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Drug Development and Industrial Pharmacy
ISSN: 0363-9045 (Print) 1520-5762 (Online) Journal homepage: http://www.tandfonline.com/loi/iddi20
Influence of spray drying and dispersing agent on
surface and dissolution properties of griseofulvin
micro and nanocrystals
Dhaval A. Shah, Manan Patel, Sharad B. Murdande & Rutesh H. Dave
To cite this article: Dhaval A. Shah, Manan Patel, Sharad B. Murdande & Rutesh H. Dave
(2016): Influence of spray drying and dispersing agent on surface and dissolution properties
of griseofulvin micro and nanocrystals, Drug Development and Industrial Pharmacy, DOI:
10.1080/03639045.2016.1178770
To link to this article: http://dx.doi.org/10.1080/03639045.2016.1178770
Accepted author version posted online: 14
Apr 2016.
Published online: 04 May 2016.
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2. RESEARCH ARTICLE
Influence of spray drying and dispersing agent on surface and dissolution
properties of griseofulvin micro and nanocrystals
Dhaval A. Shaha
, Manan Patela
, Sharad B. Murdandeb
and Rutesh H. Davea
a
Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY, USA; b
Drug Product Design, Pfizer
Worldwide R&D, Groton, CT, USA
ABSTRACT
The purpose for the current research is to compare and evaluate physiochemical properties of spray-dried
(SD) microcrystals (MCs), nanocrystals (NCs), and nanocrystals with a dispersion agent (NCm) from a poorly
soluble compound. The characterization was carried out by performing size and surface analysis, interfacial
tension (at particle moisture interface), and in-vitro drug dissolution rate experiments. Nanosuspensions
were prepared by media milling and were spray-dried. The SD powders that were obtained were character-
ized morphologically using scanning electron microscopy (SEM), polarized light microscopy (PLM), and
Flowchem. Solid-state characterization was performed using X-ray powder diffraction (XRPD), Fourier trans-
fer infrared spectroscopy (FT-IR), and differential scanning calorimetry (DSC) for the identification of the
crystalline nature of all the SD powders. The powders were characterized for their redispersion tendency in
the water and in pH 1.2. Significant differences in redispersion were noted for both the NCs in both dissol-
ution media. The interfacial tension for particle moisture interface was determined by applying the BET
(Braunauer–Emmett–Teller) equation to the vapor sorption data. No significant reduction in the interfacial
tension was observed between MCs and NCs; however, a significant reduction in the interfacial tension was
observed for NCm at both 25
C and 35
C temperatures. The difference in interfacial tension and redisper-
sion behavior can be attributed to a difference in the wetting tendency for all the SD powders. The dissol-
ution studies were carried out under sink and under non-sink conditions. The non-sink dissolution
approach was found suitable for quantification of the dissolution rate enhancement, and also for providing
the rank order to the SD formulations.
ARTICLE HISTORY
Received 29 December 2015
Revised 30 March 2016
Accepted 7 April 2016
Published online 3 May 2016
KEYWORDS
Griseofulvin; interfacial
tension; nanocrystals; non-
sink dissolution;
redispersion; spray dryer
Introduction
It has been reported that more than half of the identified potential
drug candidates have challenges related to aqueous solubility and/
or the dissolution rate1
. A majority of these compounds belong to
the BCS class II and IV categories2,3
. The rate and the extent of
absorption of the Class II compounds are highly dependent on the
performance of the formulated product4–6
. Several formulation
approaches have been suggested and reported to overcome these
problems. The formulation of nanocrystals (NCs; suspension or
solid) is one of the preferred approaches that has been used for
the drugs which belong to the above BCS classes7,8
. NCs offer sev-
eral advantages, including enhancement in bioavailability, reduc-
tion in therapeutic dose, and elimination of the food effect9–14
.
