Plasticizing effect of ibuprofen induced an alteration

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RESEARCH ARTICLE
Plasticizing effect of ibuprofen induced an alteration of drug released
from Kollidon SR matrices produced by direct compression
Chutima Wiranidchapong1, Nuchnan Ruangpayungsak2, Pattaraporn Suwattanasuk1, Duangratana Shuwisitkul1,
and Sujimon Tanvichien1
1
Faculty of Pharmacy, Srinakharinwirot University, Nakhon-Nayok, Thailand and 2Faculty of Pharmacy, Mahidol University, Bangkok, Thailand
Abstract
Keywords
The objectives of this study were to investigate the effect of storage temperature on drug
release from matrices containing 10, 40 and 70% w/w ibuprofen in KollidonÕ SR (KSR). The
matrix tablets were produced by direct compression and then kept at 30 and 45 C for 3
months. Drug release from the matrix tablets was examined after storage for 0, 1, 4 and 12
weeks. Scanning electron microscope was used to reveal physical appearance of the tablet
surface at the respective time intervals. In addition, differential scanning calorimeter was used
to investigate glass transition temperature (Tg) of ibuprofen in KSR at 0–100% w/w based on
the principle of Gordon–Taylor equation. At 45 C, the dissolution of ibuprofen in KSR as well as
the coalescence of polymer particles were observed to be higher than those of storage at 30 C.
The physical state of ibuprofen dispersed in the polymeric matrix and degree of polymer
coalescence led to the variation of drug release. The coalescence of polymer particles was a
result of the polymer transition from glassy to rubbery state according to water absorption of
KSR and plasticizing effect of ibuprofen. The reduction of the Tg of ibuprofen blended with KSR
could be better described by the Kwei equation, a modified version of Gordon–Taylor equation.
Glass transition temperature, Gordon–Taylor
equation, ibuprofen, in-vitro dissolution,
Kollidon SR, Kwei equation
Introduction
KollidonÕ SR (KSR) has been recognized as either matrixforming or film-forming excipient in extended release dosage
forms. It is composed of polyvinyl acetate and polyvinyl
pyrrolidone approximately at a ratio of 8:2 (Figure 1a). Matrix
tablet using KSR as a retarding agent can be produced by direct
compression1–4. The stability study of famotidine in KSR matrix
tablet, produced by direct compression, revealed the difference in
the dissolution profiles after storage at 40 C and 75% relative
humidity for 1, 2 and 4 weeks when compared with that of freshly
prepared matrix5. No similarity of those was a result of water
absorption of KSR. The absorbed water acted as a plasticizer to
change a completely disordered structure to network ordered
structure. Thus, the extent and rate of drug release in the network
ordered structure were altered5.
According to glass transition temperature (Tg) of KSR around
35 C3,6,7, storage temperature higher than Tg possibly causes a
transition from glassy to rubbery state. This can initiate the
structural change and the change of rate and extent of drug
release. Moreover, there are many kinds of drug exhibiting
plasticizing effect such as lidocaine HCl8, ketoprofen9, metoprolol
tartrate10, ibuprofen and chlorpheniramine maleate6,11–16.
Address for correspondence: Chutima Wiranidchapong, PhD, Department
of Pharmaceutical Technology, Faculty of Pharmacy, Srinakharinwirot
University, Nakhon-Nayok, 26120, Thailand. Tel: +66 37 395094-5. Fax:
+66 37 395096. E-mail: [email protected]
History
Received 16 February 2014
Revised 9 May 2014
Accepted 12 May 2014
Published online 11 June 2014
The increase in weight percent of these drugs in polymeric
films proportionally decreased the Tg of those films. Thus, the
system containing both drug as plasticizer and polymer with low
Tg probably promotes a dramatic increase in mobility of the
polymer chains especially at the storage temperature higher than
the Tg12,13,17. This may cause a greater degree of coalescence
associated with a reduction in the rate of drug release12,13.
There was an attempt to describe the reduction of Tg of
polymeric matrix containing ibuprofen based on the Gordon–
Taylor equation. This study revealed that the experimental Tg
values exhibited a positive deviation from the theoretical Tg
values according to molecular interactions between ibuprofen
and the polymer18. In case of an interaction between drug and
polymer, the Kwei equation, a modified version of Gordon–
Taylor, could be better for explanation19–25. If the Tg of polymeric
matrices containing various weight percents of ibuprofen can be
predicted, it will be an advantage to select the storage temperature
in order to reduce an alteration of rate and extent of drug release
from this kind of matrices.
