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Compatibility study of ranitidine with pharmaceutical excipients

Article · January 2013

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Research Article

Compatibility Study of Ranitidine with Pharmaceutical

Excipients
Neha S. Raut, Harshal M. Balpande, Chetan N. Deore, Milind J. Umekar, Nandkishor R.
Kotagale
Smt. Kishoritai Bhoyar College of Pharmacy, Behind Railway Station, New Kamptee, Dist- Nagpur 441 002, Maharashtra, India.

ABSTRACT
Binary mixtures (1:1) of ranitidine with variety of pharmaceutical excipients stored for 3 months at 50 ± 20C, 25 ± 30C, 2 -
80C, 40 ± 20C/75 ± 5% RH were observed for the physical changes, moisture gain and analyzed by UV spectrophotometer
to investigate the compatibility of selected excipients with ranitidine. Set of observations revealed RNH interaction with
butylated hydroxyanisole, polyvinyl pyrrolidone, hydroxy propyl methyl cellulose, microcrystaline cellulose and magnesium
stearate at all the storage conditions. Physicochemical characterization of stored binary mixtures by differential thermal
analysis and differential scanning calorimetry divulged that RNH was apparently incompatible with butylated hydroxyanisole,
polyvinyl pyrrolidone, hydroxy propyl methyl cellulose, microcrystalline cellulose and magnesium stearate. Further, altered
infrared spectra indicated the possibility of molecular changes in ranitidine-excipient mixtures. Analytical profiles of the
mixtures were an evidence of interactions leads to incompatibility.

Key words: Compatibility, Ranitidine, Excipients, Butylated hydroxyanisole, Polyvinyl pyrrolidone, Hydroxy propyl methyl
cellulose, Microcrystalline cellulose, Magnesium stearate

INTRODUCTION Evaluation of drug–excipients compatibility is based on the in-

New impurities are often formed as a result of an interaction
between drug and excipient during preparation and storage of
drug products, lead to shelf life issues which necessitate re-
formulation. Therefore, drug-excipient interactions are im-
portant to be considered in any preformulation study. Drug–
excipient compatibility testing at early stage helps in the selec-
tion of excipients that increase the probability of developing a
stable dosage form. Preformulation studies should identify the
proclivity for change in the drug substance and clarify the strat-
egy for development of dosage form. Preformulation is a criti-
cal phase in drug development where the physicochemical
profiling of active pharmaceutical ingredients (APIs) and excip-
ients are determined and prototype formulations are made. It
is an investigation of the physico-chemical properties of the
drug, alone and in combination with excipients. The im-
portance at the preformulation stage highlights the possible
consequences of drug-excipient interaction which may include
formation of new impurities, incomplete mass balance, de-
struction of the dosage form and changes in physicochemical
properties [1]. Physical and chemical interactions between
drugs and excipients can affect the chemical nature, the sta-
bility and bioavailability of drug products and consequently,
their therapeutic efficacy and safety [2]. Drug–excipient inter-
action encapsulates the fundamental characteristics such as
the spectral nature of the component, solubility, particle size
distribution, partition coefficient, melting point and stability.
herent properties of excipients and their importance in the de-
livery of the active ingredients. Although pharmacologically in-
ert, pharmaceutical excipients carry trace levels of reactive im-
purities that can either catalyses or directly participate in drug
degradation. Excipients are better known as promoters of deg-
radation than as stabilizers of drug substances. Functional
groups or residues in excipients can have the propensity to in-
teract with labile active ingredients, with attendant loss of mo-
lecular integrity or other changes in quality. Methodical, care-
fully planned and executed compatibility studies can save the
resources and time delays associated with stability issues aris-
ing during late stage product development. The results from
such studies can be useful in determining the causes of stabil-
ity issues if any. Ranitidine (RNH) is a representative example
of a very unstable drug component. Its chemical structure,
amine and nitro groups cause many problems, especially dur-
ing storage [3]. An incompatibility was reported in a binary
mixture with lactose and polyvinyl pyrrolidone [4]. Commer-
cially RNH is available as tablets, injections, solutions which
require the use of antioxidants, binder, diluents, disintegrants,
glidant, lubricants, pH modifiers, and preservatives, solvent
during formulations. In view of the chemical structure and its
susceptibility for degradative reactions with excipients the pre-
sent study was undertaken to demonstrate the incompatibility
of excipients in RNH formulations.
EXPERIMENTAL