The solubility behavior of crystalline nanoparticles can be
explained by the Ostwald–Frendulich equation. Based on the pub-
lished reports, the thermodynamic solubility enhancement of nano-
crystalline particles should be approximately 10–15%8,15,16
. On the
other hand, nanosuspensions have a very high surface-to-volume
ratio and high Gibbs energy, which indicates the instability of the
system. They tend to form aggregates due to Ostwald’s ripen-
ing13,17
. Nanosuspensions can be stabilized and their shelf life can
be enhanced by converting them into solid powders by spray dry-
ing and/or freeze drying10,18
.
Upon solidification, the surface properties of dried particles (i.e.
size, shape) may tend to change significantly, which will have a dir-
ect impact on the wetting and dissolution performance of the
formulation19
. Hence, it is crucial to assess the surface and the
interfacial properties of the dried particles20,21
. It is also known that
these suspensions (micro/nano) may form reversible or nonreversi-
ble aggregates upon solidification. Therefore, aggregation is
another key product quality parameter that needs to be assessed
for effectiveness with the dried particles22,23
. During spray drying,
the particle size distribution is governed by the nozzle size24
. It is
possible to have different dissolution behavior for formulations
with the same particle size due to change in surface wetting prop-
erty25
. Therefore, it will be important to determine the role of the
interfacial tension (at particle to moisture interface) in governing
the redispersion and the kinetic solubility (initial dissolution rate)
of NCs and micro crystals (MCs).
In the current study, we have formulated spray-dried (SD) nano-
crystalline powder (with and without the bulking agent mannitol)
and MCs of a poorly soluble drug. Griseofulvin (a BCS Class II com-
pound) was selected as a model compound and docusate sodium
(ionic stabilizer) and HPC-SL (Hydroxypropyl cellulose-low viscosity
grade; polymeric stabilizer) were utilized to prevent agglomeration
of nanosuspensions before spray drying, while the mannitol was
used as a dispersing agent for spray drying. The SD powders were
evaluated for surface characterization (size and shape analysis),
solid-state characterization (XRPD, DSC, and FT-IR), interfacial ten-
sion (DVSO), redispersion, and in-vitro dissolution rates (sink and
non-sink). This study shows the effect of interfacial tension in gov-
erning the dissolution of NCs and quantitates the dissolution rate
CONTACT Rutesh H. Dave rutesh.dave@liu.edu Arnold Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY 11201,
USA.
ß 2016 Informa UK Limited, trading as Taylor Francis Group
DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY, 2016
http://dx.doi.org/10.1080/03639045.2016.1178770
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3. enhancement for the SD powders using non-sink conditions to
provide them in rank order based on their in-vitro performance.
Materials
Griseofulvin was obtained from Spectrum Chemicals (New
Brunswick, NJ). The yttrium-stabilized zirconium oxide beads were
obtained from Glen Mills Inc. (Clifton, NJ). Hydroxypropylcellulose
(HPC)–SL was obtained from Nisso America Inc. (New York, NY).
Other laboratory chemicals, such as mannitol, docusate sodium
USP, acetonitrile, and trifluoroacetic acid (TFA), were purchased
from Spectrum Chemicals (New Brunswick, NJ) and were of analyt-
ical grades. All the excipients utilized in this study were of high
purity. The chemical structure of API and excipients are presented
in Figure 1.
Methods
Wet milling
Griseofulvin (50 mg/mL) was suspended in an aqueous stabilizer
solution which is a mixture of 1.25% (w/v) HPC–SL (stearic stabil-
izer) and 0.05% (w/v) docusate sodium (ionic stabilizer). The sus-
pension (500 mL) was milled using the yttrium stabilized zirconium
oxide beads (YTZ beads) at a milling speed of 1000 rpm in the con-
tinuous model8
. The suspension formulation was milled for 4 h,
and the particle size was measured during and following the mill-
ing process. The temperature of the sample was maintained below
25
C using the cold water that surrounded the milling chamber to
compensate for the heat generated by high-speed milling. The sus-
pension was harvested by filtration through a coarse sintered-glass
funnel filter (75 mm). The nanosuspension was divided into two
equal parts, and in one part the mannitol was dissolved in a 1:2
ratio (Griseofulvin: mannitol). The suspension was then stirred for
at least 30 min and then prepared for spray drying. The microcrys-
talline suspension was prepared using the same method and the
same stabilizer concentration with the absence of the milling
vehicle (i.e. YTZ beads).
