid state properties
For a highly soluble, bioavailable, and stable drug
candidate, the risk of significant impact on product
performance due to form changes of drug substance
during manufacturing and formulation processing is
relatively low and is typically manageable.
For poorly soluble compounds, or compounds with
poor solution stability, since the solid state properties
have significant impact on solubility and stability,
ability to make a desirable solid state form (salt and
crystalline form) is an important consideration for
developability assessment. Processes to screen and
select the salt and crystalline form will be discussed
later on.
Hygroscopicity is an important criteria to consider when assessing developability. If hygroscopicity is coupled with stability problem, the challenge
to develop stable formulations may become more
significant.
In general, effort should be made to avoid
developing amorphous material since amorphous
compounds carry inherent risk due to their physicochemical nature.
However, after considerable effort to make crystalline material, it is possible that only amorphous
material can be made during the candidate evaluation
phase. In this case, the risk of progressing such a
compound needs to be carefully assessed. Questions
to address include:
.
Based on solubility and permeability data, will the
conversion of the amorphous material to a crystalline
form later significantly impact the bioavailability?
. Is it feasible to formulate the amorphous material
(including both chemically and physical stability
considerations)?
. Is it feasible to formulate the amorphous material as
solid dispersion?
3.4. Synthetic process scalability
Another important aspect of developability is the
ability to scale-up the manufacturing of the desired
salt and crystal form. Some compounds may exist in
327
multiple readily desolvated solvates/hydrates. Others
may have polymorphs that have very similar thermodynamic stability, resulting in concomitant polymorphs [34]. In these cases, making the desirable
form consistent and reproducible at larger scale may
be extremely challenging. Having a good understanding of the complexity of the polymorphism issue will
help identify issues on the scalability. Thus, ability to
scale-up should be an important part of the salt and
form screening and selection process.
4. Phase appropriate strategies for studying solid
state properties
4.1. Lead identification and lead optimization phases
During the lead identification and lead optimization phases, the main objectives of developability
assessment are to identify the need for physicochemical property improvement such as solubility and
stability, and to profile them so that structural property
relationships can be established.
As discussed previously, only equilibrium solubility results are reliable enough for structure property
relationships. Thus the solid state property studies
should focus on monitoring solid state form, mainly
for checking if the material is amorphous or crystalline since the difference in solubility is most significant between crystalline and amorphous materials.
Sometimes, small-scale crystal form screening may
be necessary to discover the possibility of crystallization for representative lead compounds that are in the
amorphous form. Since the material available during
these phases is typically in very amount quantity,
miniaturization of crystallization is essential. Authors’
experience is that structure property relationship
building from a small but representative set of compounds with good quality data coupled with computational property prediction can often address the need
for the quality data that are required for the purposes
of developability assessment, yet does not sacrifice
the speed and throughput.
The risks for not studying the solid state properties
during these stages of discovery may involve variable
(batch dependent) in vivo efficacy and/or PK results,
poor structure solubility relationships, and identification of lead compounds with poor developability prop-
328
L.F. Huang, W.-Q. Tong / Advanced Drug Delivery Reviews 56 (2004) 321–334
erties that are only realized after the crystal form impact
on solubility is later brought into the equation during
the candidate evaluation or preformulation stages. This
will make it rather difficult to incorporate the desirable
pharmaceutical properties into the molecular design.
4.2. Candidate evaluation and selection phase
After lead optimization narrows down to a few
possible candidates for development, the key physicochemical properties of these candidates need to be
studied in more detail so that these properties can be
considered as part of the final selection criteria. The
solid state properties including salt and crystal forms
should be studied so that developability criteria discussed in previous section can be assessed. The
thermodynamically most stable form should be identified and tested in PK studies for compounds that
show solubility and dissolution rate limited absorption.
5. Salt and crystal form screening and selection
processes
Depending on the properties of drug candidates,
processes for salt and crystal form screening and
selection can vary.
