Article

Cite This: Org. Process Res. Dev. 2017, 21, 1509-1520 pubs.acs.org/OPRD

From Drying Kinetics, Solvate Structure, Particle Morphology, and

Modeling to Optimal Drying Protocol
Daniel S. Hsieh,*,† Qi Gao,† Ming Huang,‡ Lynn M. DiMemmo,† Mark Lindrud,§ and Thomas Razler‡
†
Drug Product Science & Technology, ‡Chemical & Synthetic Development, §API Operations, Bristol-Myers Squibb Company, One
Squibb Drive, New Brunswick, New Jersey 08903, United States

ABSTRACT: The mechanistic understanding of three key active pharmaceutical ingredient (API) drying elements: drying
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The objective of this study was to collect drying kinetic data through the use of a laboratory integrated sorption chamber to
elucidate the drying mechanism and thereby establish a drying model. In addition, the collection of drying kinetic data would
provide a greater understanding of the solvent to API ratio as well as the API stability to help develop a large-scale drying
protocol. The study material is an ethanol solvate (ethanolate) of the API. There is no fundamental crystal structure change upon
drying of the solvate in the temperature range from 50 to 90 °C, and the drying kinetic data show that the molar ratio of ethanol
to API is 1:1. This is confirmed by X-ray crystallography. An analysis of the drying kinetics showed that the diffusion of ethanol
through the crystal lattice provided the primary mass transfer resistance, which can be simulated using the Fickian principle of
diffusion through a slab. The diffusion coefficients from 50 to 90 °C at 20 mmHg were found to be strongly temperature-
dependent and fit well using an Arrhenius type relationship. The activation energy for diffusion was then determined from this
relationship. By using these diffusion parameters, the drying curves at various temperatures were generated to predict the drying
time to meet the final ethanol specification. The predicted drying time was in good agreement with experimental drying data at
high temperatures (80 and 90 °C) but shorter than that observed when drying at lower temperatures (between 50 and 70 °C).
Thermal stability data showed that the compound is stable at drying temperatures equal or below 70 °C. Drying data from this
study are generated from a static balance. Hence, the effect of shear forces imposed from cake depth and dryer agitation on
particle morphology, physical stability of the desolvated API, and drying time needs to be studied to generate the optimal drying
protocol for large-scale operation.

1. INTRODUCTION
The drying of active pharmaceutical ingredients (APIs) is an
important unit operation in the pharmaceutical industry. Many
different API forms can exist, including neat, solvate, and
hydrate forms, each with a unique drying mechanism. As a
result, API drying must be understood, and a specific drying
protocol needs to be developed to enable consistent down-
stream drug product formulation.
Recently, the Enabling Technologies Consortium (ETC1)
published a paper2 which identified three elements of API
drying key to the development of an optimum drying protocol.
These elements include drying kinetics, physical property
control, and chemical and physical stability (Figure 1). Figure 1. Steps linking the three elements of API drying to the
Individually the three elements are well-understood; however, development of a drying protocol.
good examples are needed to illustrate how to link them. The
objective of this study was to use the integrated sorption
chamber, as shown in Figure 2, to collect drying kinetic data, change via a gravimetric balance, vapor phase composition via
elucidate the drying mechanism, establish a drying model, and mass spectroscopy (MS), and solvate structure trends from
verify the molar ratio of solvent to API as well as understand API Raman spectroscopy, all as a function of drying time.
stability. In addition, the steps to link drying kinetics to the other An analysis of the drying kinetics showed that the diffusion of
two key elements, physical and stability control, are also ethanol through the crystal lattice is the primary mass transfer
proposed. The material used as an example of how to link these resistance and can be simulated using Fickian diffusion through
three key drying elements in this study is Compound A,3 which a slab. The diffusion coefficients for temperatures from 50 to 90
is an ethanolate. The outcome of this study was to propose an °C were determined, are strongly temperature dependent, and
optimal drying protocol to be used in manufacturing. are fit well using an Arrhenius type relationship. The activation
Figure 2 illustrates the capabilities of an integrated sorption
chamber in a drying laboratory. This device was used to collect Received: May 2, 2017
multiple forms of kinetic drying data, including wet cake weight Published: August 7, 2017