Spray drying
Nano (with and without the mannitol) and microcrystalline suspen-
sions were spray-dried using a B-290 spray dryer (Buchi
Labortechhnik AG, Flawil, Switzerland). The spray dryer was equili-
brated using distilled water at 128
C inlet temperature, 3 mL/min
feed rate, and 100% aspiration rate. The outlet temperature was
approximately 75
C. The aforementioned SD parameters were
determined from some preliminary experiments. Once the spray
dryer was equilibrated, the suspension formulations were subjected
to spray drying with continuous stirring using a magnetic stirrer.
SD powders were collected from the collection chamber and
immediately analyzed for particle size, process yield, and
crystallinity.
Particle size, surface and shape analysis
A dynamic light scattering (DLS) instrument (Malvern Instruments
Inc., Malvern, UK) was used to measure particle size and the size
distribution of suspensions. All three SD powders were subjected
to particle size and shape analysis. Particle size measurements of
SD powders were performed using a Sympatec GmbH System-
Partikel-Technik (Sympatec Inc., Pennington, NJ). Briefly, around
100 mg of a sample was subjected for analysis. Compressed air
was used to disperse the powder, which is blown through the laser
beam and collected by suction after the analysis. Polarized light
microscopy (PLM; Model BX60FS; Olympus BX60, Center Valley, PA)
and scanning electron microscopy (SEM, ASPEX Scanning Electron
Microscope model PSEM 3025 SEM/EDS, Fei Inc., Hillsboro, OR)
were conducted to observe the surface morphology and texture of
the pure materials and SD powders. The polarized microscopic
images were taken using a camera from Diagnostic Instruments
Inc. (Sterling Heights, MI), and the analysis was performed with the
help of SPOTTM
imaging advanced software. For the SEM imaging,
the samples were mounted on double-sided carbon tape. The low
vacuum (LV) mode was used to prevent the samples from charg-
ing. The energy beam and filament drive were adjusted to 20 kev
and 72%, respectively. The samples were analyzed under approxi-
mately 60% contrast and 30% brightness in secondary electron
mode. Particle shape and further morphological characterization
were performed using the flow cam machine (Fluid Imaging
Technologies, Scarborough, ME). Here, the sample was prepared by
dispersing the SD powders into the water and then subjected to
analysis. The machine captures particle images at up to 22 frames
per second. The analysis was performed by keeping the flow rate
at 0.3 mL/min and viewed under 4Â optical lens. The morpho-
logical measurements (i.e. shape) of particles were calculated using
the Visual spread sheetVR
Particle analysis software.
Differential scanning calorimetry
Modulated differential scanning calorimetric (mDSC) analysis was
performed using a Q200 (TA Instruments, New Castle, DE)
equipped with a cooling system. A sample (5–10 mg) was weighed
into an aluminum pan with a pin hole and hermitically sealed. The
DSC parameters used were: a sample equilibration at 30
C, modu-
lated for ±0.318
C every 60 s, isothermal for 5 min and heated to
230
C with a ramp of 2
C/min. The DSC cell was purged with
nitrogen gas at a flow rate of 50 mL/min. The data obtained were
analyzed with the Universal Analysis Software (TA Instruments,
New Castle, DE).
Powder X-ray diffraction
Powder X-ray diffraction was done using a scanning diffractometer
(Advanced Diffraction System, Scintag Inc. Model XI, Cupertino,
CA), controlled by a computer with diffraction management system
software for Windows NT. The radiation used was generated by a
copper Ka filter, with a wavelength of 1.54 A
at 45 kV and 40 mA.
High energy mixture patterns obtained by the X-ray were
Figure 1. Chemical structures of a model compound and excipients.
2 D. A. SHAH ET AL.
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4. compared to a reference drug to confirm crystallinity26
. Samples
were scanned over a range of 5–40
degrees, using a scan rate of
1
/min and a step size of 0.02. X-ray diffraction patterns were
obtained for pure griseofulvin, excipients, physical mixtures, and
formulated SD powders. Data analysis for recorded patterns was
done using X’Pert Data Viewer software.