Typically, it is desirable to have salt and crystal
form screening and selection completed prior to any
GLP toxicology studies since such studies are very
expensive and time consuming. However, for some
compounds, it may be feasible to delay selecting the
final salt and crystal form until a later stage in
development. For example, in some cases multiple
candidates may be tested in human studies, and only
one candidate will be developed to a final product. To
balance the resources and risks, a critical risk assessment should be done to determine whether it is a better
utilization of resources to delay the salt and crystal
form screening and selection until after the clinical
studies narrow down to the final candidate [26,35].
Several strategies and decision trees for salt and
crystal form selection processes have been proposed
recently [35 –39]. Some processes place the emphasis
on process and the ability to scale-up, while others
focus on maximizing solubility and on bioavailability
enhancement. The choice of which strategy to employ
may partially depend on who is driving the salt
screening and selection process within the organization. However, a rational process and decision tree
should balance various considerations in process
parameters, biopharmaceutical properties and physicochemical properties needs. It should also balance
resources and risks. Typically, to assure consistent
Fig. 2. Schematic representation of a multi-tier approach for the selection of optimal salt form for a drug.
L.F. Huang, W.-Q. Tong / Advanced Drug Delivery Reviews 56 (2004) 321–334
product quality and performance throughout shelflife, the thermodynamically most stable form is
preferred.
Morris et al. [36] took a multi-tier approach where
salts can be screened for their optimal physical form
(Fig. 2). An updated version of this approach was
reported by Serajuddin and Pudipeddi [37]. In this
approach, certain physicochemical properties of salts
are studied at each tier, and critical ‘‘Go/No Go’’
decisions are made based on the results of those studies.
Tong et al. [26,27,35] proposed a process that is
more applicable to poorly soluble compounds (Fig. 3).
Since maximizing solubility and absorption is the key
objective for poorly soluble compounds, this process
uses an in situ salt screening method as the first step to
screen out insoluble compounds. The key advantage
of this approach is that it conserves resources and drug
329
substance by minimizing the number of PK studies
required and the number of solid salts that must be
prepared and characterized.
6. Crystallization methods
To obtain various crystal forms, various crystallization methods can be used. Crystallization from
solution and recrystallization from neat drug substance are two most commonly applied methods [40].
For crystallization from solution, a typical procedure involves first selecting a series of crystallization
solvents to dissolve the compound. The filtrates are
used for crystallization with evaporation, temperature
gradient and cycling. Depending on the solubility of
drug candidates in these solvents, some of these
Fig. 3. Salt selection decision tree for insoluble compounds.
330
L.F. Huang, W.-Q. Tong / Advanced Drug Delivery Reviews 56 (2004) 321–334
Table 6
Commonly used crystallization solvents in crystal form screening
Solvent
Boiling
point
(jC)
Dielectric
constant
(q)
Proton
donor/
acceptor
N,N-dimethylformamide
Acetic acid
Water
1-Propanol
2-Propanol
Acetonitrile
2-Butanone
Ethyl acetate
Ethanol
n-Hexane
Isopropyl ether
Methanol
Acetone
Methylene chloride
Diethyl ether
153
118
100
97
83
82
80
77
78
69
68
65
57
40
35
37
6.2
78.4
20.3
19.9
37.5
18.5
6.0
24.6
1.9
3.9
32.2
20.7
8.9
4.3
A
D>A
D–A
A>D
A>D
A
A
A
A>D
N
A
A>D
A
N
A
solvents can be used as anti-solvents. For weak acids
or bases, changing solution pH is also often used as a
crystallization tool. Table 6 shows a list of solvents
typically used for crystallization.
Pharmaceutical companies are considering their
options to enhance efficiency in the search for the
desirable salt and crystal form, either by expanding
their capability internally, purchasing tools or by
outsourcing [11]. Several high throughout methods
with automated or semi-automated sample handling
and characterization for salt and crystal form screening
has recently been reported [11,41,42]. While these new
methodologies provide extra capacities for solid form
discovery, it does not replace detailed form characterization to understand interrelationship of various
forms. Additionally, the key objective of form screening for developability assessment may be to identify
the thermodynamically stable form and the possibility
of hydrate, not necessarily to discover all the possible
crystal forms. Thus, before engaging in massive
screening, it is very important that the goals of the
screening and process of decision-making are put in
place. Lower throughout with more selective and
targeted screening using more descriptive technologies
may just be as effective in meeting the objective.
