International Journal of Pharmaceutics 478 (2015) 796–803

Contents lists available at ScienceDirect

International Journal of Pharmaceutics

journal homepage: www.elsevier.com/locate/ijpharm

Moisture diffusion and permeability characteristics of

hydroxypropylmethylcellulose and hard gelatin capsules
Ahmad S. Barham a, * , Frederic Tewes b,c , Anne Marie Healy b
a
Basic Sciences Department, College of Engineering and Information Technology, University of Business and Technology, Jeddah, Saudi Arabia
b
School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland
c
INSERM U 1070, Pôle Biologie-Santé, Faculté de Médecine & Pharmacie, Université de Poitiers, Poitiers, France

A R T I C L E I N F O A B S T R A C T

Article history: The primary objective of this paper is to compare the sorption characteristics of hydroxypropylme-
Received 10 November 2014 thylcellulose (HPMC) and hard gelatin (HG) capsules and their ability to protect capsule contents.
Accepted 13 December 2014 Moisture sorption and desorption isotherms for empty HPMC and HG capsules have been investigated
Available online 16 December 2014
using dynamic vapour sorption (DVS) at 25
C. All sorption studies were analysed using the Young–
Nelson model equations which distinguishes three moisture sorption types: monolayer adsorption
Keywords: moisture, condensation and absorption. Water vapour diffusion coefficients (D), solubility (S) and
Hard capsules
permeability (P) parameters of the capsule shells were calculated. ANOVA was performed with the Tukey
Gelatin
HPMC
comparison test to analyse the effect of %RH and capsule type on S,P, and D parameters. The moisture
DVS uptake of HG capsules were higher than HPMC capsules at all %RH conditions studied. It was found that
Sorption–desorption values of D and P across HPMC capsules were greater than for HG capsules at 0–40 %RH; whereas over the
Diffusion same %RH range S values were higher for HG than for HPMC capsules. S values decreased gradually as the
Permeability %RH was increased up to 60% RH. To probe the effect of moisture ingress, spray dried lactose was loaded
into capsules. Phase evolution was characterised by scanning electron microscopy (SEM), X-ray powder
diffraction (XRD), and differential scanning calorimetry (DSC). The capsules under investigation are not
capable of protecting spray dried lactose from induced solid state changes as a result of moisture uptake.
For somewhat less moisture sensitive formulations, HPMC would appear to be a better choice than HG in
terms of protection of moisture induced deterioration.
ã 2014 Elsevier B.V. All rights reserved.

1. Introduction capsules (Chang et al., 1998). It is a good film-forming material

In the pharmaceutical field, hard capsules are used as a storage
medium for finely divided blends or formulations containing active
pharmaceutical ingredients (APIs) that are to be delivered orally or
by inhalation (Hosny et al., 2002; Steckel et al., 2004). Capsules
containing drugs are usually made of hard gelatin (HG) or
hydroxypropylmethylcellulose (HPMC) (Bae et al., 2008; Berntsson
et al., 1997).
Gelatin is a naturally occurring protein of animal collagen that
has notable hygroscopic properties and is used to manufacture HG
* Corresponding author at: Department Head of Basic Sciences, College of
Engineering and Information Technology, University of Business and Technology, P.
O. Box 11020, Jeddah 21361, Saudi Arabia. Tel.: +966 12 2159372;
fax: +966 12 2159010.
E-mail address: ahmad.s@ubt.edu.sa (A.S. Barham).
suitable for preparing capsule shells that dissolve readily in
biological fluids at body temperature (Pennings et al., 2006).
Gelatin has characteristics which make it suitable for the capsule
manufacturing processes, including gels, film-forming and surface
active properties (Sherry Ku et al., 2010). However, HG capsules
undergo shell brittleness after exposure to low humidity
conditions, are incompatible with hygroscopic materials, suscep-
tible to hydrolysis, and inherently reactive toward many sub-
stances, including reducing sugars, plasticizers and preservatives
(Missaghi and Fassihi, 2006). HPMC capsules proved to be a
suitable alternative to gelatin, with many patents granted for the
manufacturing process, including thermal gelation and a gelling
system with additives (Ogura et al., 1998). Moreover, HPMC
capsules have several distinct advantages over HG. Besides the fact
that it has no animal-derived raw materials risk, HPMC is a non-
ionic polymer and the capsule has fewer compatibility issues with
most drugs and excipients (Ogura et al., 1998). HPMC capsules are