Infrared spectroscopy (FT-IR)
FTIR spectra for all the abovementioned samples were obtained by
Nicolet-FTIR equipped with smart ATR (Thermo Fisher Scientific Inc.
Madison, WI), and a DTGS-KBr (Deuterated triglycine sulfate)
detector was used for background and baseline corrections. Small
amounts of the sample were placed on the diamond crystal of the
ATR and then the ATR knob was closed. Finally, the spectra were
collected from 400 to 4000 cmÀ1
with 264 accumulations at a reso-
lution of 4 cmÀ1
.
Gravimetric vapor sorption and interfacial energy (DVS)
Moisture sorption profiles were obtained for the SD powders using
a SGA-100 Sorption Analyzer (VTI Corporation, Hialeah, FL). The
measurements were taken at 25
C (storage temperature) and
35
C (close to physiological temperature) using a sample size of
10–20 mg. All SD samples were exposed to an automated compu-
terized sequence of increasing relative humidity (RH) in steps of
10% RH. The RH range was from 0% RH to 95% RH. The vapor
sorption analysis was carried out to calculate the interfacial tension
and water uptake capacity of all three powders as described in the
literature27
. The adsorption of moisture onto multilayer surfaces
is believed to follow the Brunauer–Emmett–Teller (BET) model.
Similarly, we made the assumption that adsorption of moisture
onto SD powder particles would follow the BET multilayer model.
The BET constants (m0 and C) were determined from the initial lin-
ear region of the moisture sorption adsorption isotherm (0.35%
w/w). The interfacial tension at particle moisture interface was
determined by calculating the binding energy (from BET constant
C) and the average surface area of a water molecule (Appendix A).
HPLC analytical method
The quantitative analysis of model compounds used in the solubil-
ity studies was performed by a reverse-phase gradient HPLC using
an Agilent 1100 System (Agilent Technologies, Palo Alto, CA)
equipped with a 4.6 Â 75 mm, 2.7 mm C18 column (Advanced
Materials Technology, Wilmington, DE). The temperature of the col-
umn was kept at 45
C, and the wavelength of detection was set
to 210 nm. The mobile phase consisted of a binary gradient of
Solvent A (acetonitrile) and Solvent B (HPLC grade water with
0.05% TFA). The linear gradient started at 5% A and increased to
95% A in 8.5 min, followed by a return to the starting condition
within 1.6 min and equilibrated at the starting condition for 2 min.
The injection volume was 10 mL. The flow rate was 1.0 mL/min, and
the total run time was set for 13.10 min. This reverse-phase gradi-
ent method provided a baseline resolution and excellent peak
characteristics for the griseofulvin. Quantification of drug concen-
trations was performed by analyzing the peak area at retention
using Agilent ChemstationVR
analytical software.
Redispersion analysis
The nanosuspensions have tendency to form loose or hard aggre-
gates when spray-dried. Sometimes these aggregates are reversible
and sometime they are not reversible. To evaluate this behavior,
we carried out the redispersion study of SD NCs (with and without
mannitol) in the DI water and in the simulated gastric media (pH
1.2). The study was performed in a conventional USP-type – II dis-
solution apparatus at 100 rpm and 37
C temperature. Here, sam-
ples were withdrawn at different time intervals and subjected to
the particle size analysis using the zetasizer28
.
