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Solid-state compatibility screening of excipients suitable for development of

indapamide sustained release solid-dosage formulation

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DOI: 10.3109/10837450.2012.717948

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 Pharmaceutical Development and Technology, 2013; 18(2): 481–489
© 2013 Informa Healthcare USA, Inc.
ISSN 1083-7450 print/ISSN 1097-9867 online
DOI: 10.3109/10837450.2012.717948

RESEARCH ARTICLE

 olid-state compatibility screening of excipients suitable

S
for development of indapamide sustained release
solid-dosage formulation
Pharmaceutical Development and Technology Downloaded from informahealthcare.com by Uppsala Universitetsbibliotek on 07/10/13

Packa Antovska1, Gjorgji Petruševski1, and Petre Makreski2

Research and Development, ALKALOID AD, Aleksandar Makedonski 12, 1000 Skopje, Republic of Macedonia and
1

Institute of Chemistry, Faculty of Science, SS Cyril and Methodius University, Arhimedova 5, 1000 Skopje,
2

Republic of Macedonia

Abstract
Differential scanning calorimetry and Fourier transform infrared spectroscopy were applied as screening analytical
methods to assess the solid-state compatibility of indapamide (4-chloro-N-(2-methyl-2,3-dihydroindol-1-yl)-
3-sulfamoyl-benzamide) with several polymers aimed for development of 24 h sustained release solid-dosage
formulation. After the initial research phase which was directed towards selection of suitable polymer matrices, based
on their solid-state compatibility with the studied pharmaceutical active ingredient, the second phase of evaluation
For personal use only.

was intended for compatibility selection of other excipients required to complete a sustained release formulation. The
preformulation studies have shown that polyvinylpyrrolydone/polyvinyl acetate might be considered incompatible
with indapamide, and the implementation of this polymer career should be avoided in the case of the entitled
development. The experimental data additionally have revealed that sorbitol is incompatible with indapamide. The
obtained results afforded deeper insight in to the solid-state stability of the studied binary systems and pointed out
directions for further development of indapamide sustained release solid-dosage formulation.
Keywords:  Compatibility, DSC, FT-IR, indapamide, polymer matrices, preformulation, sustained release

Introduction A simple superimposition of these curves is then com-

The successful formulation of a stable and effective pared with the DSC curve obtained from a well-mixed
solid-dosage form depends on the appropriate selec- 1:1 (w/w) mixture of the API and the excipient. In the
tion of excipients[1,2] and characterization of the solid- simplest case, the thermal properties of a mixture repre-
state properties using suitable analytical methods.[3,4] sent sum of the thermal properties for the individual sub-
Therefore, preformulation studies pointing out possible stances. An interaction might be identified from the DSC
drug-excipient interactions are essential for the develop- curves through changes in transition temperatures, peak
ment of fully effective solid-dosage forms.[5] shapes and peak areas. If no significant differences occur
Differential scanning calorimetry (DSC) has been between the thermal events (registered in the DSC traces
a widely utilized physico-chemical method within the of the pure components in regards to the corresponding
pharmaceutical disciplines of preformulation and for- DSC trace of their simple binary mixture), it can be con-
mulation.[6] The usual procedure for drug-excipient com- sidered that the applied thermoanalytical method do not
patibility screening is performed by separately collecting reveal an interaction between the API and the excipient.
the DSC curves of pure active pharmaceutical ingredi- According to these observations, it can be strongly sug-
ent (API) and pure excipient at standard heating rates gested that there is no solid-state incompatibility in the
(e.g., 10°C min-1), usually in a dry nitrogen atmosphere. studied binary system.[7]

Address for Correspondence:  Packa Antovska, Research and Development, ALKALOID AD, Aleksandar Makedonski 12, 1000 Skopje,
Republic of Macedonia, Tel.: +389-3104-114. Fax: +389-2-3104-114. E-mail: pantovska@alkaloid.com.mk
(Received 04 May 2012; revised 25 July 2012; accepted 27 July 2012)