This study aimed to investigate ibuprofen released from KSR
matrix tablets after storage at the temperature below and above the
Tg of KSR. To confirm the influence of temperature and
plasticizing effect of ibuprofen on the coalescence of polymer
particles, scanning electron microscope (SEM) was used to
investigate the physical appearance of tablet surface. According
to the plasticizing effect of ibuprofen, the reduction of Tg of
ibuprofen in KSR mixture was examined based on the principle
of Gordon–Taylor equation.
2
C. Wiranidchapong et al.
Figure 1. Chemical structures
KollidonÕ SR; (b) ibuprofen.
Drug Dev Ind Pharm, Early Online: 1–10
of: (a)
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Materials and methods
Materials
Ibuprofen (Lot No. IB1S1461) and KollidonÕ SR (Lot No.
14209516K0) were supplied as gifts by BASF, Ludwigshafen,
Germany. Potassium dihydrogen orthophosphate and sodium
hydroxide used as buffering agents were purchased from
Univar, New Zealand and Labscan, Thailand, respectively.
Absolute Ethanol used as a solvent in the analytical process was
purchased from J.T. Baker (Phillipsburg, NJ).
Preparation of ibuprofen in KSR physical mixture
Ibuprofen and KSR, passed through the sieve shaker mesh no. 60
(Vibratory Sieve Shaker Analysette 3 Pro, Fritsch GmbH,
Germany), were mixed with mortar and pestle for 15 min at the
concentration range of 10–90% w/w ibuprofen in KSR. The
mixtures were kept in refrigerated temperature for further
experiments.
Preparation of ibuprofen in KSR matrix tablet
The DSC cell was calibrated with indium (melting point 156.9 C
and DH ¼ 27.5 J/g). Each sample, i.e. ibuprofen, KSR, and 10–
90% w/w ibuprofen in KSR physical mixtures, was accurately
weighed into standard aluminum pan with cover and scanned
using the heating program: heating to 100 C at 10 K/min; cooling
to 60 C at 10 K/min; and finally heating to 100 C at 5 K/min.
The Tg was examined in the second heating.
Mathematical analysis
Tg values of 0–100% w/w ibuprofen in KSR versus weight
fraction of KSR were fitted to Gordon–Taylor and Kwei equations
by non-linear regression (GraphPad PrismÕ version 4.0, San
Diego, CA). The Gordon–Taylor and Kwei equations can be
expressed as displayed in Equation (1) and (2), respectively19–25.
Tg ¼
w1 Tg1 þ Kw2 Tg2
;
w1 þ Kw2
K¼
1 Tg1
2 Tg2
ð1Þ
where Tgi , wi and i are the glass transition temperatures, the
weight fractions and the densities of the components in the
mixture.
Tablets, 1 cm, i.d., of 10, 40 and 70% w/w ibuprofen in KSR were
produced by direct compression. The powder, 320 mg in weight,
was compressed by hydraulic press at 100 kg/cm2. Each kind of
the tablets was kept in either 30 C or 45 C ovens (Universal oven
UN 110, Memmert GmbH, Schwabach, Germany) for 3 months.
The humidity recorded by digital hygro-thermometer (Daeyoon
Scale Industrial, Seoul, Korea) was in the range of 45–65% RH at
30 C and 26–61% RH at 45 C throughout the storage time.
where q is an adjustable parameter corresponding to the strength
of hydrogen bonding between the components.
Eleven experimental data points were used for each fit. The
coefficient of determination (R2), runs test and the residual plot
were used to evaluate the goodness-of-fit.
In vitro drug release
Fourier transform infrared spectroscopy analysis
Matrix tablets containing 10, 40 and 70% w/w ibuprofen in KSR
either storage at 30 C or 45 C for 0, 1, 4 and 12 weeks were
examined the drug release using the USP XXXVI rotating paddle
method (900 ml phosphate buffer pH 7.2; 100 rpm; 37 C; n ¼ 3)
(Vankel VK 7000, Vankel Industries, Edison, NJ). At predetermined time intervals, samples were withdrawn (5 ml, no medium
replacement) and spectrophotometrically assayed at 222 nm for
ibuprofen (UV-1601, Shimadzu Scientific Instruments Inc.,
Columbia, MD).
