Current Bioactive Compounds 2008, 4, 213-224 213

Amorphous Active Pharmaceutical Ingredients in Preclinical Studies:

Preparation, Characterization, and Formulation
Karthik Nagapudi* and Janan Jona
Small Molecule Process and Product Development, Amgen Inc. Thousand Oaks, CA, USA

Abstract: A large number of the new pharmaceutical small molecules under development today are found to have poor
water solubility. This in turn may lead to low bioavailability, which can have a significant impact on the development of
the compound. Compounds with low bioavailability pose a greater challenge in early preclinical work involving animal
studies, where obtaining maximum exposure is the primary goal especially in toxicology studies designed to establish the
safe dose.
From the standpoint of maximizing exposure, the amorphous phase is of great interest as pharmaceutical materials since it
is the most metastable state and as such offers the potential of higher solubility and better bioavailability. However, the
amorphous approach is not actively pursued in preclinical work owing to the tendency of the amorphous phase to
crystallize thereby neutralizing the solubility advantage. This review focuses on (i) methods to generate the amorphous
phase, (ii) methods to estimate the degree of crystallinity of the amorphous phase, (iii) methods to predict the stability of
the amorphous phase against crystallization, and (iv) choice of polymers carrier and formulation of the amorphous phase
for preclinical studies.
Keywords: Amorphous pharmaceuticals, crystallization, preclinical, solid dispersions.

1. INTRODUCTION context, utilizing the amorphous phase of the compound is

Increased use of high throughput methods in drug
discovery and lead optimization has lead to compounds with
more lipophilic properties that exhibit poor water solubility.
The number of poorly soluble compounds range from 40-
50% of the entire portfolio of new molecules in major
pharmaceutical companies. Such compounds under the
biopharmaceutical classification system (BCS) fall into class
II and IV [1, 2]. Class II compounds have low aqueous
solubility and high intestinal permeability while class IV
compounds have low aqueous solubility and low intestinal
permeability. While low solubility compounds may pose
significant development challenge in the clinical arena, these
challenges are exacerbated in the preclinical arena where the
goal is to increase exposure many fold when compared to the
therapeutic dose. For example, preclinical toxicology studies
often aim to maximize exposure in order to assess the
detrimental effects of the development compound. In these
studies it is not uncommon for doses to be as high as 100-
200 times the predicted ED50 dose in humans [3]. In case of
compounds with solubility limited absorption, exposure
tends to plateau at a dose beyond which it does not increase.
Thus there is a much greater need in the preclinical arena to
increase exposure and as such preformulation groups are
actively involved in this area. While formulation approaches
have minimal impact on permeability, they can play a
significant role in improving solubility/dissolution rates. As
such increasing importance is being given to devising new
and better formulation approaches for poorly water soluble
compounds. To this end several approaches such as changing
polymorphic form, particle size reduction, salt formation and
use of solubility enhancers have been attempted. In this
*Address correspondence to this author at the Small Molecule Process and
Product Development, Amgen Inc. Thousand Oaks, CA, USA;
E-mail: karthikn@amgen.com
gaining relevance for pharmaceutical materials of poor
solubility since it is the most metastable state and as such
offers the promise of highest solubility and improved
dissolution rates. The amorphous phase is usually defined
with reference to its crystalline counterpart. Whereas the
crystal is defined by specific long range order, the amor-
phous phase is defined by the lack of such long range order.
Hancock et al. have shown that the solubility advantage of
the amorphous phase is likely to be several-fold higher than
their crystalline counterparts [4].
In spite of the solubility advantage provided by
amorphous materials, they are largely avoided during drug
development due to physical/chemical stability issues and
processing difficulties. The amorphous form tends to be
more chemically unstable than their crystalline counterparts.
However from a development standpoint, the physical
instability is the most problematic. Implicit in the term
physical stability is the resistance of the amorphous material
towards reversion to the thermodynamically favored
crystalline phase. There have been a number of publications
in the last few years where issues pertaining to amorphous
solids have been discussed [5-9]. Typically, physical
stability has been discussed in terms of relaxation times
(molecular mobility) that have been measured spectro-
scopically or calorimetrically. In spite of the progress made,
predicting the propensity for amorphous materials to
crystallize still remains challenging. While the problem of
predicting amorphous stability against crystallization is more
acute for clinical development it is less so for preclinical
studies. From the preclinical standpoint moderate stability of
three to six months for the solid active pharmaceutical
ingredient (API) and about a week worth of stability of the
API in the formulation is sufficient to progress the amor-
phous compound through all the required preclinical studies.

1573-4072/08 $55.00+.00 © 2008 Bentham Science Publishers Ltd.