http://dx.doi.org/10.1016/j.ijpharm.2014.12.029
0378-5173/ ã 2014 Elsevier B.V. All rights reserved.
 A.S. Barham et al. / International Journal of Pharmaceutics 478 (2015) 796–803
made from a cellulose–like polymer consisting of glucose units
linked together by b-1,4 glycosidic linkages and considered to be a
hydrophilic material, as characterised by its high moisture sorption
characteristics (Laksmana et al., 2009; Siroka et al., 2008).
A main limitation to the use of hard capsules resulted from an
exchange of moisture between the capsule shell and the fill
(Strickland and Moss, 1962). The usefulness of such capsules is
strongly dependent on their capacity to protect the contents in the
presence of moisture. The typical moisture content of HG capsules
generally may vary between 13 and 16% by weight of water (Chang
et al., 1998) compared to 2 and 6% for HPMC capsules (Sherry Ku
et al., 2010) when received from the suppliers. Sherry et al. (2010)
concluded that the water content of the polymeric material of the
capsules is a function of the relative humidity (RH) of the
surroundings and temperature. When the capsules are filled and
stored in a vapour tight container, the moisture will redistribute
between the various components until a uniform relative humidity
is attained in the capsule shell, fill and surrounding (Sherry Ku
et al., 2010).
Lactose is the most widely used excipient in the pharmaceutical
industries due to its low toxicity, ready availability and compati-
bility with the majority of low molecular weight drugs (Guenette
et al., 2009). It is well known that the solid state of lactose can be
either amorphous or crystalline and it exists in two isomeric forms,
namely, a-lactose monohydrate and b-lactose (Larhrib et al.,
1999). Amorphous lactose can be prepared by spray drying or
freeze drying. Spray dried lactose is thermodynamically unstable
and hygroscopic. It has a tendency to gain moisture from its
surroundings with ease and subsequently plasticize or cake
(Barham and Hodnett, 2005). Several researchers have investigat-
ed the crystallisation kinetics of lactose at different relative
humidities at room temperature. They found that the amorphous
lactose will initially sorb moisture from its surroundings and then
release the moisture when it crystallizes. This process will occur
spontaneously above 50% RH at 25
C (Barham and Hodnett, 2005;
Islam et al., 2010; Jouppila et al., 1997; Shrestha et al., 2007).
In general, the overall aim of the current study was to determine
the effectiveness of the capsules at protecting a moisture sensitive
compound and identifying which is better in this regard. Amorphous
lactose was chosen as a moisture sensitive model compound to
investigate the impact of encapsulation methods such as hard
capsules on lactose stability upon exposure to controlled humidity
environments. Evolution of lactose phases obtained upon crystal-
lisation and their interactions with water vapour were evaluated.
Sorption–desorption isotherms, water permeability, solubility, and
diffusion coefficients of empty HPMC and HG capsules were
determined at various relative humidity values at 25
C.
2. Materials and methods
2.1. Materials
2.1.1. Hard capsules
Hard gelatin (HG) capsules of size no. 3 were purchased from
Farillon Ltd. (Essex, UK). Hydroxypropylmethylcellulose (HPMC)
capsules of size no. 3 were received as a gift from Capsugel1,