© 2017 American Chemical Society 1509 DOI: 10.1021/acs.oprd.7b00162

Org. Process Res. Dev. 2017, 21, 1509−1520
Organic Process Research & Development
Figure 2. Schematic diagram of the integrated sorption chamber
showing placement of the Raman probe.
energy for diffusion was then determined from this relationship.
By using these determined diffusion parameters, the drying
curves at various temperatures were generated to predict the
required drying time to meet the final ethanol specification. On
the basis of the required drying time and an understanding of
the drying mechanism, a preliminary drying protocol was
proposed.
During the scale up of a drying process, first developed in the
laboratory and then in a commercial size dryer, two potential
risks need to be considered: (1) the risk of amorphous API
formation, which is related to the physical stability of the
particles, and (2) the change of physical properties such as the
particle size, shape, and surface properties. The risk of
amorphous API formation results from different shear forces
at different scales. In a large scale dryer, the particles are
normally subjected to shear forces from agitation and hydraulic
pressure (cake depth), resulting in the possible formation of
amorphous API. The risk related to this issue needs to be
evaluated using both theoretical and experimental approaches.
The theoretical approach includes the calculation of the Gibbs
free energy difference between the dried product and the
amorphous material.4 When this difference is small, the risk of
amorphous formation becomes significant. The experimental
approach includes the use of attrition setups2 to test for
amorphous API formation from an estimated shear force from
the commercial size dryer over the proposed drying time. The
second risk under such a shear force is the change of particle
morphology, and this change is normally studied by using
experimental setups such as the attrition devices.2
2. EXPERIMENTAL AND THEORETICAL APPROACHES
2.1. Integrated Sorption Chamber. A microprocessor
controlled vacuum oven5 (VWR model 1430M) was modified
and converted to an integrated sorption chamber. This chamber
was equipped with a load cell (Sartorius WZA523-CW), a
Raman spectrometer (Kaiser Optical System Inc. model PhAT
system analyzer), and an infrared (IR) based temperature
camera (FLIR T240). The vacuum oven vent line was
connected to a mass spectrometer (Ametek ProMaxion Dryi),
as shown in Figure 2. Note that the load cell is connected to the
sample tray within the oven chamber via a chain dropped
through a connecting pipe. For operation, the oven was set at
the desired drying temperature. The pressure within the
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sorption chamber was regulated using a microprocessor
controlled vacuum pump manifold. The sealed load cell housing
was connected to the sorption chamber and exposed to the same
vacuum level. At the beginning of an experiment, 20−40 g of
wet cake was placed on the suspended weighing pan in the
chamber. During the drying, the load cell automatically records
the sample weight change and generates the basic weight curve
for the drying mechanism elucidation. In the course of drying,
the vapor phase composition was also monitored via mass
spectroscopy (MS). The drying process was complete when
both the weight curve and the vapor phase composition show no
more changes.
The sorption chamber includes an integrated probe well with
a fixed window oriented toward the drying sample at the bottom
of the well. An infrared-transparent ZnSe window is chosen so
that the probe well can be used with either Raman probes (for
monitoring changes in crystal structure) or with an IR
temperature detector (for monitoring of the temperature of
the wet cake). A Raman probe was used in the current study.
2.2. Development of the Raman Method. The material
used in this study is referred to here as Compound A. It is a
solvate of ethanol. The structure change of Compound A was
monitored by Raman spectroscopy. The Raman spectra of the
solvate and desolvated forms have the same peak positions
indicating the crystalline structure remained unchanged during
the removal of solvent.
2.3. Modeling of Drying in Solvate. The mathematical
Fickian diffusion model, as shown in Figure 3, is set up to
describe the removal of ethanol from Compound A.
Figure 3. Geometry of the slab and the schematic of the drying process.
The Fick’s law expression, by assuming a constant diffusion
coefficient and one-dimensional diffusion, is written as follows:
∂C ∂ 2C
=D 2
∂t ∂Z (1)
Initial condition:
C = C0 , t = 0, −l < Z < l
Boundary condition:
1. Z = l , C = 0, t>0
2. Z = −l , C = 0, t>0
where D is the diffusion coefficient, C is the concentration of
solvent, Z is the direction of the diffusion, t is time, and C0 is the
initial concentration of organic solvent in API solvate before
drying. The thickness of the plane sheet is 2l. To solve eq 1, four
assumptions are made. First, a uniform solvent concentration is
present through the slab at the beginning of the drying. Second,
the diffusion occurs in the Z direction. Third, the diffusion
coefficient is not a function of solvent concentration, and fourth,
the slab is indefinitely long, and no end effect occurs.
The partial differential eq 1 can be solved by the method of
separation of variables, and its solution is available in the
literature.5 The solution of eq 1 in terms of concentration as a
function of time and location can be integrated from −l to +l to
DOI: 10.1021/acs.oprd.7b00162
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provide the measurable quantity in terms of weight loss as a a linear relationship is obtained from the plot, the slope of the
function of drying time as follows: linear line is equal to (ΔH/R), and it can be used to determine
the activation energy for diffusion.
Mt
∞
8 ⎧ D(2n + 1)2 π 2t ⎫
= ∑ exp⎨− ⎬ When the drying time is located in the linear region of the
M0 n=0
2 2
(2n + 1) π ⎩ 4l 2 ⎭ (2) Fickian diffusion, as shown in eq 3, and the effect of temperature
on diffusion coefficient is expressed by eq 6, a useful relationship
where M0 is the weight of solvent in the solvated API before the between the diffusion temperature and the drying time can be
diffusion process, Mt is the weight of solvent in the solvate derived and expressed as in eq 8.
product at drying time t, and n is an integer.
Although eq 2 provides the relationship between the weight ΔH ⎛ 1 1⎞
change and drying time, it does not offer a clear analytical ln(t 2) − ln(t1) = ⎜ − ⎟
R ⎝ T2 T1 ⎠ (8)
relationship between the weight loss and the drying time at the
beginning of drying when t is small. This kind of relationship can where t1 is the diffusion time required at temperature T1, while t2
be obtained from the solution of eq 1 via the Laplace is the diffusion time required at temperature T2.
transformation, as described in the literature.5,6 The solution 2.4. Solid-State Characterization by X-ray Diffraction.
from such transformations is provided as follows: Single crystals of the ethanolate were grown from absolute
ethanol. X-ray diffraction data were collected on a Bruker-AXS
Mt ⎛ D ⎞1/2
= 1 − 2⎜ 2 ⎟ (t )1/2 CCD diffractometer with Cu Kα radiations. Using the Bruker-
M0 ⎝ πl ⎠ (3) AXS software package,9 data collection strategy, integration, and
scaling were computed and processed, and the crystal structure
Equation 3 offers two useful features of Fickian diffusion. First, was solved by direct methods and refined by full-matrix least-
the plot of dimensionless weight loss Mt/M0 vs the square root squares methods. All non-hydrogen atoms were refined
of drying time is linear as time is small. This linear relationship is anisotropically, while hydrogen atoms were generated and
valid when the value of Mt/M0 is less than 0.5. Second, the value refined using a riding model with idealized bond lengths and
of the diffusion coefficient can be determined from eq 3 if the angles. Structural analyses of molecular geometry and
diffusion length 2l is known. conformation, crystal packing, and intermolecular interactions
Equation 2 shows that the dimensionless weight loss Mt/M0 is were performed using Mercury.10
a function of drying time t and two parameters, D and l. At the Powder X-ray diffraction (PXRD) data were obtained using a
beginning of the drying, the drying time is zero, and the value for Bruker C2 GADDS diffractometer11 with Cu Kα radiations (40
Mt/M0 is one. The term l is half of the diffusion length. In this kV, 40 mA) and sample−detector distance of 15 cm. Bulk
study, parameters D and l are combined together as one samples were placed in sealed thin-wall glass capillaries with
parameter β, and this parameter is called the diffusion parameter diameters of ≤1 mm. The capillary was rotated during data
and is defined as follows: collection. Data were collected for approximately 2° ≤ 2θ ≤ 32°
Dπ 2 with a typical X-ray exposure time of 1000 s. The resulting two-
β= dimensional diffraction arcs were integrated to create a
4l 2 (4)
traditional one-dimensional PXRD pattern with a step size of
With the definition of β, eq 2 can be rewritten as follows: 0.05° 2θ in the approximate range of 2−32° 2θ.
∞ 2.5. Scanning Electron Microscopy. Scanning electron
Mt 8
= ∑ exp{− (2n + 1)2 tβ} microscopy (SEM) images were collected on samples mounted
M0 n=0
(2n + 1)2 π 2 (5) on aluminum stubs to which adhesive carbon conductive tabs
had been applied. They were sputter coated using a Cressington
Equation 5 provides a very useful relationship between the 208 HR auto sputter coater equipped with a platinum target
dimensionless weight loss Mt/M0 and the drying time t with one (Ted Pella, Inc., Redding, CA). Secondary electron images were
parameter β. As defined in eq 4, both the diffusion length and acquired at 5 kV using an FEI XL-30 FEG SEM (FEI Electron
the diffusion coefficient are included in β. At the same value of Optics, Eindhoven, The Netherlands).
weight loss and as the diffusion length increases, the value for β
will decrease, and the drying time will increase. In addition, the 3. RESULTS AND DISCUSSION
diffusion coefficient in solids at different temperatures is
generally found to be well-predicted by the Arrhenius 3.1. Crystalline Structure. Single-crystal X-ray diffraction
equation7,8 as shown in eq 6. studies showed that the crystals grown from absolute ethanol
were a monoethanolate (Compound A).3 In addition, the crystal
D(T ) = D0e−ΔH / RT (6) structure of the desolvated form was also determined by single
crystal X-ray crystallography. The crystal data of these two
where D is the diffusion coefficient, D0 is the pre-exponential isomorphous structures are shown in Table 1. Desolvation is
term, ΔH is the enthalpy or the activation energy for diffusion, T associated with a small decrease in unit cell volume (3.4%) as
is the absolute temperature (K), and R is the ideal gas law well as all three axes, with the b-axis least impacted (0.315,
constant. 0.014, 0.2473 Å, respectively). In the crystal, the solvent
Equation 6 can be rearranged and expressed as an Arrhenius occupies 2.5% of unit cell volume per contact surface. Ethanol
type form in eq 7. molecules are found in small channels along the crystallographic
⎛ ΔH ⎞⎛ 1 ⎞ b and c axes. Each of them is involved in hydrogen bonding with
ln(D(T )) = ln(D0) − ⎜ ⎟⎜
⎝ R ⎠⎝ T ⎠
⎟
(7)
Cl− (O···Cl− = 2.815 Å) and weak interactions with the amide
group (O···H−N = 171.41, O···N = 3.120 Å, O···H = 2.267 Å)
When the diffusion coefficients at various temperatures are and the aromatic ring (O···H−C = 173.08°, O···C = 3.222 Å,
known, the value of ln(D) can be plotted as a function of 1/T. If O···H = 2.297 Å) adjacent to the amide (Figure 4). A
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Table 1. Crystallographic Data of the Monoethanolate and Desolvated Crystal Forms at Room Temperature
a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) V (Å3) SG Z dc (g cm−3)
ethanolate 27.732(3) 12.0901(11) 11.2355(9) 90 90.514(7) 90 3766.9(6) C2 4 1.268
desolvated 27.417(3) 12.0797(12) 10.9882(10) 90 90.964(7) 90 3638.6(6) C2 4 1.271