In vitro dissolution rate determination
A dissolution apparatus (Distek 2100C; Distek Inc., North Brunswick,
NJ) equipped with a USP-type-II (paddle) was used to measure the
dissolution rates of crystalline SD dispersions. The dissolution study
was carried out by comparing the initial dissolution rates of MCs
and NCs (with and without mannitol). Each dissolution study was
carried out at 37 ± 0.5
C under a 100-rpm paddle speed in a USP-
type II apparatus for 2 h. The dissolution was carried out under
sink condition (sink condition factor 5.7Â), and under non-sink
conditions (at 20%, 50%, and 90% saturation level of API in dissol-
ution media) with a 50 mg loading of griseofulvin. A 10 mL of a dis-
solution sample was withdrawn at intervals of 0, 2, 5, 7, 10, 20, 30,
45, 60, 90, and 120 min and replaced with the same volume of dis-
solution media (pre-equilibrated at 37 ± 0.5
). Samples were filtered
through 0.1-mm (MCs) and 0.02-mm (NCs) anotop syringe filters
(WhatmanTM
; GE Healthcare, Piscataway, NJ) and subjected to
HPLC analysis. The first few milliliters of each sample were dis-
carded to minimize losses because of adsorption. The discarded
volume selected for each compound was determined by a separate
filter validation experiment (data not shown). All studies were per-
formed in triplicate29–35
.
Results and discussion
Morphological characterization
The particle size of the suspensions before the spray dying was
measured using DLS. The particle sizes of the SD powders were
measured using the Sympatec GmbH System-Partikel-Technik
(HELOS RODOS). The particle size and shape analysis data are
presented in Table 1. The particle size of micronized SD powder
upon drying is approximately 14 mm, while the particle size of
both SD nanosuspension powders upon drying are around 6 mm.
The particle size of nano powders are significantly lower than the
particle size of the micronized powder, which is explainable due
to difference in particle size before spray drying. There is no sig-
nificant difference in particle size between nanosuspensions
with and without mannitol. Morphological characterization by
PLM and SEM (Figures 2 and 3) shows the particle size difference
between MCs and NCs. Moreover, the NCs in both formulations
became hollow upon particle size reduction while MCs appear
cylindrical shaped. The SEM image of nanocrystals with mannitol
(NCm) also shows the presence of mannitol on the surface of
NCs. Initial observation from SEM images of the NCs with and
without the mannitol showed formation of aggregates upon
spray drying. Therefore, redispersion analysis was carried out for
further characterization of the aggregation property (reversible or
irreversible). The FLOWCHEM machine has the ability to capture
30 unique particle measurements. The morphological measure-
ments for SD particles were calculated using Visual spread sheetVR
particle analysis software. The NCm were found to be spherical in
shape as compared to NCs without the mannitol and the MCs
(Table 1).
Solid-state characterization
It is known that changes in the crystalline state can occur during
both milling and spray drying. To ensure that the changes are due
DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY 3
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5. to particle size reduction and that no amorphous griseofulvin was
formed, MDSC, XRPD, and FT-IR were performed on the SD
samples.
Griseofulvin showed distinct crystalline peaks for 2h at 11
and
17
(Figure 4(a)) in all the SD powders. As shown by the XRPD pat-
terns (Figure 4(a)), the reduction in the intensity and broadening of
Figure 2. PLM images of (a) pure griseofulvin, (b) MC, (c) NCs, and (d) NCm.
Figure 3. SEM images of (a) HPC-SL, (b) DOSS, (c) mannitol, (d) pure griseofulvin, (e) MC, (f) NCs, and (g) NCm.
Table 1. Particle size and shape analysis.
Formulation
Avg. particle size
before spray drying PDI
Avg. particle size
after SD (lm) Span(D90–D10)/D50
Circularity
(Hu)
Aggregation based
on SEM/PLM
MC 11 lm – 14.9 2.3 0.81 Yes
NCs 210 nm 0.210 6.64 1.85 0.82 Yes
Nanocrystal-mannitol 205 nm 0.192 6.42 1.82 0.95 Yes
4 D. A. SHAH ET AL.
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6. the peaks is observed for the nanoparticles. XPRD of SD powders
showed a small hump in between 20 and 30 at 2h scale represents
possible minor amorphous conversion. Figure 4(b) shows the MDSC
thermograms for pure griseofulvin and the SD formulations. The
thermograms were compared to confirm the crystallinity upon mill-
ing and spray drying. The onset melting temperature of griseofulvin
and mannitol were detected at 219.0
C and 168.4
C, respectively.