214 Current Bioactive Compounds 2008, Vol. 4, No. 4
Thus, the issues pertaining to the development of amor-
phous materials for preclinical studies are quite different
from that for clinical studies. With the development of
increasingly potent compounds where the therapeutic doses
are low (0.15 to 1.5 μg/Kg) the real advantage of the
amorphous materials for low solubility compounds are
expected to be in the preclinical area rather than the clinical
area. While there are many papers that deal with amorphous
materials in general, there are no papers that exclusively
focus on development of amorphous materials for use in the
preclinical area. This review aims to fill this gap in the
literature. This paper focuses on (i) methods to generate the
amorphous phase, (ii) methods to estimate the degree of
crystallinity of the amorphous phase, (iii) methods to predict
the stability of the amorphous phase against crystallization,
and (iv) choice of polymer carriers and formulation of the
amorphous phase for preclinical studies.
2. METHODS TO GENERATE THE AMORPHOUS
PHASE
In order to assess the suitability of the amorphous phase
for preclinical work a number of studies have to be
performed. To facilitate these studies, the amorphous active
pharmaceutical ingredient (AAPI) or the amorphous API in
combination with a pharmaceutically acceptable polymer
must be generated. API-polymer combinations that are
amorphous are denoted as amorphous solid dispersions
(ASD). Table 1 lists the typical lab scale techniques that can
be used to make amorphous materials. While a number of
these lab-scale techniques are suitable for making a few
hundred milligrams to a gram of AAPI/ASD, they cannot be
scaled up. Melt quenching is a useful technique to produce
small quantities of amorphous phase for preliminary
evaluation. Melt quenching can only be applied to API’s that
are thermally stable. There are some reports in literature of
using melt quenching to produce the AAPI/ASD [10-12].
However, the materials produced have been predominantly
used to gauge amorphous stability against crystallization.
Milling techniques such as ball milling and cryogrinding [13,
14] are also useful to make small quantities of amorphous
materials. Their primary advantage lies in the fact that they
Table 1. Methods of Preparing Amorphous API and Amorphous Solid Dispersions
Technique AAPI1 ASD2
Melt quenching Y Y
Ball Milling Y Y
Cryogrinding Y Y
Lyophilization Y Y
Spray drying Y Y
Desolvation4 Y N
Precipitation Y Y
1
AAPI: Amorphous active pharmaceutical ingredient
2
ASD: Amorphous solid dispersions (API + Polymer)
3
Low end represents yields at small scale (<500 mgs) and high end represents yield at larger scales (> 1g).
4
Applicable only when amorphous phase is formed upon desolvation.
Y: Yes; N: No
Nagapudi and Jona
are widely available techniques which require very little in
terms of training. The final product of milling among other
things will depend on the milling temperature and its
relationship to glass transition temperature of the API and
the strength of the crystal. Descamp et al. have shown that
the milling product will be amorphous if the milling
temperature is below the glass transition temperature of the
API [15]. Thus cryogrinding that is performed at liquid
nitrogen temperatures is more likely to produce amorphous
material than ball milling but is more laborious to operate.
Desolvation is a specialized technique that is also described
in literature [16, 17] for those organic solvates that desolvate
to produce an amorphous phase. Depending on the deso-
lvation temperature this can be a useful technique to produce
gram quantities of amorphous phase. However of the
techniques mentioned so far, desolvation is the only one that
cannot be used to make ASD. Also of note is that the
methods that are not scalable are dry methods of making the
amorphous material i.e. methods without involvement of
solvent in the process.
The remaining three methods namely: Lyophilization,
spray drying and precipitation are capable of being run on
scale. Lyophilization is highly limiting in its scope when
applied to organic small molecules with poor aqueous
solubility. Although lyophilization can be performed with
organic solvents it is not a preferred technique since
complete removal of solvent from the system may be
challenging. Spray drying [18] and precipitation techniques
have both been used to make large quantities of AAPI and
ASD material. While both techniques are comparable in the
quality of AAPI they produce, they differ in the quality of
the ASD they produce. For making ASD materials spray
drying is generally a better method than precipitation as it
gives more phase mixed material. Phase separation between
the API and the polymer is not desired while making the
ASD’s since this can cause crystallization of the API [19].
Precipitation technique can also be optimized to yield ASD
that are better phase mixed, however this may take more
time and effort. While spray drying and precipitation remain
preferred methods of generating AAPI and ASD, the yields
from these processes are different. Yield is an important
Yield3 Scalability
60-70% N
50-70% N
40-50% N
75-85% Y
40-75% Y
- N
75-85% Y
Amorphous Active Pharmaceutical Ingredients in Preclinical Studies
consideration especially in preclinical studies, where the
quantity of material available for evaluation is limited.
Precipitation in general has higher yields than spray drying.
Yields for spray drying can be improved at larger scale (>1
gram). Another important technique that has been used in the
past to generate large quantities of AAPI or ASD is hot melt
extrusion [20]. Hot melt extrusion has not been included in
the list in Table 1 since it requires a minimum of 2 to 5
grams to operate and as such is not a useful technique for
preclinical evaluation studies.
3. METHODS TO QUANTIFY THE AMOUNT OF
CRYSTALLINITY IN THE AMORPHOUS PHASE
Even small amounts of crystalline material can
profoundly affect the in-vivo performance of the amorphous
material [4]. Thus, once the AAPI or ASD is generated, it is
important to have a good analytical tool to monitor the
crystallinity in the samples. There are numerous analytical
tools that are available to quantify the crystallinity based on
differences in physico-chemical properties between the
crystalline and amorphous phases (e.g. density, viscosity, x-
ray diffraction and so forth) [21]. X-ray powder diffraction
(XRPD) [22-25] and differential scanning calorimetry (DSC)
[26-28] have been widely used for this purpose as these
techniques are usually available in most pharmaceutical labs.
Limit of detection (LOD) and the limit of quantitation
(LOQ) of crystallinity often tend to be better with DSC. DSC
also requires much less material than XRPD. DSC in both
standard and modulated modes has been used to quantify
extent of crystallinity [29, 30]. An example of crystallinity
quantitation for Lactose using modulated DSC is shown in
Fig. (1). The specific heat capacity change across glass tran-
sition is used to build the calibration curve.
Use of spectroscopic tools such as Raman, IR, and NIR
has also been reported in literature for crystallinity quanti-
(a)
Fig. (1). Amorphous quantitation of spray dried lactose using modulated DSC. (a) Modulated DSC thermogram of spray dried lactose
showing total heat flow and reversing heat flow. Glass transition temoperature (Tg): 81.2 ºC and specific heat capacity change across glass
transition (
Cp) = 0.5 J/g/ºC. (b) Calibration curve for determining the weight percentage amorphous lactose in crystalline lactose showing
the specific heat capacity change across glass transition temperature as a function of amorphous lactose content. R2 =0.99.
Current Bioactive Compounds 2008, Vol. 4, No. 4 215
tation [31-34]. With the advent of chemometric techniques,
spectroscopic methods have become attractive tools for
phase quantitation. They provide chemically resolved infor-
mation with sparse material requirements. However, data
interpretation from spectroscopic methods can run into
problems because of their inability to unambiguously
separate peaks from different phases in the sample. Solid
state NMR (SSNMR) is another powerful technique that has
not been that widely used [27, 35]. SSNMR’s primary
advantage lies in its selectivity and its ability to probe a
variety of nuclei. Among the methods mentioned so far
SSNMR is the only technique that does not require a pure
reference standard for phase quantitation. LOQ down to
0.25% can be achieved when 1H, 31P, or 19F nuclei are used
for quantitation while LOQ of about 3% can be achieved
when using 13C. In spite of its inherent advantages SSNMR
usage has been limited owing to instrument availability and
large sample size requirements (60-200 mgs). An example of
crystallinity quantitation for Sulindac using 19F SSNMR is
shown in Fig. (2). The differences in 19F T1 relaxation rates
can be used to quantify the extent of crystallinity.
Solution calorimetry is another popular technique to
determine extent of crystallinity, as the amorphous phase has
in general a different heat of dissolution than the crystalline
phase. Over the last few years a host of other techniques
such as thermally stimulated depolarization current (TSDC)
[36], dielectric (DES) and dynamic mechanical analysis
(DMA) have also been used to quantify crystallinity. While a
number of techniques are available crystallinity quantitation,
XRPD, DSC, and SSNMR remain the primary tools.
The quantitation of the crystallinity in ASD can be more
challenging than in the AAPI. The amount of the API in the
ASD material could be as low as 10% and as such
interference from the polymer becomes the major challenge
(b)
216 Current Bioactive Compounds 2008, Vol. 4, No. 4 Nagapudi and Jona