Powder X-ray diffraction patterns were collected for both the

Figure 4. Hydrogen bond interactions involving EtOH, Cl−, and API
molecules in the monoethanolate API.
comparison of molecular packing in the solvate and desolvated
crystals is given in Figure 5. Disorder was observed in both
structures at the dimethylsulfonamide moiety which is near the
location of the solvent. High displacement parameters of the
solvent obtained from structural refinements also suggest
mobility of ethanol molecules.
solvated and the desolvated bulk APIs and matched the
simulated patterns calculated from the corresponding crystal
structures (Figure 6).
3.2. SEM Images. The morphology of Compound A after
desolvation (dried cake) is displayed in Figure 7. Although the
overall morphology as shown in Figure 7a includes cracks,
porous particles, and striations, the particle shape of desolvated
compound A can be described as a particle made of a loosely
bound bundle of thin slabs with some cracks between layers, as
shown in Figure 7b.
This layered structure supports the proposed mechanism of
solvent removal from the crystal as one of diffusion from a slab.
Additionally, since there is some open space between sections of
the bundle, the surface concentration of ethanol at the slab
surface is assumed to be zero because ethanol vaporizes at the
surface under vacuum at elevated drying temperature. These
assumptions provide the boundary conditions of the slab
associated with eq 1.
3.3. Drying Kinetics. The wet ethanol solvate after
crystallization contains both residual ethanol and surface methyl
t-butyl ether (MTBE) from slurry filtration before drying.
Drying was conducted under vacuum (20 mmHg) at various
temperatures, including 50, 60, 70, 80, and 90 °C. For each
temperature, the complete drying profile, from wet cake to