481
 482  P. Antovska et al.
Fourier transform infrared (FT-IR) spectroscopy has as a model drug. The design of a 24 h controlled release
achieved extensive recognition within the industry for matrix tablet from indapamide is very convenient for
raw material testing, product quality control and process patients due to the reduced frequency of application
monitoring, emphasizing its use in the pharmaceutical and improved drug safety instead of producing the simi-
sector.[8,9] The increasing interest in FT-IR spectroscopy lar antihypertensive efficacy by the use of conventional
is perhaps due to its main advantages of an easy sample therapy.[17,18]
preparation with reduced pre-treatment steps and In this study five polymers: hydroxypropylmeth-
ability to predict either physico-chemical or molecular ylcellulose (HPMC), hydroxyethylcellulose (HEC),
structure properties from a single spectrum.[10] In this polyvinylpyrrolydone/polyvinyl acetate (PVP/PVAc),
context, FT-IR spectroscopy is also extremely useful poly(ethyl acrylate-co-methyl methacrylate) (PEAMM)
as screening technique for study of polymorphism and poly(ethylene oxide) (PEO) were tested for their
in API.[11–13] The application of FT-IR spectroscopy compatibility as a matrix carriers for indapamide
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as appropriate method for solid-state compatibility sustained release formulation. The excipients further
screening between the API and the excipients during proposed for the development of the solid-dosage
the preformulation stage is well established in the formulation such as: cellulose microcrystalline, sor-
scientific literature.[14,15] In regards to the DSC protocol, bitol, lactose monohydrate, low viscosity hydroxyeth-
the FT-IR study of the binary mixtures (1:1, w/w) is ylcellulose (HEC-LV), colloidal silicon dioxide and
conducted by comparison of the IR spectra of the pure magnesium stearate were also tested for solid-state
components with the corresponding spectrum of their compatibility with indapamide. The compatibility was
binary mixture. If changes in the observed characteristic thoroughly studied by application of DSC and FT-IR
vibrational bands of the API and/or excipients are spectroscopy. DCS curves and IR spectra of pure com-
evident in the spectrum of the binary mixture, a solid- ponents (API and excipients), freshly prepared binary
state interaction might be predicted. mixtures (1:1, w/w) and binary mixtures after expo-
In addition to the initial DSC and FT-IR study of the sure for one month at 40°C and 75% relative humidity
prepared binary mixtures, an added value to the com- (RH) were recorded and interpreted. The main aim of
patibility screening is the testing of the same materials the conducted study was to select a suitable polymer
after prolonged exposure at accelerated conditions such matrix that exhibits satisfying solid-state compatibility
For personal use only.

as: raised moisture, temperature and radiation. The with indapamide. Furthermore, it will afford future
comparison of the physico-chemical data obtained for
the freshly prepared mixture with the corresponding
stressed samples introduces possibility to monitor the
effect of the external stimuli on the integral solid-state
compatibility.
Hydrophilic matrices for preparation of sustained
release formulations are one of the most used controlled
delivery systems due to their simple technology and low
cost.[16] In order to investigate the suitability of a poly-
mer as a matrix forming agent, the sole characteriza-
tion of the polymers both physically and chemically is
not satisfactory and there is need to establish potential
interactions/incompatibilities between the polymers
and the API. Indapamide, 4-chloro-N-(2-methyl-2,3-di- Figure 1. Differential scanning calorimetry curves of pure
hydroindol-1-yl)-3-sulfamoyl-benzamide (Scheme 1), a indapamide: initial (a) and stressed at 40 ºC and 75% relative
humidity for 1 month (b).
non-thiazide sulphonamide diuretic, mainly used in the
treatment of mild to moderate hypertension was chosen
Table 1.  Endothermic thermal events observed in the DSC curves
of the evaluated polymer matrices.
Polymer matrix Tonset/°C Tpeak/°C ΔH/Jg–1
PEAMM – – –
PVP/PVAc 35.9 39.4 6.71
66.8 87.0 40.31
HEC 86.2 121.6 137.1
PEO 61.7 69.5 166.6
HPMC 66.5 93.3 77.86
DSC, differential scanning calorimetry; HEC,
hydroxyethylcellulose; HPMC, hydroxypropylmethylcellulose;
PEAMM, poly(ethyl acrylate-co-methyl methacrylate); PEO,
poly(ethylene oxide); PVP/PVAc, polyvinylpyrrolydone/polyvinyl
Scheme 1.  Structural formula of indapamide. acetate.