(a) (b)
Fig. (2). (a) 19F SSNMR spectra of crystalline and amorphous Sulindac. The crystalline line shape is narrower than the amorphous line shape.
(b) 19F T1 relaxation data for crystalline and amorphous material. T1(crystal) = 72 seconds, T1(amorphous) = 2.1 seconds. The difference in
relaxation rates can be used to quantify extent of crystallinity.

in crystallinity quantitation. While, IR and Raman spectro-
scopies may work in some instances, in the majority of the
cases DSC and SSNMR are the primary tools. SSNMR
owing to its chemical selectivity can separate excipient peaks
from the API peaks. Moreover, if 19F nuclei are present in
the API, the API can be independently monitored from that
of the polymer [37]. Summary of the methods used to
estimate the extent of crystallinity is provided in Table 2. It
must also be borne in mind that the methods used to quantify
crytsallinity require AAPI or ASD relatively free of chemical
impurities. Presence of chemical impurities can confound
phase quantitation.
4. METHODS TO MEASURE AND PREDICT THE
PHYSICAL STABILITY OF THE AMORPHOUS
PHASE
4.1. Solid State Stability of AAPI
When amorphous phase is considered as a candidate for
clinical development, physical stability under normal storage
conditions is expected to be in the order of years. However,
when the amorphous is used solely for the purpose of
preclinical development, stability in the range of few months
is adequate. The shorter period of stability requirement
makes the amorphous phase a more viable candidate for
preclinical development. Thus from a preclinical perspective,
the best way of gauging amorphous stability remains
stressing the amorphous phase of known particle size under
typical accelerated conditions (25 ºC/60% relative humidity
or 40 ºC/75% relative humidity) for the required length of
time. A stability program is then established where the
amorphous material is withdrawn periodically and the degree
of crystallinity and glass transition are monitored using the
preferred analytical technique. Such stability programs take
time to implement and the therefore it is preferable to have
methods to predict the physical stability of the amorphous
phase.
Considerable progress has been in the last decade in
understanding the factors that influence crystallization from
the amorphous phase. In spite of the progress, prediction of
the physical stability of the amorphous phase remains