One of the methods that is very useful in identifying the thermodynamically stable form is the slurry
experiment. Typically an aqueous based solvent and a
water-free solvent are chosen for the purpose of
identifying the most stable anhydrous form and the
possibility of any hydrate formation. After various
Fig. 1. DSC curves for NCEX: bottom, ethanolate; top, ethanolate sample stored at 80 jC/75% RH for 20 days.
L.F. Huang, W.-Q. Tong / Advanced Drug Delivery Reviews 56 (2004) 321–334
forms from crystallization solvents are mixed in these
two solvents and equilibrated for a period of time at
room temperature or through temperature cycling, a
conversion of various forms to the thermodynamically
stable form or the hydrate typically will occur.
Often many thermodynamically more stable forms
are discovered after the process is scaled up. In a
comparison of small-scale screening with large-scale
production, the major differences are the presence of
impurities and the time required for crystallization.
Thus, as a general rule, the purest material available
(>99% pure) should be used for crystal form screening. If the purity of the material is questionable, a
purification process such as prep-scale LC should be
carried out to purify the material.
For crystalline solvates, thermal desolvation via
heating and pressure stressing can create suitable
environments for anhydrous forms to form. The
desolvation process of a non-reversible solvate
includes the following steps: molecular loosening,
breaking of the host – solvent hydrogen bonds, solution or solid solution formation and finally crystallization of the new phase. The heat and pressure
stressing of crystalline solvates may transform solvent
from ‘‘lattice glue’’ to ‘‘lattice grease’’. Huang et al.
[43] reported the formation of a new anhydrous form
after storing an ethanolate at 80 jC for 20 days in a
small vial containing a small tube of saturated sodium
chloride solution, which creates an environment for
80 jC/75% RH. The DSC curves of the ethanolates
before and after storage are shown in Fig. 1.
The effect of formulation on crystallization cannot
be overlooked. Solid dispersions or high viscosity
lipid-based formulations can be ideal environments
for the formation of a more stable crystal form.
Solubility screening using these non-aqueous solvents
should always include an examination of the residual
solid to detect any potential crystal form conversion.
7. Case studies
7.1. Example A: impact of crystal form on solubility
in lead identification and optimization phases
Compound A is a representative compound in a
structure series containing a benzimidazole scaffold.
The material first prepared by chemists was amor-
331
phous and the apparent solubility in pH 6.8 phosphate
buffer was close to 1 mg/ml after 24 h equilibration.
After the solubility sample was further equilibrated for
1 week at room temperature, the solubility decreased
to 0.001 mg/ml. The residual material has a melting
point of over 300 jC and the heat of fusion close to
150 kJ/mol.
The benzimidazole plain structure was considered
partially responsible for the close packing of this
molecule, resulting in the high crystallinity. The
chemistry strategy was then to modify certain structural features to disrupt the plain structure and to
introduce functional groups to increase the pKa. Representative compounds from the same structure series
after certain structural modifications were selected for
solubility studies. Equilibrium solubilities were determined and residual materials from the solubility
samples were examined by DSC. These data were
used to build a structure solubility relationship. A
candidate with desirable potency and selectivity along
with improved solubility in pH 6.8 phosphate buffer
was successfully identified. The bioavailability of this
candidate in rats was shown to be f40% from the
suspension of the crystalline material compared to 2 –
5% of the first candidate tested prior to structural
modification to improve solubility.
7.2. Example B: impact of the crystalline form on
bioavailability
Example B involved a project team with a goal of
identifying a more potent, more selective anti-viral
drug candidate with a desirable developability profile.
The current product on the market requires a twice
daily dosing and patients need to take two soft-gelatin
capsules. Several competitors were also developing
next generation drugs and they were targeting for a
tablet formulation suitable for once daily dosing.
Market analysis showed that in order for the drug
candidate to be successful, it has to have the properties that will enable very short development timeline
and a table formulation.