FTIR spectra of ibuprofen, KSR and 10–70% w/w ibuprofen in
KSR either physical mixtures or melted mixtures were recorded
with a Perkin-Elmer FTIR Spectrum One using potassium
bromide disks. The melted mixtures were prepared by heating
the physical mixtures at the respective weight percent of
ibuprofen in KSR by DSC using the heating program: heating
from 25 to 100 C at 10 K/min; cooling to 60 C at 10 K/min;
and finally heating to 100 C at 5 K/min. Each sample was
scanned 64 times and the spectra were recorded at a resolution of
4 cm1.
Tg ¼
w1 Tq1 þ Kw2 Tg2
þ qw1 w2
w1 þ Kw2
ð2Þ
SEM analysis
The morphology of 10, 40 and 70% w/w ibuprofen in KSR matrix
tablets stored at 30 and 45 C for 0, 1 and 4 weeks was
qualitatively evaluated using SEM. Images were taken with a
Hitachi SEM (S-3400, Hitachi, Tokyo, Japan) operating at 15 kV.
All samples were gold-coated at room temperature prior to
imaging. Each sample was analyzed as n ¼ 1.
Differential scanning calorimetry analysis
Differential scanning calorimetry (DSC) was carried out using a
Mettler Toledo DSC apparatus with a refrigerated cooling system
(DSC 823e, Greifensee, Switzerland) and nitrogen as purge gas.
Results and discussion
In vitro drug release
The cumulative drug release (%) of matrix tablets containing 10,
40 and 70% w/w ibuprofen in KSR after storage at 30 and 45 C
for 1 week, 1 and 3 months was changed when compared to that of
freshly prepared matrix tablets (Figure 2). The rate of drug
released from matrix tablet containing 10% w/w ibuprofen after
storage at 30 C for 1 week was higher than that of freshly
prepared (Figure 2a). In addition, SEM revealed the deformation
of polymer particles, which started to coalesce. However, a few
gaps between the particles were still observed (Figure 3d).
Plasticizing effect induced an alteration of drug release
3
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Figure 2. Dissolution profiles of tablets containing ibuprofen in KSR at weight percent of: (a) 10; (b) 40; (c) 70 after storage at 30 C and the respective
weight percent: (d) 10; (e) 40; (f) 70 after storage at 45 C. Key: () 0 week; (g) 1 week; (m) 4 weeks; () 12 weeks of storage time.
This might be a result of plasticizing effect of either ibuprofen6,11,13,15 or the absorbed water5,26–33. According to a little
amount of ibuprofen lowering the Tg of KSR at this ratio of drug
to polymer, the absorbed water enhanced the reduction of the Tg
of KSR below the storage temperature. Thus, the polymer
transition from glassy to rubbery state was occurred after storage
for 1 week. This might cause higher dissolution of ibuprofen in
KSR, resulting in the higher rate of drug release than that of
freshly prepared.
After storage for 1 and 3 months, the rate of drug released from
10% w/w ibuprofen in KSR matrix tablet was lower than that of
freshly prepared. Furthermore, the coalescence of polymer
particles was almost complete (Figure 3g). This might be a
longer storage time resulting in the larger amount of absorbed
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4
C. Wiranidchapong et al.
Drug Dev Ind Pharm, Early Online: 1–10
Figure 3. SEM of ibuprofen in KSR tablets at weight percent of: (a) 10; (b) 40; (c) 70 at day 0; the respective weight percent: (d) 10; (e) 40; (f) 70 after
storage for 1 week and (g) 10; (h) 40; (i) 70 after storage for 4 weeks at storage temperature of 30 C. Magnification 500.
water into the polymer5,31. Thus, the Tg of KSR was lower when
absorbed water into the polymer was higher, which was in
accordance with the relationship of Gordon–Taylor27. In this state,
the polymer transition from glassy to rubbery state easily took
place. This provided a densification and a reduction of porosity of
KSR. The loss of pores resulted in a lower rate of drug release due
to the hindered diffusion of water and ibuprofen molecules in the
tablet. So the rate of ibuprofen release was decreased.