Table 2. Methods of Quantifying Crystallinity in Amorphous API and Amorphous Solid Dispersions

Technique AAPI ASD LOQ1 LOD2

X-ray Y N 5-10% 2-5%

DSC Y M 1-5 % <1%

SSNMR Y Y 0.5-5% 0.1-1%

Raman/IR Y M 2-5% 1-2%

TSDC Y M - -

DES Y M - -

Vapor sorption Y N 1-5% <1%

Solution calorimetry Y N 1-5% <1%

1
LOQ: Limit of quantitation
2
LOD: Limit of detection
Y: Yes; N: No; M: Maybe
Amorphous Active Pharmaceutical Ingredients in Preclinical Studies
challenging since crystallization from the amorphous phase
is influenced by a number of factors, whose individual
effects is not fully understood. The primary factors that
influence crystallization from the amorphous phase can be
divided into thermodynamic, molecular, and kinetic factors
[5]. The first factor relates to the excess properties of the
amorphous phase as related to the crystalline phase. If the
excess free energy is high between the crystalline and
amorphous states, then there will be a larger driving force for
crystallization. The excess free energy (Gex) at the tempe-
rature of interest T, between the amorphous and crystalline
states is given by:

G ex (T ) =
H ex (T )  T
S ex (T )
 S (T ) 

G ex (T ) = RT ln  a  (2)
 SC (T ) 
In equations (1) and (2) R is the gas constant, Sa is the
solubility of the amorphous phase and SC is the solubility of
the crystalline phase. The excess free energy can be
calculated if the specific heat capacity of the crystalline and
amorphous phases are known as a function of temperature.
Such thermodynamic predictions have proven to be prob-
lematic since the glass properties are function of thermal
history and time. In order to make meaningful estimates of
excess free energy a well annealed glass must be used. The
excess free energy can also be calculated from the solu-
bilities of the crystalline and amorphous phases. The
solubility of the amorphous phase is difficult to measure
owing to the tendency of the amorphous phase to crystallize.
Pikal et al. [5] have pointed out that solubility measurements
in the presence of crystallization inhibitors which do not
contribute to solubilization give better match between
experimental and predicted values of solubility enhance-
ment. Similarly it has been argued that if the excess entropy
between the amorphous and crystalline states is large then
there is a higher entropic barrier to crystallization. However,
the effect of entropy on crystallization rate has not been
clearly established [38, 39].
The second factor that affects crystallization from the
amorphous phase is molecular factors such as conformation
  (5)
and its ability to dictate three dimensional packing order.
Current Bioactive Compounds 2008, Vol. 4, No. 4 217
The glass transition process is non-exponential and non-
Arrhenius in its character [44]. It has been traditionally held
that materials held well below their glass transition tempe-
ratures are difficult to crystallize due to lack of molecular
motions needed to form the crystal nuclei that aids in the
subsequent growth of crystals. However the presence of
molecular motions well below Tg has been reported [45-47]
and as such Tg by itself may not be good indicator of
physical stability. In lieu of glass transition, molecular
mobility has been quantified in terms structural relaxation
time measurements. Correlation between physical stability of
the amorphous phase and relaxation time has been explored
in a large number of publications [39, 48-51]. Structural
(1) relaxation time can be determined in the time domain using
methods like DSC and thermal activity monitor or in the
frequency domain using methods like DES, SSNMR and
TSDC [52]. Since DSC is predominantly used in the
pharmaceutical literature for relaxation time measurements, a
brief account of the procedure is given below. The amor-
phous samples are annealed at various temperatures below
glass transition for different lengths of time. For each time
period the enthalpic recovery is measured. From the
enthalpic recovery the fraction of glass that has relaxed (t)
can be calculated using:
H t (T )
 (t,T ) = (3)
H
(T )
Where Ht(T) is the enthalpic recovery at a time t and a
temperature T. H
is the maximum enthalpic recovery at
the temperature T. H
can be calculated using:
H
= C p (Tg  T ) (4)
Where Cp is the heat capacity change across glass
transition that is observed at the start of the experiment and
Tg is the glass transition temperature. The relaxation time 
can be calculated by fitting (t) to the Kohlrausch-Williams-
Watts (KWW) equation.