Address for correspondence
Nandkishor R. Kotagale, Smt. Kishoritai Bhoyar College of Pharmacy, Behind Railway Station, New Kamptee, Dist-
Nagpur 441 002, Maharashtra, India. Phone: +91-7109288650, E-mail address: nandukotagale@gmail.com.
Received: 10/08/2012, Received: 25/11/2012, Accepted: 20/12/2012

International Journal of Pharmaceutical Research | January-March 2013 | Volume 5 | Issue 1 | 83

 Kotagale et al / Compatibility Study of Ranitidine with Pharmaceutical Excipients

Materials region between 200-400 nm. An UV spectrum of RNH exposed

Ranitidine HCl (RNH) was a gift from Torrent Research Labora- (RNH E) at 50 ± 20C and 40 ± 20C/75 ± 5% RH demonstrated
tory (Ahmedabad, India). Butylated hydroxyanisole (BHA) was decreased absorbance with time at both the wavelengths for
obtained from Merck (Mumbai, India), hydroxy propyl methyl RNH, λmax 228 and 313 nm whereas its blend with excipients
cellulose (HPMC), microcrystalline cellulose (MCC) and magne- showed diminished peak height after 3 months at 313 nm [5].
sium stearate (MS) from SD Fine Chem (Mumbai, India), poly- On the basis of data obtained from preliminary study, BHA,
vinyl pyrrolidone (PVP) was obtained by Loba Chemei (Mumbai, HPMC, MCC, MS and PVP were selected for further investiga-
India) and all other chemicals used were of analytical grade. tion of RNH-excipient interaction and comparatively studied at
different storage (25 ± 30C, 2 - 80C) and accelerated conditions
(50 ± 20C, 40 ± 20C/75 ± 5% RH) for 3 months.
Methods
The mixed samples consisted of equal weights of RNH and Table 1: Physical changes, pH and moisture
each excipient was individually weighed into amber colour determination of RNH and its blends with excipients
glass ampoule to give composite weights of 40 mg. The phys- %
Condi-
ical mixtures was gently prepared at a 1:1 (RNH:excipient) Sample Physical Changes pH Weight
tions
change
weight ratio by simple mixing with a spatula. The 1:1 w/w ratio
was chosen in order to maximize the probability of interaction I Dark yellow 6.8 -19.05
detection.The samples of RNH and its mixture with different II Brown wet mass 7.05 8.05
pharmaceutical excipients in 1:1 ratio (20 mg each) stored for RNH Yellow wet
3 months at 50 ± 20C in oven, Hicon (New Delhi, India) and 40 III 6.96 2.38
mass
± 20C/75 ± 5% RH in stability chamber (Thermolab scientific Black brown liq-
equipment, Thane, India). The physical changes were recorded IV 6.97 55.81
uid
visually by comparing the transform in nature, colour, solid Dark Brown wet
characteristic and confirm by using Motic microscope I 6.62 -17.44
mass
(DMWB1-223 ASC, Canada). pH determination of 0.2% sample Dark Brown wet
solution was carried out by using pH meter (Electronics, India). II 6.93 9.64
RNH- mass
Solution (20 µg/ml) of RNH and its blends with excipients was BHA Yellow brown
scanned using UV spectrophotometer (JASCO, Tokyo, Japan) III 6.88 7.06
wet mass
in the range of 200-400 nm. Calibration curve was plotted for Black brown liq-
fresh solution of RNH; the qualitative estimation was carried IV 7.01 44.30
uid
out at λmax 313 nm [5]. The fresh and exposed samples pellets I No Change 6.52 -26.19
were prepared and then analyzed using FTIR Spectrophotom-
II No Change 6.83 16.67
eter, (Shimadzu-8400S, Kyoto, Japan). Fourty scans were RNH-
III No Change 6.83 3.70
taken in transmission mode with resolution of 4 cm-1 in the HPMC
Dark brown wet
region of 4000-400 cm-1. Thermal analysis measurements of IV 6.98 60.24
RNH as well as blends with excipient were carried out on a mass
differential thermal analysis (DTA) (SDT Q 600 V 20.9 Build 20) I No Change 6.61 -21.52
and differential scanning calorimeter (DSC) (DSC Q 20 V24.4 II No change 6.97 3.70
RNH-
Build 116) (TA Instruments, Waters LLC, New Castle, Delware III No change 6.9 9.20
MCC
USA). Method: Ramp (for both). The samples were scanned in Dark brown wet
IV 6.86 71.08
the temperature range of 0-4000C at heating rate of 100C/min mass
under the flow of nitrogen during the experiment I No Change 6.95 -14.81
RNH- II No Change 7.2 5.88
pH Determination MS III No Change 7.4 4.88
Earlier reported that RNH alone is unstable in lower pH buffer IV Brown wet mass 7.04 68.35
solutions and the percent degradation increases as the pH of I Brown wet mass 6.68 -24.10
the buffer solution was lowered [7]. Hence, in preliminary study Brown sticky
the excipients showed lower pH to 3-5 were excluded from the II 6.86 10.00
mass
further studies however, the blends of RNH with BHA, HPMC, RNH-
Brown sticky
MCC, MS and PVP exhibited pH 6-7 throughout the period of PVP III 6.86 16.05
mass
investigation as summarized in table 1. Dark brown
IV 7.03 43.21
sticky mass
RESULT AND DISCUSSION Conditions: I- 50 ± 20C, II- 25 ± 30C, III- 2 - 80C, IV- 40 ±
Preliminary interaction study at 50 ± 2 C and 40 0 20C/75 ± 5% RH
± 20C/75 ± 5% RH Physical alterations and moisture determination
RNH and its mixture with different pharmaceutical excipients RNH was almost stable on storage for 3 months under 50 ±
in 1:1 ratio (20 mg each) stored for 3 months at 50 ± 20C and 20C [6], 25 ± 30C [6] and 2 - 80C. The slight weight gain was
40 ± 20C/75 ± 5% RH were analyzed to determine the possible observed which might be associated with moisture absorption
interaction for physical changes, pH and moisture gain. Quali- due to hygroscopic nature of RNH. The % Relative humidity
tative analysis of solutions of RNH or its mixture with excipient (RH) of manufacturing environment has great effect on the
in distilled water equivalent to 20 μg/ml was scanned in the UV