Figure 5. Comparison of crystal packing in the ethanolate (left) and desolvated form (right), viewed along the crystallographic b-axis (top) and c-axis
(bottom). Ethanol molecules are highlighted in yellow and Cl− ions in green.

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Figure 6. Simulated and experimental powder X-ray diffraction patterns of the ethanolate and desolvated APIs.

Figure 7. Overall particle morphology of Compound A (a) and particle shape of Compound A as a bundle of thin layers in parallel (b).

desolvated product, was monitored. Drying was halted when the

rate of weight change became zero. The integrated sorption
chamber (Figure 2) was used to obtain the basic drying curve
(weight vs drying time), the change of vapor phase composition
over time, and the structure change during drying.
Basic Drying Curve. The basic drying curves for all
temperatures at 20 mmHg ranging from 50 to 90 °C are very
similar. In Figure 8 the drying curve recorded at 50 °C and 20
mmHg is used as an example to illustrate the different drying
mechanisms.
Drying at 50 °C and at 20 mmHg. On the basis of this
drying curve, the drying profile includes three stages: stage I:
surface evaporation, stage II: transitional, and stage III: diffusion.
The characteristics of each stage are described separately as
follows:
Stage I: Evaporation.
The first stage was classified as the evaporation stage where
MTBE and residual ethanol are rapidly removed (9 min) at a
constant drying rate from the ethanol solvate surface. Since the
cake was washed with MTBE, the major component of the
surface solvent mixture was assumed to be MTBE. The
evaporation rate is controlled by the heat transfer from the Figure 8. Drying curve at 50 °C and 20 mmHg.
surroundings to the wet cake, resulting in a constant rate of
weight loss. This is apparent in Figure 8.
1513 DOI: 10.1021/acs.oprd.7b00162
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Stage II: Transitional.
At the end of the evaporation stage, the surface of the solvate
is dry where MTBE and residual ethanol is completely removed
as is indicated by the MS trends. At this point, there are two
straight lines with two different slopes intersecting with each
other at 9 min, as shown in Figure 8. This intersection signals
the end of the stage I (evaporation) and the beginning of stage II
(transitional). The different slopes of these two straight line are
due to the difference in boiling temperature and heat of
vaporization between MTBE and ethanol which are listed in
Table 2. MTBE has much lower boiling temperature and heat of
Table 2. Physical Properties of Solvents
solvent boiling point (°C) heat of vaporization (cal/g)
MTBE 56 81
ethanol 78 205
vaporization than ethanol; hence, at the same heat transfer rate,
the removal rate of MTBE is much faster than that of ethanol.
The intersection of two straight lines were observed not only
at 50 °C but also observed at other temperatures from 60 to 90
°C. This intersection can be identified as the beginning of the
ethanol removal from the ethanolate. The weight of the cake at
this point can be used to determine the amount of ethanol
removed from the ethanol solvate when it is compared with
weight of the dried cake at the end of drying. This determination
is important for the verification of both the molar ratio of
ethanol to API and the determination of the diffusion
coefficient.
The second stage of drying, starting at 9 min until the drying
time of 36 min, is classified as the transitional stage and acts a
bridge between the rapid surface evaporation and the beginning
of the slower diffusional drying. It should be noted that, at the
beginning of this stage, the rate of weight change is constant, a
characteristic of evaporation, indicating that the removal of
ethanol from the ethanolate in this transitional stage is very fast.
The ethanol removal rate, however, gradually decreases up to
the beginning of the diffusion stage.
Stage III: Diff usion.
As shown in Figure 8, the rate of ethanol removal after the
transitional stage becomes very slow. This was attributed to the
diffusion of ethanol from the solvate, which requires a higher
activation energy to break the noncovalent bonds associated
with the solvate structure.
When the drying weight data at 50 °C is plotted as a function
of (time)0.5, as shown in Figure 9, there is a linear behavior
between weight vs (time)0.5 after the value of (time)0.5 equal to 6
(drying time of 36 min). Since the weight at the beginning of the
linear behavior (19.020 g) and the weight of the dried API
(18.547 g) are known, the amount of ethanol removed via the
diffusion process can be determined. The difference between
these two weights was found to be 0.473 g, which is equivalent
to 2.55 wt % (wt %) of the dried API. This amount, 0.473 g, is
the value for M0 defined in eq 2. Hence, the value for 0.5 M0 is
0.237 g. By knowing the weight at the beginning of the linear
behavior (19.020 g), the weight at 0.5 M0 can be calculated as
18.784 g as shown in Figure 9. It should be noted that there is a
linear behavior from the beginning of the mass transfer process
until half of the ethanol is removed, a characteristic of the
Fickian diffusion.5,6
It should be noted that the drying experiment at 50 °C and 20
mmHg continued until no further weight change was observed
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Figure 9. Diffusion of ethanol from the ethanol solvate at 50 °C and 20
mmHg.
to determine the amount of ethanol removed via the diffusion
process (Figure 9).
The in-process-control (IPC) for the drying of ethanol solvate
of Compound A is that the ethanol concentration should be less
than 0.7 wt %, as shown in Figure 9. The drying time to meet the
IPC requires 1370 min, close to 1 day (1440 min).
When both Figures 8 and 9 are linked together, the weight
loss and duration of the three stages: evaporation, transitional,
and diffusion become clear. The total loss on drying (LOD) is
19.4% (based on the weight of the wet cake before drying, 22.99
g), as shown in Figure 8. The period of each stage varies
significantly. The first stage is classified as the evaporation stage,
and it takes less than 10 min with a weight change of 3.16 g,
equivalent to 13.7% LOD. The second stage is the transitional
stage which takes 11 min, and the weight change is 0.840 g,
equivalent to 3.65% LOD. However, the third stage, as shown in
Figure 9 due to a slow diffusion process, takes more than 1500
min for the removal of 0.473 g of ethanol, equivalent to about
2.1% LOD. Obviously, the diffusion of ethanol from solvate is
the cause of the major mass transfer resistance. Hence, a process
parameter change to reduce the drying time is needed.
The Fickian diffusion behavior was not only observed at 50
°C, as shown in Figure 9, but also observed at other
temperatures from 60 to 90 °C. As shown in Figure 10, the
Fickian diffusion behavior is also valid for the drying at 80 °C
and at 20 mmHg. In addition, it should be noted that the drying
time to meet the IPC (residual ethanol) is strongly dependent
upon the drying temperature. For example, the required drying
time to meet the IPC at 50 °C is 1400 min, while it requires 90
min at 80 °C to meet the same IPC. This is only 1/15th as much
time to reach the same end point. This difference indicates that
the diffusion process for the drying of Compound A solvate is
very much temperature-dependent.
Drying Mechanism and Drying Time. The drying time of
the three stages, evaporation stage, transition stage, and
diffusion stage, at various temperatures and at 20 mmHg is
listed in Table 3. The time required for the evaporation and
transition stages decreases slightly with the increase of
temperature, while the time required for diffusion decreases
significantly with an increase of temperature.
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3 where the solvent removal is controlled by the value of the