t  
 (t,T ) = 1
exp 

  
Organic compounds with specific molecular conformations
that prevent long range order have been associated with the
formation of stable glasses. While molecular conformation
has been chosen as an explanation for crystallization tenden-
cies of organic small molecules in some cases [40], it is not
clear how this can be applied in practice to predict stability
against crystallization. However, molecular conformation
has been used more successfully in the predicting which
polymorph can crystallize from the amorphous phase rather
than the stability of the amorphous phase itself [41-43].
Among the three factors that influence crystallization,
kinetic factors remain the most important. Traditionally glass
transition temperature (Tg) has been used as a measure of
physical stability. The glass transition represents the
temperature at which the non equilibrium glass transforms to
the super cooled liquid. The glass transition (also referred to
as the alpha relaxation) is characterized by onset of low
frequency, large length-scale cooperative molecular motions.
 is a fitting parameter that represents the breadth or
skewness of the relaxation time distribution. Using Equation
(5) the average relaxation time  at a temperature T can be
calculated. Typically materials that have long relaxation
times (in order of hundreds of days to years) at the storage
temperature are said to be physically stable. Such measure-
ments can be done for either AAPI or ASD materials [10, 11,
49]. Relaxation time measurements provide an estimate for
the physical stability of amorphous materials using small
amounts of material and as such are useful measurements to
carry out while developing the amorphous phase as a
preclinical candidate. These measurements are carried out in
dry nitrogen atmosphere (~ 0% RH) in the DSC and
consequently do not shed any light on the effect of moisture
on crystallization. It is well known that moisture acts as a
plasticizer and reduces glass transition temperature and
218 Current Bioactive Compounds 2008, Vol. 4, No. 4
thereby can have a profound impact on glass transition and
the dynamics associated with glass transition.
Recent studies have been reported where crystal
nucleation has been found to occur at temperatures well
below the glass transition temperature [53]. It is believed that
at temperatures in the range of Tg-40 oC, the beta relaxation
is the dominant relaxation mechanism. As opposed to glass
transition (alpha relaxation), the beta relaxation is associated
with high frequency small length-scale molecular motions.
Examples of such localized motions include rotations of
methyl groups and ring flips in benzene groups. Such
motions well below Tg could lead to spontaneous formation
of crystal nuclei thereby generating physical instability in the
amorphous phase. Based on these observations it has been
argued that, if the storage temperature is well below Tg, then
beta relaxation process must be characterized (as it is the
dominant relaxation process) to make meaningful inferences
of amorphous stability. The beta process can be directly
observed and activation energies can be calculated when
DES and TSDC techniques are used [45]. If the activation
barrier is high, then the probability of nucleation is consi-
dered low. Recently Vyazovkin et al. have employed DSC to
study the beta relaxation in indomethacin [53, 54]. In this
study the beta relaxation manifests itself as an endothermic
peak below glass transition. By investigating the scanning
rate dependence of the temperature location of beta tran-
sition, the authors were able to calculate the activation
energy of the beta relaxation. Beta relaxation is an event
associated with low heats and as such DSC may not be the
best method to investigate it.
In addition to the aforementioned factors there are
number other contributors to crystallization from the amor-
phous phase such as surface crystallization [55] and the
Fig. (3). The solid dispersion formed from API/polymer combination can be in one of three states: (i) amorphous phase mixed (amorphous
solid solution), (ii) amorphous phase-separated (with an API rich phase and a polymer rich phase) and (iii) crystalline phase-separated
(crystalline API in the polymer matrix). States (i) and (ii) fall under the category of ASD. For physically stable ASD, state (i) is desired.
Nagapudi and Jona
method of preparation [7, 56]. Wu et al. have shown that
crystal growth rates at the surface on Indomethacin are about
two orders of magnitude faster than in the bulk. Method of
preparation of the amorphous phase also has a profound
impact on crystallization. Each method of amorphous
preparation endows the glass with a different thermal history
which in turn can affect the physical stability of the amor-
phous phase. Although inferences about amorphous stability
in the solid state can be drawn using the predictive methods,
experimental testing still remains the primary method of
evaluating stability.
4.2. Solid State Stability of ASD
In addition to the challenges faced in predicting the
physical stability of AAPI, ASD materials present a host of
new challenges. The incorporation of certain polymers with
amorphous API to make the ASD is generally found to
increase the physical stability of the amorphous API and
provide improvements in dissolution rates. Thus, from a
physical stability standpoint it is preferable to use the ASD
rather than the AAPI. The mechanism through which the
ASD material is able to improve the stability and dissolution
rate is not yet fully understood [5]. When an amorphous
polymer carrier is used to prepare the ASD, the resulting
API/polymer combination can be in one of three states: (i)
completely phase mixed (amorphous solid solution), (ii)
amorphous phase-separated (with an amorphous API rich
phase and an amorphous polymer rich phase) and (iii) crys-
talline phase-separated (crystalline API in the amorphous
polymer matrix). Fig. (3) shows a schematic of the three
different states. The third state is undesirable since the
advantages provided by the amorphous drug are lost due to
crystallization. The first and second states both fall under the
category of ASD.
Amorphous Active Pharmaceutical Ingredients in Preclinical Studies
4.2.1. Factors Affecting the Phase Behavior in ASD
The physical stability of the ASD is generally governed
by the thermodynamics state of the mixture at the storage
temperature. As experimental phase diagrams are difficult to
measure for API/polymer combinations, the final thermo-
dynamic fate of an API-polymer system remains elusive.
However, it has been argued that amorphous solid solution is
essential for physical stability, since the API can more easily
crystallize out of a phase separated system. Phase mixed
systems are generally formed when there are strong specific
interactions such as hydrogen bonding between the API and
the polymer but the effect of specific intermolecular
interactions by themselves does not provide the full picture
for polymer stabilization. Even small amounts of polymer
(2-5%) which do not cause any appreciable change in the
glass transition of the API can cause dramatic changes in the
rate of nucleation and crystal growth [10]. In addition to
specific interactions, it has also been suggested that addition
of polymer presents a diffusion barrier for the API molecules
thereby increasing the thermodynamic and kinetic barriers to
nucleation and growth [57, 58].
The final state of the API-polymer system can also be
influenced by the method of preparation. Even though the
thermodynamically preferred state of the ASD maybe a
phase separated system, the method of ASD preparation may
force the system to be phase mixed. Thus, method of
preparation may provide a kinetic route to phase mixed
systems. The interaction of ASD material with water can
also affect the phase behavior. For example Vasanthavada et
al. [59] found that the griseofulvin-PVP mixtures that
initially demonstrated a single Tg for 30 weight % of
griseofulvin sample, subsequently showed two Tg’s after
exposure to 40 ºC/69% RH demonstrating phase separation
upon exposure to moisture. Crystallization of the drug was
observed post phase separation. Thus moisture can also play
an important role in determining phase behavior. Thus the
phase behavior of ASD is influenced choice of polymer
carrier, API-polymer interactions, the concentration of the
polymer to be used, the method of preparation and the
influence of moisture.
4.2.2. Methods for Estimation of API-Polymer Miscibility
Some degree of miscibility of the API and polymer is
desired from physical stabilization point of view. Based on
this concept, many reports have been found in literature
where attempts have been made to estimate API-polymer
miscibility. The API and the polymer can be qualitatively
examined for specific intermolecular interactions which
could then lead to miscibility. Qualitative estimation of
miscibility can also be obtained using the solubility para-
meter approach. The Hildebrand solubility parameter is
given by:

H v  RT
=
Vm
Where
Hv is the heat of vaporization, R is the gas
constant, T is the temperature and Vm is the molar volume. In
general, it is difficult to estimate the heat of vaporization for
the API and the polymer since they decompose before
Current Bioactive Compounds 2008, Vol. 4, No. 4 219
vaporization. Solubility parameter can be estimated from
group contributions methods [60]. It has been proposed that
the API and polymer are miscible when the difference in
solubility parameter (
) between the API and polymer is
less than 7 units [61, 62]. Quantitative estimate of miscibility
can be obtained in favorable cases using melting point
depression [63], DSC end set method [64] and modeling of
the phase diagram [65]. These qualitative and quantitative
approaches of determining miscibility may be considered
when choosing the polymer carrier to be used in ASD. There
a number of problems associated with the quantitative
estimation of API-polymer miscibility and as such these
methods are of limited value. Moreover for a majority of
API’s the solubility in the polymer is rather limited (in the
range of 2-8%).
Glass transition temperature (Tg) can also be used as an
indicator of phase behavior of API/polymer combinations.
The polymers used to form ASD typically tend to have glass
transition temperature much higher than that of the
amorphous API. The glass transition temperature of the API-
polymer mixture will depend on the thermodynamic state of
the mixture. Phase separated systems will display two glass
transition temperatures corresponding to the two individual
phases while a phase mixed system will display a single
glass transition temperature. Thus for phase mixed systems,
polymers may have an antiplacticization effect on the API
serving to increase its glass transition temperature and
thereby retarding molecular mobility at the storage tempe-
rature. For phase mixed systems, the glass transition tempe-
rature can be predicted using the Gordon-Taylor equation
[66] based on the additivity of free volumes.
wAPI Tg, API + Kw polymerTg, polymer
Tg, mix = (6)
wAPI + Kw polymer
Where w represents the weight fraction of the component
and K is a constant given by:
Tg, API
API
K= (7)
Tg, polymer
polymer
Alternatively the Couchman-Karasz model [67] has also
been used. The equation for this model takes the same form
as that for the Gordon-Taylor, however the constant K is
given by:

C p, API
K= (8)

C p, polymer
where
Cp is the specific heat capacity change across glass
transition for the components. Since the Gordon-Taylor
equation is based on simple additivity, it does not account
(9) for specific interactions between the API and polymer.
Negative, positive, and mixed deviations from ideality have
been observed in different systems [68]. The nature of
deviation from ideality is dependent upon the presence or
absence of specific interactions in the API-polymer system.
Thus, glass transition temperature can also be used as a
measure of ASD stability.
220 Current Bioactive Compounds 2008, Vol. 4, No. 4 Nagapudi and Jona

4.3. Stability in Formulation Medium H 2C *

H 2C C
H 2C *
In addition to the solid-state stability of the AAPI or * CH
* CH
n
H m
ASD, their stability in the formulation medium must also be n
N O O
N O
determined. The formulation media for preclinical studies O
are primarily aqueous and the amorphous material tends to
crystallize much more rapidly in the medium. Typically the
amorphous material is slurried in the formulation medium at Poly(vinyl pyrrolidone) Poly(vinyl pyrrolidone-co-vinyl acetate)
the highest dose that is to be used in the preclinical study. O
Periodically the samples are withdrawn from the slurry and OH
HO O H 2C HO OH
tested for extent of crystallinity. The presence of water and H 2C * O
O O O
* CH
polymer complicates the use of XRPD or DSC for the n HO HO O
CH2
measurement of crystallinity. For the purpose of formulation C O
O OH O
stability crystallinity monitoring can be done in situ using n-2
techniques like Raman or IR if they are applicable. Crystal- O
HO
linity monitoring can also be done offline using SSNMR.
SSNMR is found to work very well with formulation Poly(acrylic acid) Hydroxypropylmethylcellulose
stability samples. These studies provide a time window for
which the formulation is stable in the desired medium and
H 2C *
thus dictate how frequently the formulations need to be * O * * CH
n
prepared during the course of the preclinical study. Stability n
OH
in the order of few hours to days in the formulation medium
is sufficient for preclinical studies. Polyethylene glycol Poly(vinyl alcohol)