France. Specifications of HPMC capsules were the same for body
and cap, i.e. Coni-snap (V43.700), Vcaps1 Capsules (Natural TR.
V900). Hypromellose (E464) was 100% of the total HPMC capsule
composition.
2.1.2. Preparation of spray-dried lactose
Anhydrous spray-dried lactose was produced by spray drying a 5%
(w/v) a-lactose monohydrate (Sigma–Aldrich, Ireland) solution in
deionised water with a Büchi 290 mini spray dryer (Büchi
797
Labortechnik GmbH, Germany), using a standard 2-fluid nozzle
with a 0.7 mm tip and 1.5 mm cap. The spray drying process was
carried out in the open mode at 8 ml/min solution feed rate. The inlet
temperature was adjusted to 160
C and the resultant outlet
temperature was 95–97
C. Aspirator setting and the atomising air
flow rate were set at 40 m3/h and 473 l/h, respectively. After the spray
drying process, anhydrous lactose was collected in air tight glass
containers and kept in desiccators containing silica gel to protect it
from environmental humidity. Amorphicity of the spray-dried
lactose was verified by X-ray diffraction as described in Section 2.4.3
Deionised water used in this work was HPLC grade and obtained from
a Purite Prestige Analyst HP water purification system.
2.2. Methods
2.2.1. Dynamic vapour sorption (DVS)
Moisture sorption and desorption characteristics of empty
HPMC and HG capsules was determined at a constant tempera-
ture of 25  0.1
C using a DVS Advantage-1 automated gravi-
metric vapour sorption analyser (Surface Measurement Systems,
London, UK). The DVS-1 measures the ingress and loss of water
vapour gravimetrically with a mass resolution of 0.1 mg. Prior to
being exposed to any vapour, capsules were equilibrated at 0% RH
to establish a dry reference mass. After drying, all empty capsule
shells in the DVS were exposed to a stepwise increase of %RH (0%;
20%; 30%; 40%; 50%; 60%; 70%). The same %RH profile was
employed for desorption. At each stage, the equilibrium
behaviour was defined when the mass variation versus time
dm/dt was 0.002 mg/min for at least 10 min before the partial
pressure was increased or decreased. An isotherm was then
calculated from the completed sorption and desorption profiles
using the DVS-1 analysis software, Surface Measurement Sys-
tems1, 2003. The amount of water taken up by the capsules was
expressed as a percentage of the dry capsule mass (equilibrated at
0% RH). All DVS measurements reported in this work were
conducted in triplicate.
2.2.2. Mathematical modelling: moisture distribution analysis using
the Young–Nelson equations
The Young–Nelson model equations were fitted to the sorption–
desorption data of the isotherms. The model can differentiate
between bound monolayer, normally condensed, externally
adsorbed moisture and internally absorbed water and is based
on equations of the form (Bravo-Osuna et al., 2005; Kachrimanis
et al., 2006; Tewes et al., 2010):
Ms ¼ Aðb þ uÞ þ BuRH (1)
Md ¼ Aðb þ uÞ þ Bu RHmax (2)
where Ms and Md are, respectively the mass percentage of water
sorbed and desorbed on the polymers at the equilibrium for each %
RH. A and B are constants characteristic of each system. In this
model, u is the fraction of the surface covered by at least one layer
of water molecules Eq. (3), where E is an equilibrium constant
between monolayer water and the normally condensed water
adsorbed externally to the monolayer (Bravo-Osuna et al., 2005;
Kachrimanis et al., 2006), and b is defined by Eq. (4).
u¼
RH
(3)
RH þ ð1  RHÞE