To compare with 10% w/w ibuprofen in KSR matrix tablet
stored at 45 C, the rate of drug release slightly decreased after
storage for 1 week according to almost complete coalescence of
polymer particles (Figure 4d). When the storage time was
extended to 1 month, the rate of ibuprofen release was increased
because of re-crystallization of ibuprofen out of the film. This
resulted in the fracture of the film, which was extensively
observed (Figure 4g). After storage for 3 months, the rate of
ibuprofen release was the lowest. This might be a result of
ibuprofen re-dissolved into the polymer, leading to the complete
film formation. This indicated that drug dissolution and recrystallization in the polymeric matrix were interchangeable
during the storage period34.
In case of matrix tablet containing 40% w/w ibuprofen in KSR,
the rate of drug release was the highest at the initial state
(Figure 2b, e). This might be a result of higher concentration of
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Plasticizing effect induced an alteration of drug release
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Figure 4. SEM of ibuprofen in KSR tablets at weight percent of: (a) 10; (b) 40; (c) 70 at day 0; the respective weight percent: (d) 10; (e) 40; (f) 70 after
storage for 1 week and (g) 10; (h) 40; (i) 70 after storage for 4 weeks at storage temperature of 45 C. Magnification 500.
ibuprofen dissolved into the rubbery polymer, which was
confirmed by the apparent deformation of polymer particles at
day 0 (Figure 3b). This indicated that the polymer transition from
glassy to rubbery state was immediately occurred. After storage at
30 C for 1 week, the coalescence of polymer particles was more
complete (Figure 3e), so that the rate of drug release was
dramatically decreased. When the storage time was extended to 1
month, the rate of drug release was increased, which corresponded to the fracture of the film (Figure 3h). Finally, the rate of
drug release was decreased to the lowest rate after storage for 3
months. This might be a densification of polymeric matrix after
longer storage.
At storage temperature of 45 C, the rate of drug release was
decreased after storage for 1 week, 1 and 3 months. The lowest
rate of drug released from 40% w/w ibuprofen in KSR matrix
tablet was observed after storage for 3 months (Figure 2e). This
was in accordance with the more complete coalescence of
polymer particles at the longer storage time (Figure 4e, h), in
which the storage temperature was above the Tg of the polymer.
For 70% w/w ibuprofen in KSR matrix tablet, the rate of drug
released from freshly prepared matrix was slow at the first 8 h and
then rapidly increased after 8 h of dissolution test. After kept at
30 C for 1 week, the rate of drug release rapidly increased after
4 h of dissolution test. The highest rate of drug release was
noticed after storage for 1 month. However, the rate of drug
release decreased after storage for 3 months (Figure 2c). It was
interesting to note that the highest concentration of ibuprofen in
KSR matrix tablet did not provide the fastest rate of drug release
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6
C. Wiranidchapong et al.
at day 0. In addition, SEM revealed both dissolved ibuprofen
around the deformed particles of KSR and crystalline ibuprofen
all over the tablet surface (Figure 3c). This might be a limited
concentration of KSR, which needed to dissolve ibuprofen into
the matrix. Only dissolved ibuprofen dispersed in KSR could
decrease the Tg of polymeric matrix whereas crystalline ibuprofen
could not alter the Tg of drug–polymer mixture23,24. Thus,
crystalline ibuprofen could not promote the deformation and
coalescence of KSR particles. According to poorly water-soluble
drugs35–37, ibuprofen was slowly released from freshly prepared
matrix at the first 8 h of dissolution test. After 8 h of dissolution
test ibuprofen was rapidly released because the porosity inside the
matrix was increased after drug release. When the storage time
was longer, the re-crystallization of ibuprofen was more observed
(Figure 3f, i). This was in an agreement with the incomplete
coalescence of polymer particles in matrix tablets kept for 1 week
and for 1 month at 30 C. This resulted in higher drug release,
especially after storage for 1 month. However, the rate of drug
release was decreased after storage for 3 months at 30 C. This
might be more coalescence of polymer particles after longer
storage time.