5. PREPARATION OF ASD: CHOICE OF POLYMER CH3

CARRIERS AND CONCENTRATION
H O O O OH
5.1. Choice of Polymers n m n

Since factors by which polymer stabilizes the API and
the phase behavior of ASD are poorly understood, the
rationale for choice of polymer carrier and concentration to
be used to make the best ASD also remains unclear. The
choice of polymers used to make ASD have been based on
the considerations described above. Survey of the literature
shows that different kinds of polymers have been used to
make ASD material. The most commonly used polymers are
Poly(vinyl pyrrolidone) (PVP), Poly(vinyl pyrrolidone-co-
vinyl acetate), Poly(acrylic acid) (PAA), Hydroxypropyl-
methylcellulose (HPMC), hydroxypropylmethylcellulose
acetate succinate (HPMCAS), Polyethylene glycol (PEG),
Poly(vinyl alcohol) (PVA) and Poly(ethylene glycol-
propylene glycol-ethylene glycol) triblock copolymers.
Chemical structure of the polymers is shown in Fig. (4).
More exotic polymers and polymer architectures have been
used for drug delivery purposes [69]. However, the afore-
mentioned list of polymers are the predominant ones used to
make amorphous solid dispersions. In our experience organic
polymers such as HPMCAS and PVP have worked well with
range of acidic, basic and neutral drugs. There are also a few
reports in literature of using inorganic excipients to stabilize
amorphous API. Kinoshita et al. have used porous calcium
silicate to stabilize amorphous drugs [70]. Bogner et al. have
shown solid dispersions made by ball milling acidic API’s
with Neusilin (magnesium aluminum metasilicate) provides
excellent physical stability to the amorphous API [71, 72].
The mechanism of stabilization of acidic API with Neusilin
was attributed to salt formation between the Silanol groups
in the surface of Neusilin and the carboylate moiety in the
API.
Poly(ethylene glycol-propylene glycol-ethylene glycol)
Fig. (4). Chemical structure of commonly used polymers to make
ASD.
5.2. Choice of Polymer Concentration
Once the polymer has been selected, the concentration of
the polymer that is to be employed has to be decided.
Depending on the phase behavior the concentration of the
API may lead to either a phase separated or a phase mixed
system. Typically drug loads in the range of 20-50% in the
ASD material is found to work well. The polymer in addition
to enhancing the physical stability of the amorphous API
also provides a good suspension medium where the
amorphous API is uniformly dispersed in the formulation
without aggregation, caking, and settling. Apart from
physical stability, the concentration of the polymer may also
influence the pharmacokinetics of the ASD. There are
varying reports in literature about the optimal concentration
that is required for good ASD performance. Law et al. found
that Ritonavir-PEG 8000 solid dispersions provided
improved oral bioavailability in pretreated fasted dogs as
compared to crystalline Ritonavir when dosed in hard gelatin
capsules [73]. The authors found that 10% dug loading
worked better than 20 and 30% drug loads. Gelation of the
ASD and phase separation at the higher drug loads were the
reasons for the poorer performance. Dissolution study in
0.1N HCl at 37 ºC correlated well with the observed in vivo
data. Tantishaiyakul et al. studied the effect of drug loading
on the dissolution properties of piroxicam-PVP solid disper-
Amorphous Active Pharmaceutical Ingredients in Preclinical Studies
sions [74]. PVP of molecular weights 9000 and 100,000
were used for the study. In all cases solid dispersions were
found to have better dissolution profiles than the pure
crystalline drug. Solid dispersions containing lower drug
loads performed better than solid dispersions with higher
drug loads. Solid dispersions made with the low molecular
weight PVP had faster dissolution than the ones made with
the higher molecular weight PVP. The authors attributed this
difference to diffusion controlled mechanism predominating
with the higher molecular weight PVP due to increased
viscosity. This study shows the additional complicating
factor of molecular weight that must be considered when
choosing a polymer carrier. Papageorgiou et al. studied the
release rates of fluconazole from amorphous solid
dispersions with PVP, HPMC and chitosan. They reported
that the release rates were found to decrease with increasing
drug loads for PVP-based ASD while the release rates were
found to increase with increasing drug load for HPMC-based
ASD. Using the different release rates from different
polymers they were able to tailor the release of fluconazole
by making amorphous solid dispersions in binary polymer
blends of PVP and HPMC or PVP and Chitosan [75].
Depending on the API-polymer system either increasing or
decreasing drug loads may perform optimally. Thus, in order
to ascertain the best polymer concentration to be used,
knowledge of API-polymer phase diagram is necessary. As
has been previously mentioned such phase diagrams are
difficult to experimentally measure and predictive tools are
found to be inaccurate. In light of these difficulties, the best
way to ascertain the best polymer concentration is by making
50-100 mgs of two to three blends of different API-polymer
weight ratios using the method of choice and performing
dissolution testing. Dissolution testing may provide discri-