84 | International Journal of Pharmaceutical Research | January-March 2013 | Volume 5 | Issue 1

 Kotagale et al / Compatibility Study of Ranitidine with Pharmaceutical Excipients

moisture level of RNH as it absorbs maximum amount of mois- showed near same absorbance as of alone exposed RNH indi-
ture at higher % RH. While 20-25% RH is considered as the cates slight changes occur as a result of interaction. Exposed
optimum for RNH stability, almost 70% degradation was deter- RNH-MCC at 40 ± 20C/75 ± 5% RH exhibited prominent de-
mined at 60-70% RH [7]. RNH exposed at 40 ± 20C/75 ± 5% creased in absorbance, suggests degradation of RNH in pres-
RH for 3 months turned to black brown liquid and showed ence of MCC. The absorbance of RNH-MS exposed to 50 ± 20C
55.81% weight gain demonstrating water absorption and con- increased as compared to alone exposed RNH. Similarly, at 25
firm its role in degradation of RNH. ± 30C, 2 - 80C showed increased absorbance as compared to
RNH which might be associated with absorbance of new com-
The physical changes and moisture determination observed in pound at 313 nm, formed as a consequence of interaction be-
RNH-excipients blends shown in table 1. tween MS and RNH. Moreover, the prominent decreased in ab-
As described, the RNH with BHA and PVP were showed physi- sorbance of exposed blend RNH-MS at 40 ± 20C/75 ± 5% RH
cal transforms at all storage conditions whereas with HPMC, was observed as compared to alone exposed RNH indicated
MCC and MS not exhibited any alteration at 50 ± 20C, 25 ± 30C major degradation of RNH in presence of MS. The UV spectra
and 2 - 80C. of exposed RNH-PVP showed maximum absorption at 313 nm
which might be associated with formation of new compound
The blends stored at 50 ± 20C turned to dark brown wet mass show absorbance at same wavelength on exposure to 50 ±
and no significant weight gain indicates the temperature pos- 20C. Duplicate blends of RNH-PVP stored at 25 ± 30C, 2 - 80C
sibly responsible for interaction and at 25 ± 30C, 2 - 80C turned showed slight decreased in absorbance as compared with
to dark brown wet mass and increment in weight of samples RNH. Moreover, exposed RNH-PVP to 40 ± 20C/75 ± 5% RH
were observed which associated with moisture absorption in- showed the decreased absorbance suggesting major degrada-
dicates its role in interaction. Similarly, the blends exposed to tion in presence of PVP.
40 ± 20C/75 ± 5% RH turned to black brown wet mass and the
prominent weight gain was observed which associated with Thermal Analysis
water absorption, associated with interaction of BHA and PVP
with RNH. The mixture of RNH with HPMC, MCC and MS ex-
posed to 40 ± 20C/75 ± 5% RH turned to black brown wet
mass and exhibited major weight gain associated with water
absorption and its key role in interaction. Since HPMC, MCC,
MS [8] and PVP are hygroscopic, weight gain can be accounted
for absorption of moisture at 75 ± 5% RH during storage and
thus providing water for dissolution of drug as well as it pro-
motes the molecular collision between the reactant.
UV Spectrophotometric determination
The spectrophotometric detection was conducted for the mix-
tures with RNH and excipients individually at specific analytical
wavelength of maximum absorbance for RNH, λmax 228 and
313 nm. The UV spectra of RNH E at 50 ± 20C showed mini- (A)
mum absorption. These results substantiate the report demon-
strating the instability of aqueous RNH injection at increased
temperatures (55 and 400C) [9]. Moreover, the RNH stored at
25 ± 30C and 2 - 80C indicates slight decomposition. Similarly,
RNH exposed to 40 ± 20C/75 ± 5% RH illustrated the promi-
nent decreased in absorbance. These all relates to absorption
of moisture at 75 ± 5% RH during storage and its role in deg-
radation of RNH. The absorption spectra of RNH-BHA blend ex-
hibited alterations in spectral pattern as well as decrease in the
intensity of absorption peak for RNH at 40 ± 20C/75 ± 5% RH,
50 ± 20C and 25 ± 30C. Likewise, at 2 - 80C showed minimum
absorption as compared to RNH, indicated prominent interac-
tion between RNH and BHA at all storage conditions. The mix-
ture of RNH with HPMC stored at 50 ± 20C was showed in-
creased absorbance as compared with exposed RNH however
lower as compared to RNH which might be associated with for-
mation of degraded product showed absorbance at 313 nm. (B)
The blends stored at 25 ± 30C and 2 - 80C demonstrated min-
imum absorption and at 40 ± 20C/75 ± 5% RH, UV absorption Figure 1: Overlain of (A) DTA and (B) DSC
spectra reveals a sudden decreased in absorbance indicated thermogram of RNH and RNH/alone or its blends
prime degradation of RNH in presence of HPMC. The blend of with BHA, PVP stored at 25 ± 30C for 3 months.
RNH-MCC stored at 50 ± 20C demonstrated increased absorb-
ance as compared to exposed RNH. Moreover, blend stored at As shown in Figures 1 (A) and (B), the DTA and DSC thermo-
25 ± 30C showed decreased in absorbance and at 2 - 80C gram of RNH stored at 25 ± 30C exhibited all endo/exothermic