E  RH E2 E  ðE  1ÞRH
b¼ þ ln
E  ðE  1ÞRH E  1 E
 ðE þ 1Þlnð1  RHÞ (4)
798 A.S. Barham et al. / International Journal of Pharmaceutics 478 (2015) 796–803
Au is the mass of water in a complete adsorbed monolayer
expressed as a percentage of the dry mass of each system. A(b + u)
is the total amount of adsorbed water, and Ab is the mass of water
which is adsorbed beyond the mass of the monolayer (i.e. in
multilayer or cluster adsorption). B is the mass of absorbed water at
100% of RH, and, hence, BuRH is the mass of absorbed water when
the water coverage is u for a given %RH. The experimental data
were fitted to Eqs. (1) and (2) by means of an iterative multiple
linear regression using, as fitting criteria, the sum of the squares of
the residuals between the experimental and the calculated values.
The degree of adjustment was expressed by the multiple
correlation coefficients (Microsoft1 Excel 2007). According to
the model characteristics, from the estimated values of A, B, and E,
the corresponding profiles of water adsorbed in monolayer (Au ),
multilayer (Ab) and absorbed (BuRH) were obtained.
2.2.3. Determination of diffusion coefficients
Water sorption–desorption kinetics obtained for different %RH
were analysed in order to determine the diffusion coefficient (D) of
water molecules in the capsule walls using the Crank's solution to
Fick's 2nd law for gaseous diffusion in a planar sheet [15–16]
(Eq. (5)):
rffiffiffiffiffiffi
Mt 4 Dt
¼ (5)
Meq l p
where Mt is the amount of moisture sorbed by the capsule at a time
t, Meq is the corresponding mass sorbed at equilibrium, and l is the
thickness of the capsule wall. This relationship is linear at the
initial condition, that is for 0.1  Mt/Meq  0.5, and was used to
calculate D. The wall thickness (l) of HPMC and HG capsules was
accurately determined using a Zeiss AxioVision optical microscope
(Carl Zeiss Microimaging, Göttingen, Germany). Cross sectional
images of the capsules were collected after exposing the capsules
individually to a series of constant %RH environments of 0 %RH, 40
%RH, and 70 %RH at 25
C in the DVS apparatus. Equilibrium was
defined for each %RH when the mass variation versus time (dm/dt)
was 0.002 mg/min for at least 10 min. All the optical images were
examined using AxioVs V 4.7.0.0 software in order to determine the
cross section thickness (l) of each capsule studied. The l value was
calculated as an average of three capsules of each type in a series of
approximately 10 measurements at magnification levels of
200 and 400.
2.2.4. Calculation of permeability and solubility coefficients
Water permeation coefficients P [(Kg moisture/m3 capsules
Pa)  (m2/s)] across HPMC and HG capsules were calculated from
the relationship: P = SD, where S (Kg moisture/m3 capsules Pa) and
D (m2/s) are the solubility and diffusion coefficients respectively of
water molecules at a given RH condition. The solubility coefficients
were calculated from the equilibrium moisture content data using
(Gouanve’ et al., 2007; Mwesigwa et al., 2008):
c
S¼
p
This relationship defines the solubility coefficient in terms of
the vapour pressure (p, Pa) exerted by the water above the capsule.
The term c is the equilibrium concentration of water in the capsule
shell and was calculated using Eq. (7), the volume of the capsule
wall (Vp, m3) and the difference between the final mass (Meq, kg) to
the initial mass (M0, kg) of the capsule during water ingress
(Gouanve’ et al., 2007; Mwesigwa et al., 2008).
Meq  M0
c¼ (7)
Vp
True density measurements of HPMC and HG capsules and Vp
were determined by an AccuPyc 1330 Pycnometer (Micromer-
iticsTM) using helium gas (99.995% purity). All capsules were dried
in the DVS apparatus at 0% RH (25
C) prior to density analysis. The
pycnometer was calibrated immediately before performing the
analysis at room temperature. A 1 cm3 sample cup was used.
During each analysis the evacuation rate was 0.034 kPa/min, the
number of purges and runs was 5. Measurements were carried out
in triplicate on each empty capsule and the averaged results were
recorded.
2.3. Statistical analysis
Analysis of variance (ANOVA) was performed using a general
linear model with the Tukey comparison test using Minitab Release
16.2.3. For all tests, p  0.05 was used as the criterion to assess
statistical significance.
2.4. Characterisation of physicochemical properties of lactose
2.4.1. Capsules filled with spray-dried lactose
Prior to sorption–desorption experiments being conducted, all
capsules were filled manually with approximately 10–12 mg of
anhydrous spray dried lactose and were immediately transferred
to the dynamic vapour sorption (DVS) apparatus, held at 25
C.
2.4.2. Scanning electron microscopy
Scanning electron micrographs of anhydrous spray dried
lactose and lactose, which had been loaded into HPMC or gelatin
capsules and following the DVS experiments, were captured using
a Tescan Mira XMU (U.S.A) variable pressure scanning electron
microscope. All samples were fixed on an aluminium stubs with
double-sided adhesive tabs and a 10 nm thick gold film was then
sputter coated on the samples before visualisation.
2.4.3. X-ray diffraction
X-ray powder diffraction measurements (XRD) were conducted
on samples in low background silicon mounts, using a Rigaku
Miniflex II, desktop X-ray diffractometer (Japan) with the Ilaskris
cooling unit. The samples were scanned over a range of 5–40
2u
using a step size of 0.05
2u per second. The X-ray source was Cu Ka
radiation (l = 1.542 Å) with Ni-filter suppressing Kb radiation. The
Cu tube was run under a voltage of 30 kV and a current of 15 mA.
2.4.4. Differential scanning calorimetry
The thermal behaviour of spray dried lactose samples was
studied using a PerkinElmer Pyris Diamond differential scanning
calorimeter. The instrument was calibrated using indium (mp
156.6
C; DH = 28.45 J/g). Approximately 2–4 mg of sample was
accurately weighed into a sealed aluminium pan. An empty
(6) aluminium sample pan was placed in the reference holder and
both holders were covered with platinum lids. Sample and
reference pans were heated up to 240
C at 20
C/min using N2
as a purge gas (40 ml/min), and the heat flow (mW) was measured
as a function of temperature.
2.4.5. Particle sizing
Particle size measurements of anhydrous spray dried lactose
were determined as previously described using a Malvern
Mastersizer 2000 (Nolan et al., 2009).
 A.S. Barham et al. / International Journal of Pharmaceutics 478 (2015) 796–803 799