mination between the different blends. Usually 0.1N HCl at
37 ºC is used as the dissolution medium as per USP
guidelines. Alternatively 0.1 to 1% SDS may also be used as
the dissolution medium.
6. FORMULATION OPTIONS FOR AAPI/ASD IN
PRECLINICAL STUDIES
Once the polymer carrier and the concentration are
determined, the formulation that needs to be used for the
preclinical study needs to be decided. In preclinical work a
variety of excipients such as solubilizers, suspension agents,
surfactants, and complexation agents are used for oral
dosage. In a typical formulation for a crystalline material a
combination of these excipients are used in addition to pH
control to improve the solubility and the wettability of the
API. However, when considering formulations for AAPI or
ASD materials, simple aqueous formulations are found to
work the best. Addition of any solubilizers or surfactants
may compromise the physical stability of AAPI or ASD in
formulation medium. The formulations that have worked
best in our experience are aqueous suspensions of the AAPI
or ASD in vehicles containing 1-5% polaxmer or 1-2%
HPMC. Use of simple aqueous formulations with amorphous
materials is an advantage for toxicological studies when
compared to complex organic-aqueous mixtures that have to
be used with insoluble crystalline drugs to achieve the same
exposure. pH adjustment of the formulation may be
attempted if necessary, bearing in mind that increasing
solubility with pH adjustment may come with the attendant
Current Bioactive Compounds 2008, Vol. 4, No. 4 221
decrease in physical stability. In cases where pH adjustment
is necessary the stability of the amorphous material in the pH
adjusted formulation medium must be determined apriori. In
the event that physical stability of the amorphous material is
poor (< few hours in the formulation), the fresh formulations
have to prepared daily for toxicology studies. ASD or AAPI
generated by spray drying are in general free flowing
materials that can be tailored to have unimodal particle size
distributions with sizes that can be controlled by selecting
the appropriate spray drying conditions. Spray dried
materials tend to suspend well in the simple aqueous
formulations described above and as such making fresh
formulation just before dosing can be easily done. Finally the
formulated amorphous material needs to be tested in a
pharmacokinetic study in the species of interest at relevant
doses to determine if the oral bioavailability is enhanced
when compared to the best formulation for the crystal. A
decision tree for evaluating the feasibility of employing
amorphous materials for preclinical work is shown in Fig.
(5). Feasibility testing can be done with 500-700 mgs of
compound.
7. SUMMARY
Among the methods available for increasing exposure for
preclinical, amorphous materials hold a lot of promise.
Amorphous materials have not been used widely due to their
propensity to crystallize. Methods to predict the propensity
of the amorphous phase to crystallize have so far proven to
be inadequate. In spite of the problems posed by physical
instability of the amorphous phase, they are suitable candi-
dates for preclinical development since stability require-
ments in this area are not as stringent as in the clinical area.
AAPI and ASD material can be generated from small to
large scale using spray drying and precipitation methods.
Addition of polymers to amorphous API’s to make ASD’s
has proven to be useful in preventing crystallization of the
amorphous phase. With the right choice of polymer carrier
and polymer concentration, the amorphous API can be
optimized to yield required exposures with reasonable
physical stability. These materials have proven useful in
toxicological evaluation studies as they are able to improve
exposure with formulations in simple aqueous vehicles.
Amorphous materials thus provide an excellent avenue to
overcome the toxicological exposure barrier in preclinical
development.
ABBREVIATIONS
AAPI = Amorphous Active Pharmaceutical
Ingredient
API = Active Pharmaceutical Ingredient
ASD = Amorphous Solid Dispersion
BCS = Biopharmaceutical Classification System
DES = Dielectric Spectroscopy
DMA = Dynamic Mechanical Analysis
DSC = Differential Scanning Calorimetry
IR = Infrared
LOD = Limit of Detection
222 Current Bioactive Compounds 2008, Vol. 4, No. 4 Nagapudi and Jona

Fig. (5). Decision tree to evaluate the feasibility of using amorphous materials for preclinical work.

LOQ = Limit of Quantitation correlation of in vitro drug product dissolution and in vivo
bioavailability. Pharm. Res., 12, 413-420.
NIR = Near Infrared [2] Takagi, T., Ramachandran, C., Bermejo, M., Yamashita, S., Yu,
L.X., Amidon, G.L. (2006) A Provisional Biopharmaceutical
SSNMR = Solid State NMR Classification of the Top 200 Oral Drug Products in the United
States, Great Britain, Spain, and Japan. Mol. Pharm., 3, 631-643.
TSDC = Thermally Stimulated Depolarization [3] Neervannan, S. (2006) Preclinical formulations for discovery and
Current toxicology: physicochemical challenges. Expert Opin. Drug Metab.
Toxicol., 2, 715-731.
XRPD = X-ray Powder Diffraction [4] Hancock, B.C., Parks, M. (2000) What is the true solubility
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fluconazole using solid dispersions in polymer blends. Drug Dev.
Ind. Pharm., 34, 336-346.
Accepted: September 17, 2008