International Journal of Pharmaceutical Research | January-March 2013 | Volume 5 | Issue 1 | 85

 Kotagale et al / Compatibility Study of Ranitidine with Pharmaceutical Excipients
peak in RNH predicted thermal stability. As illustrated in Fig-
ures. 2 (A) and (B), the shifting of melting endotherm from
144.410C to 121.680C as well as appearance of broad exother-
mic peak at 170.820C in DTA thermogram and the shifting of
melting endotherm from 145.330C to 109.120C with additional
small broad endothermic peaks at 57.920C, 223.870C and a
broader exotherm at 174.110C in DSC thermogram of RNH
stored at 40 ± 2 0C/75 ± 5 % RH were observed corresponding
to thermal decomposition of RNH.
As depicted in Figure 1 (A), DTA thermogram of RNH-BHA blend
stored at 25 ± 30C exhibited broader exotherm at 182.600C and
a small endotherm at 247.870C (thermal decomposition of RNH
or its associated impurity) that could not be correlated directly
either with BHA or RNH. As shown in Figure 2 (A), DTA thermo-
gram of RNH-BHA exposed to 40 ± 20C/75 ± 5% RH revealed
similar thermal behaviors indicates interaction of BHA with
RNH. As observed in Figure 1 (B), DSC thermogram of RNH-
BHA stored at 25 ± 30C showed a small sharp endotherm at
136.700C (shifting of melting peak of RNH) and broader exo-
thermic peak at 184.550C that could not be correlated directly
either with BHA or RNH, suggests that there may be some in-
teraction. As shown in Figure 2 (B), DSC thermogram of RNH-
BHA blend exposed to 40 ± 20C/75 ± 5% RH demonstrated
shifting of melting peak of RNH to small broad endothermic
peak at 109.120C in addition to two endothermic peaks at
57.920C, 223.870C and a broader exotherm at 174.110C corre-
sponding to thermal decomposition of more than one compo-
nent as a consequence of RNH and BHA interaction. However
DTA and DSC pattern observed with exposed blends was dif-
ferent at storage conditions as compared to exposed un-
blended RNH which suggest the difference in the composition
of degraded substances.
Figure 2 (A): Overlain of DTA thermogram of RNH
and RNH/alone or its blends with BHA, HPMC, MCC,
MS stored at 40 ± 20C/75 ± 5% RH for 3 months.
DSC curves of HPMC presented a characteristic profile of elim-
ination of water surface between 35 and 900C, thermal stability
between 100 and 3000C, following thermal decomposition as
evidenced by the exothermic transition in temperature at about
3750C [10]. In the DSC thermogram of HPMC, a broad endo-
86 | International Journal of Pharmaceutical Research | January-March 2013 | Volume 5 | Issue 1
thermic peak at 65.960C, due to evaporation of adsorbed mois-
ture, was observed [11]. In present study, as shown in Figure
2 (A) and (B), DTA thermogram of RNH-HPMC blend showed a
broad endothermic peak at 241.990C corresponds to thermal
decomposition of RNH as well as melting endotherm of RNH
was not observed; suggests some interaction between RNH
and HPMC. DSC thermogram of exposed RNH-HPMC blend
showed a broad endothermic peak at 78.940C due to loss of
adsorbed moisture and small broad endothermic peak at
