Objective
To investigate the wetting characteristics of hydroxypropylcellulose (HPC) solutions during the granulation
process on model active systems of low water solubility.
Introduction
In recent years, an increasing number of active agents exhibit low aqueous solubility. In addition to the
bioavailability issues with these hydrophobic systems, wetting of the actives during the granulation process
is an important aspect. Poor wetting of the substrate typically leads to weak, porous granules and inadequate
binder distribution. As a result, granule flow and tablet mechanical properties can be compromised
(1,2). In this study, we investigate a method to measure the wetting kinetics of various binder solutions on
porous beds of two low soluble actives, ibuprofen and naproxen; and evaluate the surface energy of these
actives. This work is discussed in relationship to wet binder performance in these model formulations.
Methods
Dry blends of ibuprofen and lactose (83.3% and 9.9% of the total formulation respectively) or
naproxen (93% of formulation) were granulated with binder solutions in a low shear planetary mixer. The
binder solutions were prepared so that their concentration in the final granulation was 4%. The granulations
were dried to 0.5% moisture and milled through a 0.065" FitzMill screen. 0.25% colloidal silicon dioxide
and 2% croscarmellose sodium were hand-screened (20 mesh) and blended with the granulation for 5 minutes.
This was followed by addition of 0.5% magnesium stearate through a 20 mesh screen and further
mixing for 2 minutes. Powder flow properties were evaluated using an Aero-FlowTM powder flowability
analyzer of TSI Incorporated to measure the mean time to avalanche (MTA). Free-flowing powders will
produce a short mean time whereas less freely flowing powders will have a longer mean time. Surface
energy of the actives and wettability of the granulating solutions were characterized using a Krüss tensiometer
system for measurement of porous solids. Viscosities of the binder solutions were measured on a
Brookfield viscometer using the Ultra Low Spindle set. 600 mg tablets were compressed on an instrumented
rotary press using 7⁄16" standard concave tooling and measured for crushing strength (diametral compression),
friability and tablet weight uniformity, as previously detailed (3).
*This work was presented at the 2003 American Association of Pharmaceutical Scientists Annual Meeting, October 26-30, 2003 Salt Lake City, Utah.
Hercules Incorporated
Aqualon Division
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www.aqualon.com
Pharmaceutical Technology Report
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Materials
1. HPC: Klucel® EF Pharm Hydroxypropylcellulose, marketed by Aqualon Division, Hercules
Incorporated,Wilmington, DE.
2. HPMC: Methocel® E5 Premium Hypromellose Type 2910, USP, marketed by Dow Chemical
Company, Midland, MI.
3. PVP: Plasdone® K29/32 Povidone, USP, marketed by International Specialty Products,Wayne, NJ.
4. IBU: Ibuprofen, USP, marketed by BASF Corporation, Mount Olive, NJ.
5. NAP: Naproxen, USP, marketed by Spectrum Chemicals, New Brunswick, NJ.
6. Ac-Di-Sol® croscarmellose sodium, NF, marketed by FMC Corporation, Philadelphia, PA.
7. Cab-O-Sil® amorphous fumed silica (colloidal silicon dioxide), NF, marketed by Cabot Corporation,
Tuscola, IL.
8. Lactose, regular grind, NF, marketed by Foremost Farms USA, Rothschild, WI.
9. Magnesium stearate, NF, marketed by The Crompton Corporation (formerly Witco Chemical
Corporation), Middlebury, CT.
Results
Wetting Studies
The Washburn theory describes the phenomenon of liquid rising into the pores of a powder bed due to
capillary action when the solid is brought into contact with a liquid (4, 5). The following equations describe
this event:
t = Am2,
A = /C2cos
where
t is the time after the solid and the liquid are brought into contact,
m is the mass of the liquid drawn into the solid,
A is a constant dependent on the liquid properties (viscosity , density and surface tension ) and
the solid/liquid contact angle , and
C is a material constant dependent on the porous architecture of the powder bed.
In performing Washburn experiments, the mass of liquid drawn into the porous solid bed can be measured
as a function of time. The liquid density, viscosity, and surface tension are easily evaluated, and C
and are two unknowns. In order to determine C, wetting experiments can be performed using n-hexane
which has a very low surface tension, so that is equal to zero in most cases. Once C has been determined
for a particular solid, the solid can then be tested for wettability by a range of other liquids, and contact
angles can be calculated. For this study, the wetting behavior of several 0.5 wt% binder solutions was
investigated on the actives ibuprofen and naproxen, both virtually insoluble in water and known to be difficult
to granulate.