diffusion coefficient D, which is temperature-dependent. This
means that, when the drying temperature is kept the same, the
drying time of a cake is the same regardless of the scale.
Vapor-Phase Composition in the Course of Drying. The
vapor-phase composition over the course of drying was
monitored via MS, as shown in Figure 11. It should be noted
that the MS used in this study was tuned for performance but
not calibrated. Hence, the intensity shown in Figure 11 is not
proportional to the concentration of the solvent, and when the
intensity of the solvent levels off, the solvent concentration is
assumed to be zero. The objective of using MS coupled with the
use of the balance for weight change during drying is to elucidate
the drying mechanism.
The sequence of solvent appearance by MS detection can be
clearly determined from Figure 11a from which three interesting
results were observed. First, both MTBE and ethanol are present
at the beginning of drying at 80 °C (Stage I evaporation).
Second, as the vapor concentration of MTBE goes down at the
Figure 10. Diffusion of ethanol from ethanol solvate at 80 °C and 20 drying time of 20 min, the ethanol vapor concentration increases
mmHg. (kink for Stage II transitional). Third, as the ethanol vapor
concentration goes down at the drying time of 30 min, there is
Table 3. Period for Drying Stage at Various Temperatures an increase in ethanol concentration (kink for Stage III, diffusion
and at 20 mmHg process).
time (min) When the vapor phase concentration in Figure 11a is
expressed as a function of (time)0.5, it becomes Figure 11b,
drying temp. (°C) evaporation transition diffusion
and the kink occurs at 5 (minute)0.5. This is in good agreement
50 9 11 1370 with that shown in the drying curve in Figure 10.
60 7 7 625 Chemical and Physical Control. As mentioned earlier, the
70 6 14 196 drying operation from the drying temperature 50 to 90 °C and
80 6 12 85 at 20 mmHg was stopped when there is no further weight
90 4 10 49 change at the end of the drying as shown in Figures 9 and 10.
The sample at the end of each drying operation was taken for
The drying behavior for the stage I and stage II are classified chemical analysis to determine the residual ethanol and the
as constant rate periods.2 The rate of solvent removal in these chemical purity and potency. The results of this analysis are
two periods is controlled by the heat transfer from the heat presented in Table 4.
source (jacketed equipment wall) to the wet cake which is scale- As shown in Table 4, the ethanol level at the end of each
and equipment-dependent. In contrast, the stage III diffusion drying is very low, almost negligible. Hence, by assuming the
process is controlled by the drying temperature and is not scale- residual ethanol at the end of drying is zero, the cake weight at
dependent. This can be illustrated by using governing eqs 2 and the end of each drying, as shown in Figures 9 and 10, can be

Figure 11. Vapor phase concentration during drying at 80 °C: (a) intensity vs time; (b) intensity vs (time)0.5.