 Pharmaceutical Development and Technology

 Excipients for indapamide SR solid-dosage formulation  483
development of sustained release drug product, com- total reflectance (ATR) spectra were obtained by
parable with originator’s product, but formulated with MIRAcle ZnSe ATR module (PIKE technologies) with
novel combination of excipients. low pressure micrometer clamp. The ATR method was
applied in the case of PEAMM, because of the physical
properties (water dispersion) of this matrix. Sample of
Experimental
the PEAMM solution was slowly evaporated at 60°C
Materials until thin polymer film was formed, consecutively ana-
Indapamide was acquired from IPCA Laboratories Limited, lyzed using ATR device.
Mumbai, India. Hydroxypropylmethylcellulose (Methocel
K 15 M) and poly(ethylene oxide) (Polyox WSR 301 Leo)
were supplied by Colorcon Limited, Dartford Kent, UK.
Hydroxyethylcellulose (Natrosol HHX) and low viscosity
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hydroxyethylcellulose (Natrosol 250 G pharm) were sup-

plied by Ashland Industries, Barendrecht, Netherlands.
Polyvinylpyrrolydone/polyvinyl acetate (Kollidon SR)
was supplied by BASF Chemtrade Gmbh, Limburgerhof,
Germany; poly(ethyl acrylate-co-methyl methacrylate)
(Eudragint NE30D) from Evonik Industries AG, Darmstadt,
Germany; cellulose microcrystalline (Avicel PH 102) from
FMC Biopolymer, Cork, Ireland; colloidal silicon dioxide
(Aerosil 200) from Evonik Industries AG, Darmastadt,
Germany; magnesium stearate from Faci SpA, Carasco
GE, Italy; sorbitol (Parteck Sl 200) from Merck KGaA,
Darmstadt, Germany and lactose monohydrate from
Meggle Waserburg Gmbh & Co., Wasserburg, Germany.

Preparation of samples
For personal use only.

Binary mixtures were prepared by mixing equal amounts

of indapamide and each excipient in 1:1 ratio (w/w) by
simple blending of components in mortar, for 10 min, at
room temperature followed by passing of the obtained
mixtures through 0.315 mm sieve. Binary mixtures with
low viscosity HEC, sorbitol and lactose monohydrate were
prepared by wetting of the already mixed binary mixture
with purified water until paste was obtained. The paste was
then granulated through 2.0 mm sieve and dried in an oven
dryer (Sanyo OV-112) at 40–50°C until obtaining 2–3% loss
on drying. Re-granulation was obtained with passing of the
dried binary mixtures through 0.315 mm. Binary mixture
with sorbitol was also prepared by dry mixing technology.
Both technological procedures were involved in prep-
aration of binary mixtures in order to mimic the possible
technological processes of wet granulation and dry mix-
ing (direct compression) technology.

Differential scanning calorimetry

Weighed samples of 2–3 mg (Sartorius CPA225D) of the indi-
vidual components and the prepared binary mixtures were
scanned in aluminum pans with a perforated lid at speed of
10°C min-1, from 21°C to 200°C, in dry nitrogen atmosphere,
using a Netzsch DSC 204 F1 Phoenix instrument.

FT-IR spectroscopy
The FT-IR spectra were recorded in the region 4000–
400cm-1 using KBr pellets method (16 averaged scans Figure 2.  Differential scanning calorimetry curves of: indapamide
per spectrum, 4cm-1 resolution) at ambient temperature (a), corresponding (denoted) polymer matrix (b), fresh binary
with Varian-660 series FT-IR spectrometer. Attenuated mixture (c) and stressed binary mixture (d).

© 2013 Informa Healthcare USA, Inc.