Figure 1 shows the adsorption of n-hexane into ibuprofen and naproxen powder beds, each with duplicate
runs showing good reproducibility. A plot of mass2 versus time is linear, as predicted by the Washburn
equation, until a plateau is reached indicating the bed is saturated. With the slope of the adsorption plots
(1/A) and assumption that cos = 1, the material constants for ibuprofen and naproxen are determined as
CIBU = 1.28e-5 cm5 and CNAP = 7.71e-6 cm5, respectively.
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Figure 1
Mass2 vs Time for Hexane Uptake Into Ibuprofen and Naproxen Beds
and Material Constant Determination
Figure 2 depicts the mass uptake of various binder solutions into a bed of ibuprofen. A range of absorption
behavior is shown, depending upon the ability of the binding solution to wet the ibuprofen substrate.
For instance, water does not wet the ibuprofen at all as no mass is absorbed as a function of time. At the
other extreme, the HPC solution rapidly wets the ibuprofen as shown by the fast rate of adsorption. The
HPMC solution has an intermediate adsorption rate while the PVP solution shows only a slight improvement
over water with gradual adsorption of the binder solution into the powder bed.
Figure 2
Mass2 vs Time for Various Binder Solutions Into Porous Ibuprofen Bed
PRINTED IN U.S.A.
0
0.1
0.2
0.3
0.4
0.5
0.6
0 10 20 30 40
Time (sec)
NAP (run1)
NAP (run 2)
IBU (run 1)
IBU (run 2)
CNAP = 7.71e-6 cm5
CIBU = 1.28e-5 cm5
Mass2 (g2)
0
0.1
0.2
0.3
0.4
0.5
0.6
0 10 20 30 40 50 60 70 80 90 100
HPC
HPMC
PVP
Water
Time (sec)
Mass2 (g2)
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Using the slope of these uptake lines together with the measured solution viscosities, surface tensions
and densities, the wetting contact angle can be calculated for the various binder solutions. Table 1 illustrates
that HPC wets the ibuprofen surface with the lowest contact angle, followed by HPMC and PVP.
Table 1
Wetting Characteristics on Ibuprofen
Surface Tension Viscosity Contact
Wetting Solution (mN/m) (cP) Angle (°)
n-Hexane 18.4 0.3 0°
HPC 40.0 2.3 68°
HPMC 48.4 1.9 81°
PVP 53.6 1.5 88°
Water 72.1 1.0 No wetting, >90°
From the contact angle data, one can estimate the surface energy of the solid using Zisman’s approach
(6, 7). From Young’s equation, S - SL = Lcos, Zisman defines the solid surface energy as the surface
tension of a liquid that has the highest possible surface tension that will still wet the solid surface with a 0°
contact angle. A plot of the cosine of the contact angles (cos ) against the surface tensions of the liquids
and extrapolating to 1 (cos 0°) provides an estimate of the surface energy, as shown in Figure 3. The data
suggests that ibuprofen has a surface energy ~19 mN/m, consistent with its low wettability. Extrapolating to
0 (cos 90°), the data indicates that liquids with surface tensions higher than ~57 mN/m can be expected to
have contact angles greater than 90°, indicating that there will be no spontaneous wetting or penetration into
the powder bed. Water, with a surface tension of 72 mN/m, shows no wetting, as a validation of this concept.
Figure 3
Zisman Surface Energy for Ibuprofen
Figures 4 and 5 show analogous data for the second active, naproxen. The HPC binder solution again
wets this active the most efficiently, relative to the other binder solutions. The Zisman plot suggests
naproxen has a surface energy of ~40 mN/m, consistent with the fact that HPC solutions wet the naproxen
with contact angle of 0° as detailed in Table 2.
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 20 40 60 80
Surface energy IBU = 19 mN/m
Liquids with > 57 mN/m
will NOT wet IBU
, Liquid Surface Tension (mN/m)
cos, cosine of Contact Angle
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Figure 4
Mass2 vs Time for Various Binder Solutions Into Porous Naproxen Bed
Figure 5
Zisman Surface Energy for Naproxen
PRINTED IN U.S.A.
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 25 50 75 100 125 150
HPC
HPMC
PVP
Water
Time (sec)
Mass2 (g2)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 20 40 60 80
Surface energy
NAP = 40 mN/m
, Liquid Surface Tension (mN/m)
cos, Cosine of Contact Angle
Liquids with > 75 mN/m
will NOT wet NAP
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Table 2
Wetting Characteristics on Naproxen
Surface Tension Viscosity Contact
Wetting Solution (mM/m) (cP) Angle (°)
n-Hexane 18.4 0.3 0°
HPC 40.0 2.3 0°
HPMC 48.4 1.9 37°
PVP 53.6 1.5 63°
Water 72.1 1.0 85°
Binder Performance in Model Formulations
To establish the relevance of the wetting data to binder performance, binder solutions of HPC, HPMC or
PVP were used to granulate ibuprofen and naproxen. Granule flow as well as tablet properties were measured.