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Table 4. Compound A Chemical Purity and Residual Solvent
temp. (°C) purity assay as is residual EtOH total residual solvent
50 99.89% 93.9% 0.06% 0.06%
60 99.90% 93.7% <0.02% <0.02%
70 99.88% 91.7% 0.03% 0.03%
80 99.89% 86.7% <0.006% <0.02%
90 99.89% 93.9% <0.006% <0.02%
used to determine the total amount of ethanol removed from
the solvate.
Inspection of the residual solvents by gas chromatograph
shows no detectable MTBE. This is in agreement with the
theory that MTBE is only present on the surface of Compound
A and is the first to be removed through evaporative drying. All
residual ethanol results pass the 0.7 wt % ethanol IPC for drying;
however, the higher temperatures are more effective at fully
removing ethanol during the diffusional period of drying. Less
than 0.006% residual ethanol was found at both 80 and 90 °C
drying temperature compared to 0.06% residual ethanol found
using 50 °C drying.
As can be seen from Table 4, Compound A is stable even
when dried at 90 °C. No change in the chemical purity or
potency was found between drying at 50 and 90 °C. The lower
potency in Compound A with 80 °C drying is probably an
outlier that does not agree with the high chemical purity and low
residual solvents found in any other drying conditions for this
sample. Additional testing is needed to verify that result.
Determination of Molar Ratio of Ethanol with Respect to
API in Ethanol Solvate. As mentioned earlier, the difference
between the weight at the end of the evaporation and the weight
at the end of the drying (dried API) is the amount of ethanol in
the ethanol solvate. As shown in Table 5, the weight at the end
of evaporation (when two straight lines meet) at 50 °C is 19.840
g (Figure 8), and the weight at the end of drying is 18.547 g,
resulting in a weight difference of 1.293 g. This amount
quantifies the ethanol in the ethanol solvate. Since the molecular
weights of Compound A (659.84 g/g mole) and ethanol (46.07
g/g mole) are known, the moles of API and ethanol are
calculated at 0.281 mol each. Hence, the molar ratio of ethanol
with respect of API in the ethanol solvate at 50 °C is 1.00.
The molar ratio of ethanol to API determined from the drying
curves at other temperatures such as 60 °C, 70 °C, and 90 °C is
1.00 as well, as shown in Table 5. It should be noted that the
result of the molar ratio of ethanol to API from the drying curves
is in excellent agreement with that from the crystalline
monoethanolate.
3.4. Raman Results. Raman spectra were collected
continually during the drying process. During the initial
evaporation phase of drying, Raman frequency shifts were
observed corresponding to the removal of surface solvent as
seen in the Figure 12.
Once the initial surface solvent was removed, the Raman peak
positions remained unchanged throughout the diffusion-
controlled drying period. This indicates that the crystalline
structure remained unchanged even though ethanol is removed
from the crystalline lattice during this period, as seen in Figure
13.
3.5. Modeling of Diffusion Process. Determination of
Diffusion Coefficient at Various Temperatures. The drying
data at 50 °C and at 20 mmHg, as shown in Figure 9, can be
plotted as a dimensionless diagram of Mt/M0 vs (time)0.5, as
shown in eq 3, where the characteristics of diffusion were
exhibited. The weight difference between the beginning of the
diffusion, 19.020 g and the end of diffusion 18.547 g, which is
0.473 g, was designated as the value for M0, the amount of
ethanol in the ethanol solvate at the beginning of desolvation.
Hence, the ratio of Mt to M0 is equal to 1.0 at the beginning of
the diffusion process and is equal to 0 at the end of diffusion
process. The weight % of ethanol at the beginning of the
diffusion process is equal to 2.6 wt % (0.473 g/18.547 g). By
using the same approach, at 50 °C, the weight % of ethanol at
the beginning of diffusion, defined as W0, at temperatures other
than 50 °C were determined, and they are listed in Table 6.
Since the drying process from 50 to 90 °C exhibits the Fickian
D 0.5
behavior, the value of ( )πl 2
can be easily determined by using
eq 3. An example, the drying at 50 °C in Figure 9, is given here
to illustrate this determination. First, a time shift is required.
When the beginning of the diffusion process starts, the value of
t0.5 is equal to 0, shifted from 6, and the value of t0.5 is equal to
D 0.5
18, shifted from 24. Hence, the value of ( )πl 2
can be calculated
from eq 3, where Mt/Mo equal to 0.5 as the value of t0.5 is equal
D 0.5
to 16. By using the same procedure, the value of ( )πl 2
at
drying temperatures other than 50 °C can be determined, and
they are listed in Table 7.
To determine the diffusion coefficient from the value of
D 0.5
( )
πl 2
, the diffusion length l must be known. Since the primary
particle of compound A solvate is composed of a bundle of thin
slabs as shown in Figure 7a and b, the thickness of the thin slab,
which is the diffusion length, can be approximately estimated.
When the thickness of the slab from Figure 7 is used, which is
approximately equal to 2 μm, the value for l is equal to 1 μm.
Then the value of the diffusion coefficient can be determined, as
shown in Table 7, ranging from 1.01 × 10−13 cm2/s at 50 °C to
1.01 × 10−11 cm2/s at 90 °C. These values are similar to the
diffusion coefficients in the solid state.7
D
Once the value of ( ) is determined, the diffusion parameter
πl 2
β defined in eq 4 can be calculated without the information on
the diffusion length. The value for β at various temperatures are
listed in Table 7.

Table 5. Molar Ratio of Ethanol to Compound A

drying temperature (°C) 50 60 70 80 90

weight at the end of evaporation (g) 19.840 16.633 17.186 16.789 16.760
weight at the end of drying (g) 18.547 15.548 16.064 15.694 15.668
ethanol removed from solvate (g) 1.293 1.085 1.122 1.095 1.092
mole of API (g mol) 0.0281 0.0236 0.0243 0.0238 0.0237
mole of ethanol (g mol) 0.0281 0.0236 0.0244 0.0238 0.0237
mole ratio of ethanol to API 1.00 1.00 1.00 1.00 1.00

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Figure 12. Overlay of Raman spectra during the evaporation period. The red trace is the first trace at time zero.