The lead candidates were all in their amorphous
stage when chemists first made them. Compounds are
not ionizable, so salt formation is not an option for
enhancing solubility and dissolution rate. Solubilities
of these lead compounds in two different structure
series are in the range of 10 – 100 ug/ml in water with
332
L.F. Huang, W.-Q. Tong / Advanced Drug Delivery Reviews 56 (2004) 321–334
a projected dose in the range of 250 –500 mg. Bioavailabilities of several lead compounds were compared in rat using PEG400 solution and suspension of
the amorphous material (with particle size controlled
to <10 ug). Bioavailabilities from PEG400 formulations are in the range of 50– 80% compared to the
bioavailabilities of 20 – 50% from suspensions.
The key issue to address in candidate selection was
the impact of crystal form on the bioavailability.
Developing amorphous material would present significant challenges in this case since conversion of the
amorphous material to a crystal form is most likely to
reduce the bioavailability significantly. A compound
that gives best bioavailability from suspension of the
crystalline material can have significant advantage in
developability.
The strategy was then to carry out crystal form
screening of top five lead compounds and repeat the
PK studies using the most thermodynamically stable
form of each compound. The PK results from these
studies were then used as criteria for lead compound
selection.
7.3. Example C: impact of crystal form on stability
Compound C is an acidic lead compound containing a group that can undergo acid catalyzed hydrolysis. Stability screening in 0.1 M HCl showed that the
half-life of this compound is <30 min. However, the
solubility of this compound is very low in 0.1 N HCl
(<0.001 mg/ml). The question is should improving the
chemical stability be part of the lead optimization
strategy?
To assess the impact of this stability issue on the
solid dosage development, a small-scale crystal form
screening was carried out using 200 mg material. A
very fine needle shaped crystalline material with a
melting point of about 160 jC (Form I) was discovered along with a meta-stable form (Form II) with a
melting point of 140 jC. After 4 weeks storage at 40
jC/75% RH, Form I shows 0.3% total degradation
compared to 6% for Form II and 20% for amorphous
material.
These results suggest that it may be feasible to
develop a solid dosage form of this compound.
However, significant challenges are to be expected
with process control during chemical synthesis and
formulation processing in order to process the needle
shaped crystalline while avoiding generating amorphous material. Based on this assessment, the team
decided to include stability enhancement as part of the
lead optimization whenever possible. The final candidate selected showed a half-life of 6 h in 0.1 HCl.
The solid stage stability was also significantly enhanced. Only 3% degradation was observed after 4
weeks storage at 40 jC/75% RH with the amorphous
material while no degradation was observed for the
crystalline material.
8. Conclusions
Solid state properties including polymorphs, solvates and salt formations have profound impact on
solubility and stability. To be able to assess the
developability of drug candidates and provide input
to the molecular design regarding the biopharmaceutical properties, one must take into account the impact
of solid state properties on solubility and stability. The
phase appropriate characterization strategies and appropriate salt and crystal form screening and selection
processes should balance the need of speed and
throughput of modern discovery with the quality of
data needed for key decisions regarding the developability assessment, thus balance and minimize resource needs and risks.
Acknowledgements
The authors wish to acknowledge helpful discussions with colleagues at GlaxoSmithKline, especially
Dr. Richard Winnike, Dr. Om Dhingra, Dr. Graham
Whitesell, Dr. Dave Igo, Dr. Joel Sutton. Special
thanks also go to Dr. J. Keith Guillory of the
University of Iowa for his editorial comments.
References
[1] C.A. Lipinski, Experimental and computational approaches to
estimate solubility and permeability in drug discovery and
development settings, Adv. Drug Deliv. Rev. 23 (1997) 3 – 25.
[2] C.A. Lipinski, Poor aqueous solubility—an industry wide
problem in drug discovery, Am. Pharm. Rev. 5 (3) (2002)
82 – 85.
[3] S. Venkatesh, R.A. Lipper, Role of the development scientist
L.F. Huang, W.-Q. Tong / Advanced Drug Delivery Reviews 56 (2004) 321–334
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
in compound lead selection and optimization, J. Pharm. Sci.
89 (2000) 145 – 154.
E.H. Kerns, High throughput physicochemical profiling for
drug discovery, J. Pharm. Sci. 90 (2001) 1838 – 1858.
C. Bevan, R.S. Lloyd, A high throughput screening methods
for the determination of aqueous drug solubility using laser
nephelometry in microtiter plates, Anal. Chem. 72 (2000)
1781 – 1787.