 484  P. Antovska et al.

Table 2.  Characteristic values (onset, maximum temperature and enthalpy) for the melting endotherm of indapamide obtained by DSC for
the corresponding initial and stressed binary mixtures.
Tpeak /ºC Tonset /ºC H/Jg–1
Binary mixture Initial Stressed Initial Stressed Initial Stressed
Polymer matrices
PVP/PVAc 169.6 174.0 157.8 163.7 41.58 19.44
HEC 176.5 176.5 167.5 167.1 25.34 29.48
PEO – – – – – –
HPMC 176.0 176.2 165.1 165.5 30.87 33.11
PEAMM 167.4 166.2 155.2 155.3 41.7 53.9
Other excipients
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Magnesium stearate 176.0 176.3 166.2 176.3 40.4 37.2

Microcrystalline cellulose PH 102 169.6 168.5 162.5 168.5 45.09 52.52
HEC LV 168.6 175.6 161.5 167.1 29.42 20.47
Colloidal silicon dioxide 173.9 176.3 165.2 176.3 44.92 38.91
Sorbitol (dry mixing) 166.6 160.8 156.9 160.8 17.28 31.8
Sorbitol (wet granulation) 167.7 161.5 156.5 161.5 34.12 24.34
Lactose monohydrate, 174.2 175.1 166.1 166.3 32.81 33.37
(wet granulation)
DSC, differential scanning calorimetry; HEC LV, low viscosity hydroxyethylcellulose; HPMC, hydroxypropylmethylcellulose; PEAMM,
poly(ethyl acrylate-co-methyl methacrylate); PEO, poly(ethylene oxide); PVP/PVAc, polyvinylpyrrolydone/polyvinyl acetate.
For personal use only.

Figure 3. Differential scanning calorimetry curves of: PEO (a),

indapamide (b), PEO-indapamide 1:1 (w/w) binary mixture (c),
and PEO-indapamide 10:1 (w/w) binary mixture (d).

Results and discussion

DSC compatibility study
The DSC curve of indapamide exhibits a single sharp Figure 4.  Differential scanning calorimetry curves of: indapamide
endothermic event at 172.6ºC (∆H = 93.6/Jg−1). After (a), sorbitol (b), fresh binary mixture (c) and stressed binary
mixture (d).
exposure on stressed conditions, the DSC curve did
not revail any changes (Figure 1). As no temperature
and/or humidity alteration occurred in the DSC curve, and 87°C), attributed to glass transition and absorbed
the results confirmed the stability of indapamide on water/moisture evaporation, respectively.[19,20] The PEO
elevated temperature and humidity pointing out its showed only one sharp melting endotherm (69°C),
completely suitablity for technological manipulations whereas the DSC traces for HEC and HPMC matrices
such as wet and dry granulation production procedures. exhibited broad melting endotherm at 121°C and 93°C,
Due to the fact that the final intention of the study respectively.
was to develop sustained release formulation, DSC The solid-state compatibility of the potential polymer
curves of five potential polymer matrices were thor- matrices with indapamide was evaluated on the basis of
oughly studied. The obtained thermoanalytical data binary mixtures (Figure 2, Table 2). The observed endo-
(Table 1, Figure 2) showed that PEAMM did not exhibit therms in the DSC curves of the pure constituents (API
any thermal phenomenon in the studied region. PVP/ and polymer matrix), were compared to the endotherms
PVAc clearly revealed two separate endotherms (39°C observed in the freshly prepared binary mixtures and in

 Pharmaceutical Development and Technology

 Excipients for indapamide SR solid-dosage formulation  485
the binary mixtures after prolonged exposure to facili- the DSC curve of the stressed sample (40ºC/75% RH) for
tated external stimuli (temperature and moisture). this binary mixture shows significant difference (statisti-
Comparison of the three key parameters: onset tem- cal p = 0.1; Student’s t-test: paired two sample for means)
perature (Tonset), temperature in the maximum of the peak compared to the corresponding DSC curve of the freshly
(Tpeak) and the corresponding process enthalpy (∆H) for prepared sample (Figure 2, Table 2). In fact, the onset
the melting endotherm of indapamide, in the prepared temperature of the melting endotherm of indapamide
binary mixtures are presented in Table 2. The evalua- shifts from 157.8ºC to 163.7ºC and the peak temperature
tion of the suitable matrix for the indapamide sustained from 169.6ºC to 174.0ºC.
release solid-dosage form, based on the comparison of Moreover, the changes of enthalpy of the solid-liquid
the three examined DSC parameters lead to a conclusion phase transition from 41.58-1 to 19.44–1 as well as the nota-
that changes of these parameters are observable for the bly altered shape of the corresponding DSC peak (Figure 2,
binary mixture of PVP/PVAc and indapamide. Namely, Table 2) suggests that PVP/PVAc is incompatible matrix not
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suitable for sustained release carrier of indapamide.