After milling and spray drying, a reduction in the onset of the melt-
ing temperature (2–4
C) and the heat of fusion was observed for
both griseofulvin and mannitol. The melting peaks of griseofulvin
shifted in the SD formulations (Figure 4(b)). The observed melting
point reduction and peak shift have been reported to be in agree-
ment with the particle size reduction. It can also be explained by
the Gibbs–Thomson equation36
, which explains that, the melting
temperature of a material is proportional to its cohesive energy.
Since the atoms at the surface have reduced cohesive energy com-
pared to bulk material due to physical milling and spray drying.
Therefore, they require less energy to free from the solid phase (i.e.
melting), which results in the reduction of melting point. Based on
the MDSC and XRPD data, it can be concluded that the wet-media
milling and spray drying might have affected the crystalline struc-
ture of the model compound by partially (minor) converting it in to
the amorphous form. For further clarification of the crystalline struc-
ture, FT-IR spectroscopy was conducted on the SD samples (Data
not shown). The SD formulation with mannitol showed intense peak
at 3288À1
cm and 3388À1
cm (–OH stretching) suggesting the pres-
ence of mannitol in the formulation. These transmissions were
absent in the IR spectra of MCs and NCs without the mannitol. The
IR spectra of all three SD formulations are same except the increase
in the –OH and –CH stretching intensity due to the presence of
mannitol in the SD formulation with mannitol.
Interfacial energy and water uptake tendency
The dynamic vapor sorption analysis was performed to evaluate the
moisture uptake tendency of the SD powders. The water uptake
tendency of NCm was found to be higher compared to both the
MCs and NCs. For a detailed evaluation of this, we calculated the
interfacial energy as described in Appendix A, and the results are
presented in Table 2. For the colloidal dispersion systems, the inter-
facial energy plays an important role. For different compounds, the
solubility and, eventually, the dissolution rate increased as the sol-
id–liquid interfacial tension decreases37
. The interfacial tension val-
ues for the MC and NC do not have any significant difference at
either temperature (both at 25
C and 35
C). The NCm showed less
interfacial tension values compared to MCs and NCs without manni-
tol at both temperatures. Here, mannitol has a characteristic prop-
erty to act as a solubilizing and dispersing agent. Mannitol acts by
forming capillaries in contact with aqueous solutions and generates
rapid dispersion and dissolution38
. Based on these studies, we can
conclude that the dissolution and redispersion behavior for NCm
will be significantly higher due to the enhancement of the wetting
property and a reduction in interfacial tension. Crisp39
and his col-
leagues have also reported that the dissolution of NCs is more
dependent on interfacial tension than the surface area.
Redispersion analysis
The nanosuspensions have a tendency to form loose or hard
aggregates when SD. Nanoparticle aggregation was visually
observed for SD powders in SEM images. Sometimes these aggre-
gates are reversible and sometime they are not reversible. In order
to assess their aggregation property, the redispersion analysis was
carried out. The SD powder of NCm redispersed quickly during the
redispersion study in water and in pH 1.2 (Figure 5(a) and (b)). The
NCm quickly reached the initial particle size. On the other hand,
the NCs without the mannitol were not able to achieve the initial
particle size (200–300 nm) when spray-dried. The dispersion behav-
ior of particles in the liquid phase is mainly affected by the inter-
action between the particles and the dispersion media. Therefore,
the presence of mannitol aids in wetting the particles quickly by
forming reversible aggregates. In the case of the NCs without the
Figure 4. Solid-state characterization and comparison of pure API, physical mixture, MCs, NCs, and NCm (a) XRPD, and (b) DSC.
Table 2. Determination of BET constants and interfacial tension.
Formulation Particle size (lm)
C
(binding constant)
m0
(monolayer g/g
solids)
DE (J/mole) (sur-
face binding
energy)
c
(mN/m) (interfacial
tension)
25
C 35
C 25
C 35
C 25
C 35
C 25
C 35
C
MC 14.9 À20.58 À20.43 12.15 1.77 7492 7726 138.2 142.5
NCs 6.64 À17.00 À17.26 19.60 24.07 7681 7790 133 134
Nanocrystals-mannitol 6.42 À11.48 À11.24 32.26 21.19 6047 6195 111.6 114.3
DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY 5
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7. mannitol, they showed different wetting behavior in both water
and pH 1.2, resulting in a significantly different redispersion profile.