20 adsorbent-adsorbate interaction is weak as compared with the

adsorbate-adsorbate interactions and the material are mesopo-
(A )
rous.
Fig. 1B presents the extent of hysteresis between desorption
N et C h an g e in M ass (% )

15 and sorption processes for HPMC and HG capsules isotherms.

Hysteresis was calculated from the difference between the net
mass equilibrium values of the capsules revealed for desorption
and sorption processes at certain %RH values. The degree of the
10 hysteresis was then calculated according to Eq. (8) as described by
(Okubayashi et al., 2004; Siroka et al., 2008), where: Mdesorption and
Msorption were the equilibrium moisture gains in desorption and
sorption phases, respectively, at the same %RH. At 20% RH, the
5 hysteresis value of HG capsules was the highest among all the
studied capsules, at 66%, and was then gradually decreased to 8% at
60% RH. At 40% RH, the hysteresis value was 30% for HPMC capsules
and this decreased to 11% at 60% RH. This trend could be attributed
0
0 10 20 30 40 50 60 70 80 to the effects of moisture contents and the moisture holding ability
of the capsule walls (Okubayashi et al., 2004).
R elative Hu mid ity (%)
Mdesorption  Msorption
Hysteresisð%Þ ¼  100% (8)
75 Msorption
(B)

There can be a variety of reasons for the occurrence of isotherm

hysteresis. For example, hysteresis appearing in the multilayer
50 range of physisorption isotherms is usually associated with
H ys teresis (% )

capillary condensation in mesopore structures. However, for

amorphous or partially amorphous polymers, hysteresis is often
due to bulk absorption of water, which may also result in swelling
effects (Hill et al., 2009). The higher the hysteresis value, the more
25 water molecules are retained within the capsule shells. The
presence of hysteresis between the sorption and desorption

8.0%
HPMC Capsules
0 7.0% Monolayer
20 40 60 A = 3.78
Multilayer
6.0% B = 5.91
Moisture Content (%)

Relative Hum idity (% ) Absorbed E = 0.57

5.0%
Fig. 1. Comparisons of the HPMC and HG capsules measured using DVS at 25
C
(n = 3) of: (A) Moisture sorption and desorption isotherms, and (B) Hysteresis (%) 4.0%
values between the desorption and sorption processes calculated from sorption–
desorption isotherms. 3.0%

2.0%
3. Results and discussion
1.0%

3.1. Moisture sorption and desorption isotherms of the capsules 0.0%

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7
Sorption and desorption isotherms for the capsules are Relative Humidity
displayed in Fig. 1A. This figure was constructed from the average 8.0%
equilibrium values of the moisture contents of the capsules Monolayer
HG Capsules
7.0%
obtained at each %RH interval. Data indicated that the maximum A = 3.94
Multilayer
sorption capacity of water vapour is significantly higher for HG B = 10.25
Moisture Content (%)

6.0%
than for HPMC capsules. The maximum mass gain was Absorbed E = 0.13
14.97%  0.32 for HG capsules, which was significantly different 5.0%

to the HPMC capsules (10.60%  0.05). When the %RH was

4.0%
gradually increased from 0 to 20%, the amount of water vapour
sorbed for HPMC capsule was equal to 2.15%  0.03, which was 3.0%
significantly lower than the amount sorbed by the HG capsule
4.37%  0.17. This step is generally attributed to the surface 2.0%

adsorption process that is typically limited to only a few percent 1.0%

increase in mass (Burnett et al., 2006). The isotherm obtained for
HG could be related to the Type IV isotherm of the IUPAC 0.0%
classification, obtained with mesoporous adsorbent. This isotherm 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7

represents unrestricted monolayer–multilayer adsorption. The Relative Humidity

isotherm obtained for HMPC can be related to the Type V isotherm, Fig. 2. The predicted water distributions according to the Young–Nelson model for
as observed by Villalobos et al. (2006). In such an isotherm, the HPMC and HG capsules presented as monolayer, multilayer, and absorbed moisture.
800 A.S. Barham et al. / International Journal of Pharmaceutics 478 (2015) 796–803