Peculiar thermal phenomenon was noticed examin-
ing the DSC profile of indapamide–PEO binary mixture
(Figure 2). As it can be seen, sole melting endotherm of PEO
was registered in the DSC curve of both freshly prepared
binary mixture and the stressed sample (no evidence of
the indapamide peak was observed). One possibility for
such phenomenon could be attributed to the formation
of indapamide-melted polymer matrix solution, prevent-
ing registration of indapamide melting endotherm.[21] In
order to check the assumption, binary mixture of inda-
pamide–PEO with the lowered corresponding ratio of
10:1 w/w, was submitted to DSC analysis (Figure 3).
The results (Figure 3d) clearly indicate the expected
indapamide melting endotherm on the DSC curve.
For personal use only.

This confirms that the observed absence of the melting

endotherm in the DSC curve of 1:1 w/w binary mixture
is pure physical phenomenon and no implications
regarding the chemical stability of the prepared binary
mixture exist.
According to the established testing protocol, the
obtained thermoanalytical data for the remaining poly-
mer matrices (Figure 2, Table 2) reveal compatibility with
indapamide.
The results from the DSC compatibility study of other
excipients, tested for possible introduction in the formula-
tion (besides the polymer matrix), are also included in Table
2. On the other hand, the obtained DSC curves of these
binary mixtures (freshly prepared and stressed), compared

Figure 5.  Differential scanning calorimetry curves of: indapamide Figure 6.  Fourier transform infrared spectra of indapamide: initial
(a), corresponding excipient (b), fresh binary mixture (c) and sample (a) and stressed sample for one month at 40ºC and 75%
stressed binary mixture (d). relative humidity (b).

© 2013 Informa Healthcare USA, Inc.

 486  P. Antovska et al.
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Figure 8. Fourier transform infrared spectra of: indapamide (a),

sorbitol (b), fresh binary mixture (c) and stressed binary mixture (d).

from 156.9ºC to 160.8ºC and the peak temperature from

For personal use only.

166.6ºC to 160.8ºC. The most significant evident is the

change of the melting enthalpy which changes from 17.28
to 31.8−1. When sorbitol and indapamide are subjected to
wet granulation, the corresponding onset temperature
of indapamide melting endotherm shifts from 156.5ºC to
161.5ºC and the peak temperature from 167.7ºC to 161.5ºC.
The change of enthalpy is in the range from 34.12 to 24.34−1.
These changes are probably attributed to the hygroscopic
nature of sorbitol and are more pronounced in the binary
mixtures prepared by dry mixing instead of wet granula-
tion. It is most probable that during wet granulation pro-
cess, the mixture is already exposed to high humidity levels,
but the wet mass is subsequently dried until the specified
loss on drying. Therefore, the starting loss on drying in this
binary mixture is probably less when compared to the dry
mixture of sorbitol and indapamide having in mind the
hygroscopic nature of the particular excipient.
Regarding the rest of the used excipients, minor
Figure 7.  Fourier transform infrared spectra of: indapamide (a), changes are observed for the melting endotherm of inda-
corresponding polymer matrix (b), fresh binary mixture (c) and pamide when mixed with HEC-LV (Figure 5). As the peak
stressed binary mixture (d). shape and the corresponding process enthalpy (Table 2)
are not affected by this small temperature variation, it is
to the DSC curves of the pure constituents are presented in most probable indicator for pure instrumental phenom-
Figures 4 and 5. It is evident that the view of the DSC traces enon arising from the sample preparation.
including sorbitol show different behaviour compared to the According to the DSC results obtained for the binary
other excipients (Figures 4 and 5 and Table 2). mixtures of indapamide with colloidal silica, micro-
The changes can be identified regardless of the techno- crystalline cellulose, magnesium stearate and lactose
logical procedure (dry mixing or wet granulation) applied monohydrate (Figure 5, Table 2), it can be considered
for sample preparation. In the case of the sample prepared that they are compatible with this API. Namely, no sig-
by dry mixing of sorbitol with indapamide, the onset tem- nificant alteration was observed in the DSC curves of
perature of the melting endotherm of indapamide shifts the fresh and the stressed binary mixtures, respectively.