One possible reason might be the generation of nanocrystalline
particles with a high adhesive hydrophobic surface, which has
more of a tendency to form aggregates in the absence of the dis-
persion agent (mannitol).
Initial dissolution rate determination
The dissolution studies were performed to discriminate the effect-
iveness of the micro suspension, nanosuspension, and nanosuspen-
sion with mannitol upon spray drying. The in-vitro dissolution
profile of a formulation can serve as a predictive tool for in-vivo
analysis40,41
. Here, the energy of the formulation system is reduced
upon spray drying and with the rapid removal of water. For nano-
particles, the rate limiting and more important step is the solvation
step (surface kinetics) at the solid–liquid interface (the dissociation
of drug molecules from the solid)39,42
. Therefore, the
Noyes–Whitney model seems to be ineffective in generating the
discrimination in the dissolution process of the NCs with a mean-
ingful way.
Our objective was to design a conventional in-vitro dissol-
ution method, which can be easily applied to discriminate the
dissolution profiles among the MCs, NCs, and NCm. Initially, the
dissolution studies were carried out by maintaining the sink con-
dition as described in the Method section (n ¼ 3). The sink con-
dition dissolution profile did not show significant discrimination
among MCs, NCs, or NCm (Figure 6(a)). Therefore, for efficient
quantitative discrimination, the dissolution was carried out under
non-sink conditions (n ¼ 3, Figure 6(a) and (b)). The non-sink dis-
solution displayed discrimination in the dissolution profile by
reducing the dissolution velocity. In the sink condition dissol-
ution, the initial dissolution rate ratio of NCs and NCm is negli-
gible. But, as the saturation level increased, the discrimination
increased, and at the 90% saturation level, the initial dissolution
rate ratio for NCs to MCs was 1.8, NCm to MCs was 6.7, and
NCm to NCs was 4.9-fold compared to their dissolution ratios at
initial phase in sink conditions (Table 3). The reported dissolution
rate enhancement behavior can be attributed to the presence of
mannitol during spray drying. This can be further explained by
the improvement in the wetting property and a reduction of
the interfacial tension (tension at solid–liquid interface during
dissolution) for the SD particles of NCm. Also, the partial conver-
sion of crystalline form to amorphous might play a contributing
role in the dissolution behavior for the SD products. However,
since the conversion of crystalline form to amorphous form is
minor (probably less than 5%), the rate of crystallization of the
amorphous form during dissolution expected to be very fast.
Therefore, it will have negligible impact on the dissolution
behavior. The current study justifies the use of non-sink condi-
tion over sink condition for better quantitative discrimination of
nanocrystalline and microcrystalline powder dissolution.
Conclusion
Much of the published work in the area of drying nanocrystalline
suspensions has focused on the impact of the process parameters
on the final product. This study shows the importance of particle
Figure 5. Redispersion study of SD powders of NCs and NCm (a) in pH 1.2, and (b) water.
Figure 6. In-vitro sink and In-vitro non-sink dissolution: comparing MCs, NCs, and NCm: (a) 0% and 20% saturation, and (b) 50% and 90% saturation levels.
6 D. A. SHAH ET AL.
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8. size reduction and the incorporation of mannitol as a dispersing
agent during the spray drying of nanocrystalline suspension of
poorly soluble compounds (BCS class II/IV). Upon spray drying, the
fundamental properties (surface and in-vitro dissolution under non-
sink condition) change drastically. The interfacial tension at the
particle moisture interface and redispersion behavior and non-sink
dissolution profile of griseofulvin–mannitol nanocrystalline suspen-
sions show superior performance as compared to the micron/un-
milled and nanocrystalline suspension formulations. The present
study provides an in-depth understanding to a formulation scien-
tist who can quantitate the change in the interfacial tension (at
particle moisture interface) and in the in-vitro dissolution rate
enhancement during initial phase. This provides a platform to
apply a practical approach to screen and rank order the SD formu-
lation with different initial particle size (before drying) with manni-
tol as a dispersing agent.