Figure 13. Overlay of Raman spectra during the diffusion-controlled period. The red trace is the first trace at the beginning of diffusion period.

Table 6. Value of Mt/M0 at 0.7 wt % Ethanol Compound A are known, the weight percent of ethanol in
temp. (°C) W0 (wt %) Mt/M0 at 0.7 wt % ethanol
Compound A was found to be 6.9 wt %. As shown in Table 6,
the amount of ethanol at the beginning of the diffusion is 2.71 wt
50 2.6 0.269
60 3.04 0.230 %. This means that 39% (2.71 wt %) of the ethanol in the
70 2.71 0.258 ethanolate is removed via diffusion while 61% (4.18 wt %) of
80 2.58 0.271 ethanol in the ethanolate is removed via evaporation.
90 2.63 0.266 Effect of Temperature on the Diffusion Coefficient. The
ave. = 2.71 ave. = 0.26 effect of temperature on the diffusion coefficient is expressed in
Equation 7. As the values of the diffusion coefficients at various
The molar ratio of ethanol to dried Compound A is 1 in the temperatures are plotted as ln(D) vs (1/T), a nice linear
ethanol solvate. Since the molecular weights of both ethanol and relationship is obtained and is shown in Figure 14.
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Table 7. Effect of Temperature on Diffusion Coefficient and Diffusion Parameter

Dπ 2
temp. (°C) 1/T (K) ( )
πl 2
D 0.5 D
πl 2
Da (cm2/s) β=
4l 2
50 0.003094 1.39 × 10−2 1.93 × 10−4 1.01 × 10−13 0.00150
60 0.003001 2.50 × 10−2 6.25 × 10−4 3.27 × 10−13 0.00484
70 0.002914 4.72 × 10−2 2.23 × 10−3 1.17 × 10−12 0.0172
80 0.002831 8.33 × 10−2 6.94 × 10−3 3.64 × 10−12 0.0538
90 0.002753 1.39 × 10−1 1.92 × 10−2 1.01 × 10−11 0.150
a
Diffusion length l = 1 μm.

Figure 14. Arrhenius plot of diffusion coefficients as a function of

temperature. Figure 15. Drying time from the diffusion model vs from the
experimental drying time.

The slope of the Arrhenius plot is equal to the value of ΔH/R.

First, it could be due to a higher diffusion activation energy
Since the value for R is known, the value for the enthalpy, which
when the ethanol concentration becomes very low. Second, it
can be interpreted as the activation energy for diffusion, can be
could be due to the dependence of the diffusion coefficient on
determined and was found to be 113.37 kJ/mol. This activation
solvent concentration. Lastly, some of the ethanol could be
energy is similar to those for the diffusion of carbon in iron7 (80
trapped in the areas where particles join together, as shown in
kJ/mol) or for the diffusion of Mg in Al (131 kJ/mol).12
Figure 7. Hence the removal of the trapped ethanol from those
Determination of Drying Time from Diffusion Model vs
areas takes longer, and this removal could not be simulated by
from Drying Data. Since the values of β from 50 to 90 °C were
using the model of the diffusion through slabs. Further studies
determined and listed in Table 7, the diagram of Mt/M0 vs
are needed to understand these issues.
(minute)0.5 was constructed using eq 5 to determine the drying
Approximate Estimation of Drying Time. The experimental
time from the diffusion model. This was compared with the
drying times at various temperatures to meet the ethanol
drying time from the experimental data, shown in Figure 15.
specification, as shown in Figures 9 and 10, are summarized in
Several interesting points from Figure 15 are summarized
Table 8.
below:
These drying times are not far away from the linear region of
• A linear behavior between Mt/M0 and (minutes)0.5 up to
the Fickian diffusion, especially at drying temperatures of 80 and
Mt/Mo equal to 0.5 is valid for all temperature cases. This linear
90 °C, as shown in Figure 15. Equation 8 is used to plot the
behavior indicates the characteristics of Fickian diffusion. The
actual drying time from 50 to 90 °C vs 1/T as shown in Figure
experimental data are in good agreement with the prediction
16. A very good correlation (R2 = 0.9917) is obtained.
from the Fickian diffusion model, eq 5.
• The diffusion time to meet the ethanol specification of 0.7
wt % (Mt/Mo = 0.26) can be predicted well by the diffusion Table 8. Drying Time Required To Meet the IPC at Various
model at drying temperatures of 80 and 90 °C. However, the Temperatures and at 20 mmHg
actual drying time to meet the ethanol specification at the drying
temp. (°C) temp. (K) 1/T (K)−1 time (min) ln(time)
temperature from 50 and 70 °C is longer than that from
prediction of the diffusion model. 50 323.2 0.00309 1370 7.22
• The actual drying time is much longer than that from the 60 333.2 0.00300 625 6.44
diffusion model when the ethanol concentration in the solvate is 70 343.2 0.00291 196 5.28
less than 0.7 wt % (Mt/M0 is less than 0.26) as shown in Figure 80 353.2 0.00283 85 4.44
15. Three speculations could cause this difference in drying time. 90 363.2 0.00275 49 3.89