isotherms of the capsules indicated that the diffusion of water
molecules from the bulk to the surface was slower than surface to
the bulk. Hysteresis of HG capsules was significantly decreased
when the %RH increased. HG capsules retained more moisture than
HPMC capsules at lower %RH, as observed from Fig. 1B.
The most well-known approach for modelling hysteresis in
organic polymer isotherms is that of Young and Nelson (Fig. 2). For
HG capsules, absorption represents the main way in which water is
taken up, as can be confirmed by the low values of the A parameter,
compared with those of the B parameter of the Young–Nelson
equations (Fig. 2). Moreover, HG capsules were saturated by a
Between 0 and 40% RH in the sorption process, D values across
HPMC capsules were as high as 69.1 1014 m2/s and decreased by
2-fold at 70% RH (Fig. 4B). In HG capsules, D values increased
gradually up to 60% RH to 32.7  1014 m2/s and then decreased to
24.9  1014 m2/s at 70% RH. In the desorption process, maximum D
values were obtained for both HPMC and HG capsules at 50% RH.
Lower water D values obtained across HG capsules could result in
higher interaction of water molecules with HG than with HPMC.

S (Kg m o istu re/ (m 3 C ap su les P a ))

water monolayer from 20% RH (3.0 wt%). In contrast the monolayer 0.18

development in HPMC capsules increased slowly up to 70% RH (A)

(2.5 wt%), showing a weak water-HMPC interaction as compared
with the water-water interactions in HG capsules. During the
formation of the water monolayer on the surface of HPMC 0.12
capsules, water molecules were adsorbed as multilayers and as
well as being absorbed in the same proportions. Whereas, for HG
capsules, water molecules were, interestingly, absorbed between
20% RH (approximately 2.0 wt%) up to 70% RH (approximately
8.0 wt%). 0.06
Fig. 3 demonstrates the swelling phenomenon which occurred
in HPMC and HG capsule shells in a manner such as to change their
thickness dimensions during the moisture ingress experiments. In
HPMC capsules, when the %RH was changed from 0 to 40% the
0.00
thickness of the capsule wall (l) increased. Surprisingly a further 0-20 20-30 30-40 40-50 50-60 60-70
increase in %RH up to 70% lead to a notable decrease in the l value of
R elative Humidity (%)
HPMC. From 0 to 40% RH for HG, l values were increased and were
not further affected when the RH was increased up to 70% RH. This -12
1.6x1 0
swelling behaviour of the capsules can be attributed to the water
absorbed, as predicted by Young and Nelson equations. (B)

3.2. Diffusion, solubility and permeability coefficients of the capsules 1.2x1 0

-12

Fig. 4A presents a comparison of the solubility coefficients (S)

D (m 2/s )

calculated from the sorption and desorption isotherm character- -13

8.0x1 0
istics of all HPMC and HG capsules studied in this work. In general,
all S values obtained for HPMC and HG capsules decreased
progressively when the %RH increased up to 30% and levelled off
-13
from 40% RH up to 70% RH. 4.0x1 0
Mwesigwa et al. (2008) claimed that the S parameter identified
the amount of water distributed in the polymer films under
equilibrium conditions in relation to the amount present in the 0.0
vapour phase above the film. It can be interpreted as a partition 0-20 20-30 30-40 40 -50 50-60 60-70
coefficient of water molecules between the two phases (Mwesigwa
Relative Humidity (%)
et al., 2008).
-14
3.0x1 0
P [(Kg mois ture/m caps ules Pa)x(m /s)]

(C)
2

120
HPMC Capsules
Capsule thickness layer ( l, µm)

HG Capsules -14
2.0x1 0

80
3

-14
1.0x1 0
40

0.0
0 0-20 20-30 30-40 40 -50 50-60 60-70

2 62 92 Relative Humidity (%)

Relative Humidity (%)
Fig. 4. Water vapour parameters determined for HPMC and HG capsule shells at
Fig. 3. Effect of % Relative Humidity on HPMC and HG capsules thickness layers (l) 25
C (n = 3) of: (A) water solubility coefficients S, (B) water diffusion coefficients D,
measured after DVS experiments at 25
C (n = 3). and (C) water permeability coefficients P.
 A.S. Barham et al. / International Journal of Pharmaceutics 478 (2015) 796–803 801