Disclosure statement
The authors report no declaration of interests.
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Dissolved in 2 min (%) Initial dissolution rate ratios
MC NC Nanocrystals-mannitol NCa
/MCb
NCmc
/MC NCm/NC
Sink 31 83 96 2.7 3.1 1.1
20% 11 33 37 3.0 3.3 1.1
50% 6 13 30 2.16 5.0 2.3
90% 4 7 28 1.75 7.0 4.0
a
NC spray-dried, b
micro SD powder, c
nanocrystal with mannitol spray-dried.
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Appendix A
The adsorption of moisture onto multilayer surfaces is believed to
follow the Brunauer–Emmett–Teller (BET) model. Similarly, we make
the assumption that adsorption of moisture onto spray-dried pow-
der particles follows the BET multilayer model. In this assignment,
an attempt is made to relate surface energy from BET to interfacial
tension based on moisture adsorption onto powder particles.
Determination of BET parameters
The BET equation is given by:
m
m0
¼
CX
ð1 À XÞ½1 þ ðC À 1ÞXŠ
(A1)
From thermodynamics, the ratio of partial pressure of water
and that of pure substance is represented by:
aw ¼
p
p0
¼ X (A2)
We can now rearrange Equation (A1) to obtain the multilayer
model of BET as shown by:
m ¼
awm0C
ð1 À awÞ½1 þ awðC À 1ÞŠ
(A3)
where m is the moisture content in g/g solids; aw, is water
activity; m0, is the moisture content of monolayer in g/g solids;
C ¼ e
DE = RT
, the BET model is typically applicable up to 0.5aw.
The experimental application of the BET multilayer model involves
obtaining some initial values of water activity, aw, with correspond-
ing moisture content values, m. The analytical method involves lin-
earization of Equation (A3) to obtain:
½1 þ awðc À 1ÞŠ
m0c
¼
aw
ð1 À awÞm
(A4)
Finally,
aw
ð1 À awÞm
¼ aw
c À 1
m0c
þ
1
m0c
(A5)
where a plot of aw
ð1Àaw Þm versus aw gives a straight line with slope as
cÀ1
m0c
h i
and the intercept as 1
m0c. The BET parameters, m0, and C were
experimentally obtained as m0 ¼ 1
slopeþintercept and C ¼ 1
interceptÃm0
.
Determination of the cross-sectional area of the water molecule
Assume monolayer saturable sites with each molecule of water
spreading across the spray-dried powder particle. From quantum
thermodynamics, the spatial separation between two water mole-
cules is given by:
V
N
1=3
18x10À6
m3
6x1023
1=3
¼ ð30x10À30
m3
Þ1=3
¼ 3x10À10
m (A6)
8 D. A. SHAH ET AL.
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10. 3x10À10
m à 3x10À10
m ¼ 9x10À20
m2
¼ 0:9x10À19
m2
The cross-sectional area of a water molecule is then derived as:
Note: The actual cross-sectional area of a water molecule:
1.06 Â 10À19
m2
.
Determination of interfacial tension (c) between particle and
moisture
The molecular relationship between solid–liquid interface may be
described by the changes in surface energy (DE). The deposition of
monolayer of moisture on the powder molecules creates an inter-
facial tension that is expressed based on Young–Laplace expression:
DE ¼ cA
where DE is the surface or binding energy of the monolayer; c is
the molecular interfacial tension; and A is the molecular cross sec-
tional area.
If we assume non-interactive particle–particle behavior as
espoused by BET, then the molecular interfacial tension between
powder and water molecules could be estimated from the binding
or surface energy at the saturable sites as given by:
c ¼
DE
NAvogadro
Ã
1
AH20
(A7)
where DE is monolayer binding or surface energy; NAvogadro is the
Avogadro’s number,
(6:02x1023
molecules=mol); AH20 is the cross-sectional area of
water molecule (1:06x10À19
m2
). In conclusion, the BET model
allowed the estimation of powder-moisture interfacial tension
through the construct of surface energy of saturable
monolayer.
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