Figures 6 and 7 show binder performance with respect to tablet hardness as a function of compression
force for ibuprofen and naproxen tablets, respectively. With both of these low-soluble actives, the tablet
strength improves as the wetting ability of the binders improves. Dramatic differences in tablet hardness and
friability are shown in Figure 7 and Table 4 for the naproxen formulations when comparing HPC (best wetting
properties) with PVP (poorest wetting properties). The flow properties of the granules containing PVP
were poor and the fill-weight was low due to low bulk density also indicative of poor wetting during the
granulation process. HPMC binder performance was intermediate. With both HPC formulations, the tablet
physicals were excellent and the granules flowed adequately as detailed in Tables 3 and 4. The combined
thermoplasticity and wetting behavior of HPC provides an excellent choice as a wet granulation binder.
Figure 6
Effects of 4 Wt % Binders on Ibuprofen Tablet Hardness
10
11
12
13
14
15
16
17
18
0 5 10 15
HPC
HPMC
PVP
Compression Force (kN)
Hardness (kP)
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Page 7 of 8
Figure 7
Effects of 4 Wt % Binders on Naproxen Tablet Hardness
Table 3
Physical Properties of Ibuprofen Granules and Tablets
Bulk Compression Tablet Tablet Tablet Tablet
Binder MTA Density Force Weight Thickness Hardness Friability
4 Wt % (sec) (g/ml) (kN) (mg) (in) (kP) (%)
HPC 4.9 0.52 3 601 0.272 10.6 0.6
HPC 5 600 0.265 14.5 0.6
HPC 10 598 0.261 16.7 1.0
HPC 15 598 0.250 17.3 1.1
HPMC 7.4 0.48 3 600 0.275 10.1 0.7
HPMC 5 600 0.268 13.7 0.6
HPMC 10 598 0.262 16.1 0.9
HPMC 15 601 0.262 16.2 1.1
PVP 4.2 0.49 3 600 0.271 10.7 0.7
PVP 5 593 0.263 13.1 0.7
PVP 10 601 0.262 15.0 1.1
PVP 15 598 0.261 15.3 1.4
PRINTED IN U.S.A.
5
10
15
20
25
30
35
40
0 5 10 15
HPC
HPMC
PVP
Hardness (kP)
Compression Force (kN)
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Table 4
Physical Properties of Naproxen Granules and Tablets
Bulk Compression Tablet Tablet Tablet Tablet
Binder MTA Density Force Weight Thickness Hardness Friability
4 Wt % (sec) (g/ml) (kN) (mg) (in) (kP) (%)
HPC 9.8 0.38 3 605 0.318 5.7 2.0
HPC 5 596 0.282 14.1 0.9
HPC 10 596 0.259 29.9 0.5
HPC 15 596 0.249 37.5 0.8
HPMC 9.3 0.39 3 602 0.308 8.3 2.2
HPMC 5 601 0.290 12.7 1.4
HPMC 10 601 0.260 24.7 0.7
HPMC 15 600 0.251 26.4 0.9
PVP 14.5 0.34* 3 564* 0.297 7.3 3.3
PVP 5 569* 0.269 15.8 2.0
PVP 10 567* 0.248 21.8 1.5
PVP 15 564* 0.239 15.1 23.4
*Low bulk density & fill weight
Conclusions
1. The Washburn method is an easy and robust technique to investigate the wetting behavior of binder
solutions on low-soluble, hydrophobic actives.
2. The surface energy of these actives can be estimated from contact angle measurements.
3. HPC binder solutions show superior wetting characteristics compared to commonly used binders
such as PVP and HPMC.
4. The combined thermoplastic properties and excellent wetting behavior of HPC makes it an allaround
binder choice.
References
1. Rowe, R.C., Inter. J. of Pharmaceutics, 58, 209 (1990).
2. D. Zhand et al, Colloids & Surfaces, 206, 547 (2002).
3. Skinner, G.W. et al, Drug Dev Ind Pharm 25, 1121 (1999).
4. Washburn, E.W., Phys. Rev. 17, 374 (1921).
5. Hiemenz, P.C., Principles of Colloid & Surface Chemistry, 3rd Edition, ISBN 0-8247-9397-8.
6. Fox, H.W. and Zisman,W.A., J. Colloid Sci., 5, 514 (1950).
7. Zisman,W.A., ACS Advances in Chem. Series, 43, 1 (1964).
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