In a recent study, the water diffusion coefficient through
amorphous HPMC films stored in a wide range of %RH and
temperatures was predicted. The authors found that D values
ranged from 600  1014 to 2.4  1014 m2/s (Laksmana et al.,
2009). When the glassy HPMC films take up moisture from the
environment, water molecules induce both swelling of the films
and the reduction of the glass transition temperature. The diffusion
of the small water molecules across the polymer films was
assumed to occur through the free volume in the polymer film
(Laksmana et al., 2009).
Permeability parameters (P) calculated for HPMC and HG
capsules are shown in Fig. 4C. In HPMC capsules during the
sorption process, the maximum P value was observed at 20% RH
and it decreased gradually up to 70% RH. A similar trend was
observed for HG capsules. The P value for HPMC was greater than
HG by 5-fold at 20% RH and levelled off for both capsules at 60% RH.
Interestingly, P values for HPMC and HG capsules exhibited a
similar trend in the desorption process when moving from 70% RH
up to 30% RH. At 20% RH, the P value for HPMC was 2-fold greater
than that of HG.
Between 50 and 70% RH, the overall water permeability
measured across HPMC capsules was smaller than for HG capsules.
At this range the flux of water molecules across HPMC capsules was
lower compared to HG capsules. This could be explained by the
swelling behaviour and the free volume space of the HPMC
capsule.
The significance of the capsule type and %RH on the response of
S, D, and P parameters was assessed using ANOVA. All the P-values
obtained from the statistical analyses were less than 0.05 in this
work. It can be concluded that the S, D, and P parameters are
significantly different for the two capsule types at the different %
RH values.
3.3. Effect of capsules as a moisture buffer upon moisture ingress by
lactose using DVS
Fig. 5A presents the SEM micrograph of free flowing spray dried
lactose recorded after the spray drying process. The general
appearance of the anhydrous lactose particles consisted of
spherical shaped particles with smooth surfaces. These particles
have a median particle size less than 5 mm, as determined by the
laser diffraction technique. Anhydrous lactose was then loaded
into HPMC and HG capsules to examine their effectiveness in
protecting the contents from ambient conditions. These loaded