 Pharmaceutical Development and Technology

 Excipients for indapamide SR solid-dosage formulation  487
one month (40ºC and 75% RH) is presented in Figure
6b. As it can be seen, no changes in the position, shape
and number of bands regarding the spectrum of the
initial sample are found (Figure 6a). It confirms that
indapamide exhibits satisfying solid-state stability when
exposed at raised temperature and moisture.
The IR spectra of the binary mixtures of the studied
polymer matrices with indapamide (initial and stressed),
compared to the corresponding spectra of the pure con-
stituents are presented in Figure 7. The majority of the
indapamide IR bands are clearly observed in the spec-
tra of the binary mixtures. The bands from the polymer
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matrices are practically overlapped by the strong indap-

amide bands. Only in the case of PEAMM, PVP/PVAc and
PEO few bands from the corresponding polymer matrix
can be identified (Figure 7).
The spectral behavior is very similar for the rest of the
studied binary mixtures (Figures 8 and 9), where only in
the case of colloidal silica and magnesium stearate, few
characteristic bands arising from these two excipients
can be identified. Therefore, the characteristic vibrational
bands of indapamide were used to make stability corre-
lations between the IR spectra of the initial and stressed
binary mixtures.
Contrary to the DSC results, the spectrum of the
stressed binary mixture of indapamide with PVP/PVAc
does not exhibit any significant spectral variation in
For personal use only.

regards to the corresponding spectrum of unstressed

sample (Figure 7, Table 3). It directs to additional conclu-
sion that the observed interaction in the DSC experiment
is facilitated at higher temperatures whereas the dynam-
ics at temperatures between 25 and 40°C are found to be
very low.
In the case of FT-IR spectrum of indapamide–PEO
binary mixtures (Figure 7), all of the listed (Table 3) char-
acteristic indapamide bands are found at unchanged posi-
tions in the FT-IR spectra of the initial and stressed binary
mixtures. This is additional confirmation for the previous
(Figure 3) experimental observation that the absence of
the melting endotherm in the corresponding binary mix-
tures (1:1, w/w) is physical phenomenon. The absence of
alterations in the infrared spectra of the stressed binary
mixture in regards to the infrared spectrum of the initial
sample proves the solid-state stability and compatibility
Figure 9.  Fourier transform infrared spectra of: indapamide (a), of indapamide when blended with PEO.
corresponding excipient (b), fresh binary mixture (c) and stressed The infrared spectra of the stressed PEAMM, HEC
binary mixture (d). and HPMC binary mixtures with indapamide (Figure 7,
Table 3) did not reveal any significant changes compared
The obtained result is in agreement with the previously to the corresponding initial binary mixtures, confirming
published data concerning indapamide solid-state com- the overhaul solid-state stability and the compatibility of
patibility with magnesium stearate, colloidal silica and these polymer matrices with indapamide.
lactose monohydrate.[22] The infrared spectra of the remaining studied excipi-
ents-API binary mixtures are presented in Figures 8 and
FT-IR spectroscopy compatibility study 9 (Table S1).
FT-IR spectroscopy was used as complementary screen- Strong interaction was detected in the binary mixtures
ing tool to DSC analysis of the solid-state stability for the of sorbitol (wet granulation and dry mixing) with inda-
prepared binary mixtures. The FT-IR spectrum of inda- pamide (Figure 8, Table S1). As it can be seen (Figure 8),
pamide obtained after exposure to stress conditions for notable changes in the spectrum of the stressed binary

© 2013 Informa Healthcare USA, Inc.