In case of storage at 45 C, ibuprofen release (%) after
storage for 1 week obviously increased when compared with that
of freshly prepared matrix tablet. The highest rate of drug
release was also observed after storage for 1 month. When the
storage time was extended to 3 months, the rate of drug release
was almost similar to that at the beginning (Figure 2f). This
might be a result of the storage temperature well above the Tg of
KSR, which enhanced the polymer transition from glassy to
rubbery state. This was in an agreement with the deformation
and the coalescence of polymer particles, which were more
intense than those of storage temperature at 30 C at the same
period (Figure 4f, i). In addition, the disappearance of ibuprofen
crystal from the tablet surface was observed after storage for
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1 month (Figure 4i). The more dissolved ibuprofen in KSR
resulted in the faster rate of drug release. Thus, the rate of
ibuprofen released from 70% w/w ibuprofen in KSR matrix
tablet after storage at 45 C for 1 week and for 1 month was
increased. Conversely, the more amount of dissolved ibuprofen
in KSR greatly enhanced the complete coalescence of polymer
particles. This resulted in the reduction of the porosity inside the
matrix tablet. Thus, the rate of drug release was decreased after
storage for 3 months.
DSC analysis
DSC curve of ibuprofen investigated by heating from 25 to 100 C
at 10 K/min exhibited the melting point around 77.87 C. The Tg
of ibuprofen was observed around 44.10 C when the melted
ibuprofen was cooled to 60 C at 10 K/min and then heated to
100 C at 5 K/min (Figure 5). Similar heating program was used to
investigate the Tg of physical mixtures containing 0–100% w/w
ibuprofen in KSR. The Tg of KSR was around 39.09 C. For
10–90% w/w ibuprofen in KSR physical mixtures, the Tg values
were between the Tg of pure components. In addition, the Tg of
the mixture was decreased as the increase of weight percent of
ibuprofen (Figure 6). This Tg behavior was in an agreement
with the principle of Gordon–Taylor19–25. It was meant that only
amorphous ibuprofen could decrease the Tg of KSR. Thus,
ibuprofen acted as a plasticizer when it was in an amorphous form
or a dissolved form blended with the polymer. In addition, DSC
curves of 80 and 90% w/w ibuprofen in KSR mixtures exhibited
the exothermic peaks onset around 40 C, followed with the
endothermic peak around 75 C and 77 C, respectively. This
indicated that at high concentration of ibuprofen in KSR melted
mixture amorphous ibuprofen tended to rapidly re-crystallize into
crystalline ibuprofen, which displayed the melting point depression as an increase of weight fraction of KSR.
Figure 5. DSC curve of ibuprofen. Program: heating to 100 C at 10 K/min; cooling to 60 C at 10 K/min; and finally heating to 100 C at 5 K/min.
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Plasticizing effect induced an alteration of drug release
7
Figure 6. DSC curve recorded in the second heating from (60) – 100 C; 5 K/min: (a) KSR; mixtures containing ibuprofen in KSR at % w/w of (b) 10;
(c) 20; (d) 30; (e) 40; (f) 50; (g) 60; (h) 70; (i) 80; (j) 90; (k) ibuprofen.
Figure 7. Tg versus weight fraction of KSR curves based on experimental
data (g); Gordon–Taylor equation (- - -); Kwei equation (—).
Tg analysis
Fitting Tg values of 0–100% w/w ibuprofen in KSR to Gordon–
Taylor and Kwei equations gave coefficient of determination (R2)
equal to 0.8730 and 0.9026, respectively (Figure 7). By means of
runs test, experimental Tg and estimated Tg obtained from
Gordon–Taylor equation were significantly different (p value
¼ 0.0238) but experimental Tg and estimated Tg obtained from
Kwei equation were insignificantly different (p value ¼ 0.2619).
This indicates that Tg of ibuprofen in KSR is a better fit to the
Kwei equation. K and q values, the Kwei equation parameters,
determined by curve-fitting were 1.002 and 80.05, respectively.