A. Aveef, High throughput measurements of solubility profiles, in: B. Testa, H. van de Waterbeemd, G. Folkers, R. Guy
(Eds.), Pharmacokinetic Optimization in Drug Research: Biological, Physicochemical, and Computational Strategies, Verlag Helvictica Chimica Acta, Zurich, Switzerland, 2001, pp.
305 – 326.
H.Y. Ando, G.W. Radebaugh, Preformulation, in: A.R. Gennaro (Ed.), Remington, the Science and Practice of Pharmacy,
20th ed, Lippincott, Williams & Wilkins, Philadelphia, PA,
2000, pp. 700 – 720.
D.J.W. Grant, T. Higuchi, Solubility Behavior of Organic
Compounds, Wiley, New York, 1990.
S. Yalkowsky, Solubility and Solubilization in Aqueous Media, American Chemical Society, Washington, DC, 1999.
S.R. Byrn, R.R. Pfeiffer, J.G. Stowell, Solid-State Chemistry
of Drugs, 2nd ed., SSCI, West Lafayette, 1999.
O. Almarsson, C.R. Gardner, Novel approaches to issues of
developability, http://www.currentdrugdiscovery.com, January
2003, 21 – 26..
G. Davies, Changing the salt, changing the drug, Pharm. J.
266 (2001) 322 – 323.
L.D. Bighley, S.M. Berge, D.C. Monkhouse, Salt forms of
drugs and absorption, in: J. Swarbrick, J.C. Boylan (Eds.),
Encyclopedia of Pharmaceutical Technology 13,Marcel Dekker, New York, 1995, pp. 453 – 499.
W.Q. Tong, G. Whitesell, In situ salt screening—a useful
technique for discovery support and preformulation studies,
Pharm. Dev. Tech. 3 (1998) 215 – 223.
B.C. Hancock, M. Parks, What is the true solubility advantage for amorphous pharmaceuticals?, Pharm. Res. 17
(2000) 397 – 404.
Anon, Manufacturing problems hit Abbott’s HIV drug ritonavir, Pharm. J. 261 (1998) 150.
S.R. Chemburkar, J. Bauer, K. Deming, H. Spiwek, K. Patel,
J. Morris, R. Henry, S. Spanton, W. Dziki, W. Porter, J. Quick,
P. Bauer, J. Donaubauer, B.A. Narayanan, M. Soldani, D.
McFarland, K. McFarland, Dealing with the impact of ritonavir polymorphs on the late stages of bulk drug process development, Org. Process Res. Dev. 4 (2000) 413 – 417.
R. Liu, Water Insoluble Drug Formulation, Interpharm Press,
Boca Raton, FL, 2001.
W.Q. Tong, Applications of complexation in the formulation
of insoluble compounds, in: R. Liu (Ed.), Water Insoluble
Drug Formulation, Interpharm Press, Boca Raton, 2001.
H.G. Brittain, D.J.W. Grant, Effects of polymorphism and
solid state salvation on solubility and dissolution rate, in:
H.G. Brittain (Ed.), Polymorphism in Pharmaceutical Solids,
Marcel Dekker, New York, NY, 1999, pp. 279 – 330.
L.F. Huang, Z. Bao, Crystal form screening and selection as
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38]
333
part of the developability evaluation for a drug candidate,
AAPS Annual Meeting and Exposition, Denver, CO, 2001.
R.D. Schoenwald, Pharmacokinetics in Drug Discovery and
Development, CRC Press, Boca Raton, FL, 2002.
A.J. Aguiar, J. Krc, A.W. Kinkel, J.C. Samyn, J. Pharm. Sci.
56 (1967) 847.
J.K. Pandit, S.K. Gupta, K.D. Gode, B. Mishra, Effect of
crystal form on the oral absorption of phenylbutazone, Int.
J. Pharm. 21 (1984) 129 – 132.
Y. Kato, M. Kohketsu, Relationship between polymorphism
and bioavailability of amobarbitol in the rabbit, Chem. Pharm.
Bull. 29 (1981) 268 – 272.