1518 DOI: 10.1021/acs.oprd.7b00162

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Organic Process Research & Development
Figure 16. Arrhenius plot of drying time as a function of temperature.
Figure 16 can be used in many ways. For a large-scale
operation, more than 1 day is needed to meet the IPC for
residual ethanol when dried at 50 °C (Figure 9). This amount of
time may be too long for the manufacturing facility. Addition-
ally, the amount of wet cake agitation used in the large scale
dryer may also be excessive, affecting the particle morphology
due to attrition. A possible solution would be to increase the
drying temperature from 50 to 70 °C. This temperature change
would reduce both drying time and amount of agitation from 1
day to less than 4 h. Hence, Figure 16 is very useful as an
approximate estimation of the drying time to meet IPC.
Table 9. Mechanistic Understanding of API Drying Key and Preliminary Drying Protocol
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3.6. Drying Protocol from Drying Kinetics, Physical
Property, and Stability. Some mechanistic understandings of
the three elements of drying important for Compound A have
been generated. On the basis of these, albeit incomplete, a
preliminary drying protocol can be proposed, as summarized in
Table 9.
As far as the physical property control is concerned, there is
no structure change upon drying from the comparison of crystal
packing of the ethanolate vs the desolvated form. In addition, no
Raman shift was observed during the transition from wet cake to
dried cake.
From the chemical and physical stability viewpoint, the
chemical analysis of the desolvated API shows that there is no
change in purity and potency when the drying temperature is up
to 70 °C. Hence, the drying temperature should be kept equal to
or below 70 °C. It is recommended that the effect of shear force
on particle morphology during drying needs to be studied to
understand the risk of amorphous formation and how to prevent
such a risk during scale up.
The drying kinetics of desolvation generated from the
integrated sorption chamber shows that both MTBE, the
washing solvent, and 61% of ethanol in ethanolate can be
removed easily via evaporation. The remaining ethanol in the
ethanolate, 39%, needs to be removed by diffusion. The
diffusion process is strongly temperature dependent. On the
basis of the experimental data, expected drying times to meet the
IPC can be predicted from the diffusion model.
Since MTBE and 61% of ethanol in the ethanolate are easily
removed via evaporation, a centrifugation process could be used
for the removal of these solvents. Hence, there are two options
for the drying of Compound A. The first option would be to use
centrifugation for the removal of a majority of the two solvents
followed by the use of heat for the removal of the remaining
ethanol via the diffusion process. The second option would be to
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Organic Process Research & Development
use heat to vaporize MTBE and 61% of the ethanol in the
ethanolate followed by the drying of the remaining ethanol by
heat via the diffusion process. The results of this evaluation can
be used for dryer selection and adjustment of the drying
operating conditions.
The diffusion process in the solid is dependent upon
temperature and is not scale-dependent. This means that, if
the temperature is kept the same, the drying time to meet the
specification is the same regardless of the size of the batch. This
is true if the mass transfer through the particles is not the
limiting step. In contrast, the evaporation process is scale-
dependent because the rate of solvent removal is related to the
heat transfer rate which is dependent upon the heat transfer area
and the temperature difference between the jacket wall and the
temperature of the particles.
It should be noted that the rate of diffusion of ethanol from
the solvate is dependent upon both temperature and the
diffusion length as shown in eqs 2 and 6. As the particles are
agitated in a large scale dryer, the particles may be broken into
smaller sizes, and this change in size may affect the diffusion
length and the surface area for mass transfer. Hence the drying
time to meet the IPC may change.
As far as the drying temperature is concerned, it is suggested
that the drying temperature is controlled equal or below 70 °C
to ensure chemical stability. The drying time to meet the IPC via
the diffusion process at 70 °C is less than 4 h.
The effect of the shear force imposed from the cake height
and the agitation needs to be studied to evaluate the physical
properties of the powder and the risk of amorphous API
formation.
4. CONCLUSIONS
The drying of Compound A occurs in three stages. In the first
stage, mainly MTBE is removed from the surface of the API via
evaporation. Next, in the transitional stage (Stage II) some
ethanol in ethanolate is removed by evaporation. The diffusion
process starts at the beginning of the third stage. An analysis of
the drying kinetics shows that the diffusion of ethanol in the
crystal lattice is the primary mass transfer resistance and can be
simulated using Fickian diffusion from a slab. The diffusion
coefficients from 50 to 90 °C were determined and are strongly
temperature-dependent and follow an Arrhenius type relation-
ship. The activation energy for diffusion was then determined
from this relationship. By solving the diffusion parameters, the
drying curves at various temperatures were generated to predict
the required drying time to meet the ethanol specification at the
end of drying. The drying time from the prediction is in good
agreement with that from drying data at high temperatures such
as at 80 and 90 °C but is shorter than that from drying data at
lower temperatures from 50 to 70 °C. It is suggested that the
drying temperature for diffusion is kept at 70 °C or less to keep
the drying cycle time less than 8 h and maintain the product
stability.
On the basis of the mechanistic understanding of the drying
process, two options for the drying of Compound A can be used.
The first option is to use centrifugation for the removal of
solvents followed by the use of heat for the removal of the
remaining ethanol via the diffusion process. The second option
is to use heat for both evaporation and diffusion following bulk
solvent removal via depth filtration.
Since the drying data from this study were generated from a
static balance, the effects of the shear force imposed from the
cake height and agitation on particle morphology, physical
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stability of the desolvated API, and drying time need to be
studied to generate the optimal drying protocol for large-scale
operation.
■ AUTHOR INFORMATION
Corresponding Author
*E-mail: daniel.hsieh@bms.com.
ORCID
Daniel S. Hsieh: 0000-0002-4452-9673
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
The authors would like to thank project team members for
providing technical discussion. A special appreciation is
expressed toward Dr. Babu Murugesan for providng samples
for this study.
■
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Org. Process Res. Dev. 2017, 21, 1509−1520