Fig. 5. SEM micrographs of: (A) anhydrous spray-dried lactose (directly recorded after the spray-drying process), (B) free flowing powder of spray dried lactose after
recrystallisation in DVS, (C) spray dried lactose stored in HPMC capsule after recrystallisation in DVS, and (D) spray dried lactose stored in HG capsule after recrystallisation in
DVS. Samples of B, C, and D were recorded immediately without grinding following the DVS experiments between 0%–70%–0% RH for consecutive 12 steps at 25
C
(magnification of 5 K).
802 A.S. Barham et al. / International Journal of Pharmaceutics 478 (2015) 796–803
Fig. 6. Kinetic profiles generated by exposure to increasing humidity in DVS from
50% to 70% RH of: (A) anhydrous spray dried lactose, (B) anhydrous spray dried
lactose stored in HG capsule, and (C) anhydrous spray dried lactose stored in HPMC
capsule.
capsules were exposed to increasing RH from 50% to 70% RH. After
DVS experiments, SEM micrographs revealed that the crystallisa-
tion of lactose from the amorphous state (Fig. 5A) led to the
formation of a plate-like crystalline habit (Fig. 5B–D). This result
was in a good agreement with previous findings relating to the
change in habit of freely powder form of spray dried lactose upon
crystallisation in humid air (Barham and Hodnett, 2005). Further-
more, the kinetics of water ingress observed during the change of %
RH from 50 to 70% for of the free flowing powder the free as well as
the encapsulated lactose within HPMC and HG capsules showed a
decrease in mass ingress during the equilibrium stage (Fig. 6). The
decrease in mass could be explained by the crystallisation of the
amorphous spray dried lactose, which expels moisture on
crystallisation (Ambarkhane et al., 2005).
The PXRD pattern of spray dried lactose, recorded directly after
the spray-drying process was typical of X-ray amorphous material,
showing an amorphous “halo” in the diffraction pattern (Fig. 7,
trace A). Following DVS experiments, lactose examined by XRD was
crystalline and resulted in a mixture of two anomers of lactose,
namely a-lactose monohydrate characterized by 2 Bragg peaks of
diffraction at 2u = 12.5
, 16.4
and anhydrous b-lactose character-
ized a Bragg peak at 2u = 10.5
(Fig. 7, traces B–D) (Barham and
Hodnett, 2005).
500
(a.u.)
monohydrate
-Lactose
2 =12.5º
Intensity (a.u.)
-Lactose
2 =10.5º
1000
(a.u.)
10 20 30
Pos. [°2 Th.]
Fig. 7. Typical XRD patterns of: (A) anhydrous spray-dried lactose (directly
recorded after the spray-drying process), (B) free flowing powder of spray dried
lactose after recrystallisation in DVS, (C) spray dried lactose stored in HPMC capsule
after recrystallisation in DVS, and (D) spray dried lactose stored in HG capsule after
recrystallisation in DVS. Samples of B, C, and D were recorded immediately without
grinding following the DVS experiments between 0%–70%–0% RH for consecutive
12 steps at 25
C.
Fig. 8. Comparative DSC thermograms of: (A) anhydrous spray-dried lactose
(directly recorded after the spray-drying process), (B) free flowing powder of spray
dried lactose after recrystallisation in DVS, (C) spray dried lactose stored in HPMC
capsule after recrystallisation in DVS, and (D) spray dried lactose stored in HG
capsule after recrystallisation in DVS. Samples of B, C, and D were recorded
immediately without grinding following the DVS experiments between 0%–70%–0%
RH for consecutive 12 steps at 25
C.
The DSC thermogram of lactose recorded after the spray drying
process (Fig. 8A) exhibited a change in the heat capacity of 0.54 J/
g
C with an onset value at 118
C, indicative of a glass transition.
This event was followed by a single exothermic peak with onset at
180
C, peaking at 194
C (DH = 26 J/g) and characteristic of a
crystallization step. An endothermic melting feature of anhydrous
a-lactose occurred at 209
C (onset), peaking at 215
C (DH = 29 J/
g). This phase decomposed and no further thermal behaviour was
observed up to 240
C (Garnier et al., 2008).
After DVS experiments, evolution of lactose phase’s upon
exposure to moist air resulted in a mixture of a-lactose
monohydrate and anhydrous b-lactose. This was confirmed by
the DSC thermal behaviour of lactose as presented in Fig. 8B.
Hence, a-lactose monohydrate exhibited an endothermic peak
associated with the dehydration, and of water molecules being
removed from the crystal lattice. The dehydration process was
characterised by an onset step observed at 139
C, peaking at 145
C
(DH = 111 J/g) (Lehto et al., 2006). However, two successive
endothermic peaks were consequently observed as a result of
a-lactose melting at 212
C, peaking at 219
C (DH = 68 J/g) and
b-lactose melting onset at 228
C, peaking at 233
C (DH = 65 J/g),
respectively (Islam and Langrish, 2010).
In Fig. 8, traces C and D present the thermal behaviour of lactose
loaded into HPMC and HG capsules, respectively. As observed in
these traces, the thermal events such as dehydration and melting
of lactose phases were similar to those observed in Fig. 8B, showing
that HPMC and HG capsules were not able to protect amorphous
lactose from crystallisation.
4. Conclusions
In this study moisture sorption and desorption isotherms were
determined for HPMC and HG hard capsules that are widely used in
the pharmaceutical industry. It was observed that values of S, D, P
parameters were significantly affected by the factors analysed in
this study i.e. capsule types and %RH. Thus, different moisture
characteristic behaviour as well as different water flux occurred for
the same %RH range studied in HPMC and HG capsules. Moisture
sorption resulted in crystallisation of the loaded lactose into
a-lactose monohydrate and anhydrous b-lactose. Therefore,
neither capsule type adequately protected the contained
 A.S. Barham et al. / International Journal of Pharmaceutics 478 (2015) 796–803
hygroscopic amorphous lactose from crystallisation or deteriora-
tion which was induced by moisture ingress, possibly impairing
the formulation stability. Overall, HPMC capsules would be more
appropriate to use than HG for a formulation that was not quite as
moisture sensitive.
Acknowledgements
This work was funded by Science Foundation Ireland (Grants
07/SRC/B1154 and 12/RC/2275) & Enterprise Ireland (Grant CFTD/
06/119) under the National Development Plan.
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