A negative q value indicates that the inter-associated hydrogen
bonding between ibuprofen and KSR is weaker than the selfassociated hydrogen bonding of each component21,23,24. In
addition, the residuals corresponding to the fits of Gordon–
Taylor and Kwei equations were apparently non-random
(Figure 8). The non-randomness of the residuals suggests that
Figure 8. Residual analysis corresponding to the Gordon–Taylor fit
(a) and the Kwei fit (b).
even Kwei equation does not completely described Tg behavior of
ibuprofen in KSR. This might be a result of rapid re-crystallization of ibuprofen out of the polymeric mixture. This crystalline
ibuprofen could not lower the Tg of KSR.
FTIR analysis
FTIR spectrum of ibuprofen displayed peaks around 3000, 1720
and 1230 cm1 corresponding to O–H stretching vibration,
asymmetrical carbonyl stretching vibration and C–O stretching
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C. Wiranidchapong et al.
Drug Dev Ind Pharm, Early Online: 1–10
Figure 9. FTIR spectra recorded at room temperature in the range of 4000–400 cm1: (a) KSR; physical mixtures of ibuprofen in KSR at % w/w of (b)
10; (c) 20; (d) 30; (e) 40; (f) 70; (g) ibuprofen.
Figure 10. FTIR spectra recorded at room temperature in the range of 4000–400 cm1: (a) KSR; melted mixtures of ibuprofen in KSR at % w/w (b) 10;
(c) 20; (d) 30; (e) 40; (f) 70; (g) ibuprofen.
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vibration of carboxylic acid, respectively38–42. For KSR, composed of polyvinyl acetate (PVA) and polyvinyl pyrrolidone
(PVP) at the ratio of 8:2, the peak around 1739 cm1 corresponding to the carbonyl stretching vibration of ester group in PVA
was observed. In addition, the bands around 3469 and 1663 cm1
corresponding to N–H stretching vibration and carbonyl stretching vibration, respectively, of amide group in PVP38,41 were also
observed.
The N–H stretching band shifted to lower wave number was
noticed in both physical mixture and melted mixture of 10–30%
w/w ibuprofen in KSR (Figures 9 and 10). Furthermore, the peak
around 1663 cm1 shifted to 1658 cm1 was noticed in 30% w/w
ibuprofen in KSR melted mixture. This implied that hydrogen
bonding between carbonyl group of PVP and hydroxyl group of
ibuprofen might be occurred41. This was in an agreement with the
shift of the peak around 1230 cm1 to 1240 cm1 in melted
mixture of 10–40% w/w ibuprofen in KSR. This indicated that C–
O stretching vibration of carboxylic acid group of ibuprofen was
changed to C–O stretching vibration of ester group38. The
occurrence of the interaction between ibuprofen and KSR
supported the finding why the Kwei equation could be better
described the Tg behavior of amorphous ibuprofen blended
with KSR.
The appearance of the shoulder around 1700 cm1 in melted
mixture of 70% w/w ibuprofen in KSR implied the presence of
crystalline ibuprofen in the mixture41. This phenomenon revealed
rapid re-crystallization of amorphous ibuprofen in 70% w/w
ibuprofen in KSR after DSC analysis42–44.
Conclusions
The compressed matrix tablet containing ibuprofen dispersed in
KSR displayed the alteration of drug release during storage at 30
and 45 C, which were the temperature below and above the Tg of
KSR, respectively. The degree of the coalescence of polymer
particles and physical state of ibuprofen dispersed in the
polymeric matrix caused the variation of drug release. Either
plasticizing effect of ibuprofen or water absorption of KSR
promoted the polymer transition from glassy to rubbery state
leading to drug dissolved in the polymer and the coalescence of
polymer particles. Only dissolved ibuprofen made the Tg of KSR
lowering, which could be better described by the Kwei equation, a
modified version of the Gordon–Taylor equation. Prediction of
the Tg of KSR blended with ibuprofen at various weight percent is
useful for designing the conditions used in manufacturing process.
In addition, it is helpful for selection of the storage temperature to
prevent the polymer transition, which causes the alteration of
physical state of ibuprofen dispersed in the polymer matrix and
the variation of drug release, respectively.
Acknowledgements
The authors would like to express their heartfelt thanks to Boonta
Chatweerasakul for her support to proof the language of this work.
Declaration of interest
The authors report no conflicts of interest. The authors alone are
responsible for the content and writing of this article.
This research work was funded by Faculty of Pharmacy,
Srinakharinwirot University, Grant number: 318/2557.
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