W.Q. Tong, Crystal form screening and selection strategies in
the accelerated drug discovery and development process: balancing resources and risks, Polymorphism and Crystallization
in Pharmaceutics Conference, Philadelphia, PA, June 15 – 16,
2000.
W.Q. Tong, G. Alva, D. Carlton, F. Viscomi, K. Adkison, A.
Millar, O. Dhingra, A strategic approach to the salt selection
of an insoluble drug candidate, 13th AAPS Meeting, New
Orleans, 1999.
S. Yoshioka, V.J. Stella, Stability of Drugs and Dosage
Forms, Kluwer Academic Publishers, Plenum Publishers,
NY, 2000.
J.K. Guillory, R.I. Poust, Chemical kinetics and drug stability,
in: G.S. Banker, C.T. Rhodes (Eds.), , 4th ed., Modern Pharmaceutics. Drugs and the Pharmaceutical Sciences 121,MarMarcel Dekker, New York, NY, 2002, pp. 139 – 166Revised
and expanded.
K. Johnson, A. Swindell, Guidance in the setting of drug
particle size specifications for minimizing variability in absorption, Pharm. Res. 13 (1996) 1795 – 1798.
W. Curatolo, Physical chemical properties of oral drug candidates in the discovery and exploratory development settings,
Pharm. Sci. Tech. Today 1 (1998) 387 – 393.
G.L. Amidon, H. Lennernas, V.P. Shah, J.R. Crison, A theoretical basis for a biopharmaceutic drug classification: the
correlation of in vitro drug product dissolution and in vivo
bioavailability, Pharm. Res. 12 (1995) 413 – 420.
W.Q. Tong, Solubility and stability screening: theoretical and
practical considerations, AAPS Meeting, Indianapolis, IN,
Oct. 31, 2000.
J. Bernstein, R.J. Davey, J. Henck, Concomitant polymorphs,
Angew. Chem. Int. Ed. 38 (1999) 3440 – 3461.
W.Q. Tong, L.F. Huang, Salt and crystal screening and selection strategies in accelerated drug discovery and development
processes, Polymorphism and Crystallization in Pharmaceutics Conference, Philadelphia, PA, June, 2002.
K.R. Morris, M.G. Fakes, A.B. Thakur, A.W. Newman, A.K.
Singh, J.J. Venit, C.J. Spagnuolo, A.T.M. Serajuddin, An integrated approach to the selection of optimal salt form for a
new drug candidate, Int. J. Pharm. 105 (1994) 209 – 217.
A.T.M. Serajuddin, M. Puddipeddi, Salt-selection strategies,
in: P.H. Stahl, C.G. Wermuth (Eds.), Handbook of Pharmaceutical Salts, VHCA and Wiley-VCH, Weinheim, 2002, pp.
135 – 160.
R.J. Bastin, M.J. Bowker, B.J. Slater, Salt selection and opti-
334
L.F. Huang, W.-Q. Tong / Advanced Drug Delivery Reviews 56 (2004) 321–334
mization procedures for pharmaceutical new chemical entities,
Org. Process Res. Dev. 4 (2000) 427 – 435.
[39] M.J. Bowker, A procedure for salt selection and optimization,
in: P.H. Stahl, C.G. Wermuth (Eds.), Handbook of Pharmaceutical Salts, VHCA and Wiley-VCH, 2002, pp. 161 – 190.
[40] K. Guillory, Generation of polymorphs, hydrates, solvates and
amorphous solids, in: H.G. Brittain (Ed.), Polymorphism in
Pharmaceutical Solids, Marcel Dekker, New York, NY, 1999,
pp. 183 – 226.
[41] R. Hilfiker, Including high throughout polymorphism screen-
ing as part of an integrated approach to solid state issues,
Barnett International Polymorphism and Crystallization Conference, Philadelphia, PA, June 5 – 6.
[42] R. Jain, Implementing high-throughput workflows in preformulation, Barnett International Polymorphism and Crystallization Conference, Philadelphia, PA, June 5 – 6, 2003.
[43] L.F. Huang, C. Spancake, G. Limentani, A. Vickers, B. Lancaster, Effect of various factors on the physical stability of the
ethanol solvate of compound X, AAPS Annual Meeting and
Exposition, San Francisco, CA, 1998.