 488  P. Antovska et al.

Table 3.  Characteristic IR bands (in cm–1) in pure indapamide and in initial/stressed binary mixtures with polymer matrices.
Indapamide PVP/PVAc HEC PEO HPMC PEAMM Tentative
Initial Stress Initial Stress Initial Stress Initial Stress Initial Stress Initial Stress assignment[23]
3654 3654 3563 3564 3654 3654 3564 3563 3654 3563 3563 3563 ν(OH)
3502 3502 3502 3501 3502 3501 3500 3502 3501 3502 3504 3500 ν(OH)
3314 3315 3315 3314 3315 3315 3315 3315 3315 3315 3312 3314 ν(NH)amide
3219 3219 3226 3223 3222 3225 3222 3222 3226 3228 3215 3220 ν(NH)amide
1657 1658 1659 1658 1659 1659 1658 1658 1659 1659 1657 1658 ν(CO)amide
1599 1599 1599 1599 1599 1599 1599 1599 1599 1599 1599 1599 δ(C=C)aromatic
1341 1341 1340 1341 1340 1340 1341 1341 1340 1340 1339 1339 ν(SO2)as
1302 1300 1298 1301 1300 1301 1301 1300 1301 1302 1300 1300 ν(CN)
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1257 1257 1256 1257 1256 1257 1257 1256 1257 1257 1256 1256 δ(CH)in-plane
1174 1174 1175 1174 1174 1175 1174 1174 1174 1175 1174 1174 ν(SO2)as
753 753 753 753 753 753 753 753 753 753 752 752 δ(CH)out-of-plane
as, antisymmetric; HEC, hydroxyethylcellulose; HPMC, hydroxypropylmethylcellulose; IR, infrared; PEAMM, poly(ethyl acrylate-co-methyl
methacrylate); PEO, poly(ethylene oxide); PVP/PVAc, polyvinylpyrrolydone/polyvinyl acetate; ν, stretching mode, δ, bending mode.

mixtures (wet granulation and dry mixing) in regards to thermoanalytical findings regarding this interaction were
the infrared spectrum of the freshly prepared sample can not supported by FT-IR spectroscopy screening, predic-
be noticed. The band originating from the free OH stretch- tion of the high temperature nature of the observed phe-
ing vibration (3563-1) is totally obscured in the spectrum nomenon was established.
of the stressed samples. Additionally, the bands from the The testing of the rest of the excipients reveled that
hydrogen bonded OH and NH stretching vibrations of sorbitol (filler, acting as a pore former in the sustained
indapamide (Table S1) are overlapped by the strong OH release formulations) is incompatible with indapamide.
mode from the sorbitol. The band assigned to the indap- This fact was confirmed by both applied instrumental
amide aromatic ring deformation vibration (1599-1) can analytical methods, regardless of the technological
For personal use only.

not be detected in the stressed sample. The FT-IR spectra procedure applied for preparation of the studied binary
of the stressed samples (Figure 8) show induced band mixture (wet granulation or dry mixing). Therefore,
broadening and slight shift of the baseline. The described sorbitol was replaced by alternative compatible water-
spectral changes, leads to conclusion that sorbitol and soluble filler, such as lactose monohydrate. All other
indapamide undergo strong hydrogen bonding when pre- studied excipients exhibited satisfying solid-state com-
pared as binary mixtures (by wet granulation and dry mix- patibility with indapamide being suitable for the pro-
ing). These observation are in accordance with the results posed application.
obtained by DSC (Figure 4, Table 2), proving that sorbitol Solid-state compatibility studies as a part of prefor-
can be considered incompatible with indapamide. mulation screening of the excipients aimed for develop-
The IR spectroscopy analysis of all other studied binary ment of indapamide sustained release formulation were
mixtures (Figure 9, Table S1), did not show considerable beneficial and give useful directions for development of
changes in the spectra of the stressed samples compared a stable and cost/effective formulation.
to the corresponding spectra of the freshly prepared
samples. The most prominent bands of indapamide are Acknowledgment
clearly detected in all cases having constant shape and at
found at unchanged positions. The authors cordially thank Mrs. Sonja Ugarkovic (R&D,
ALKALOID AD) for the support and given useful sug-
gestions during the preparation of the manuscript, Ms.
Conclusions Marina Kajdzanoska (R&D, ALKALOD AD) for the help
The present study demonstrates the suitability of DSC with the DSC curves and IR spectra collection and Mrs.
and FT-IR spectroscopy as adequate screening analytical Bosilka Stefanova (R&D, ALKALOID AD) for the prepara-
techniques for selection of suitable polymers as matrix tion of the tested samples.
carriers for indapamide sustained release formulations.
Additionally, the applied selection procedure was benefi- Declaration of interest
cial in determination and defining the qualitative compo-
The authors declare no conflicts of interest.
sition of the complete sustained release tablet formulation.
According to the obtained results, all studied matrices
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