245.210C which may be corresponds to thermal decomposition
of RNH. The melting peak of RNH was missing indicates
stronger interaction of HPMC with RNH on exposure to 40 ±
20C/75 ± 5% RH for 3 months.
Figure 2 (B): Overlain of DSC thermogram of RNH
and RNH/alone or its blends with BHA, HPMC, MCC,
MS, PVP stored at 40 ± 20C/75 ± 5% RH for 3 months.
DSC scan of MCC showed a broad endotherm at 63.290C,
which may be attributed to the loss of adsorbed water [11]. In
current study, as observed in Figures 2 (A) and (B), the mixture
of RNH with MCC exposed to 40 ± 20C/75 ± 5% RH showed
broad exothermic peak at 161.340C in addition to small endo-
thermic peak at 234.030C in DTA thermogram and broad en-
dothermic peak at 89.300C, broad exothermic peak at
167.100C, a small endothermic peak at 250.360C in DSC ther-
mogram, respectively. The melting endotherm of RNH was
missing; suggests physico-chemical interaction between RNH
and MCC which might be associated with moisture absorption.
As suggested earlier the broadening of endotherm at 89.300C
may be due to desorption of adsorbed water as observed ear-
lier since MCC is hygroscopic in nature and moisture absorp-
tion as determined in the blends showing incompatibility [11].
As reported, MCC shows heat flow time curves at 800C that
might be caused by moisture redistribution. Moreover blends
of RNH and MCC yielded an exothermic peak at 800C demon-
strating physico-chemical interaction that can be attributed to
water redistribution from the MCC to RNH [12].
As represented in Figure 2 (A), DTA thermogram of RNH-MS
exposed to 40 ± 20C/75 ± 5% RH, the melting endotherm of
RNH was disappeared and an endothermic peak at 92.490C
which is superimposed on the dehydration peak of MS. Similar
DTA transforms were reported from the blends of ketoprofen-
 Kotagale et al / Compatibility Study of Ranitidine with Pharmaceutical Excipients

MS mixture due to heating [13]. In addition, as depicted in Fig- changes in blend of RNH with BHA. At 2 - 80C, RNH-BHA
ure 2 (B), DSC thermogram of RNH-MS blend demonstrated an showed changes in spectral pattern as well as absence of NO2
endothermic peak at 98.700C which might be corresponds to peak (1568.02 cm-1), secondary amine CN stretch (1132.14
dehydration of MS, a melting endothermic peak of RNH shifted cm-1) whereas NH bend secondary amine (1591.16 cm-1) and
to lower temperature at 140.330C with an occurrence of addi- conjugated C=C stretch (1620.09 cm-1) of RNH were shifted to
tional exothermic peak at 346.100C indicates thermal decom- lower wavenumbers (1571.88 cm-1 and 1616.24 cm-1 respec-
position or formation of new compounds as a consequence of tively). Moreover, phenolic OH (3394.48 cm-1) shifting to
physico-chemical interaction between RNH and MS. Similar in- 3242.41cm-1 was also observed which indicates the possibility
teractions between MS and glibenclamide, glipizide, atenolol, of chemical interaction. Exposed RNH-BHA at 40 ± 20C/75 ±
captopril, olanzapine have been reported [11, 14-16]. 5% RH exhibited diminished in peak area as well as disappear-
ance of NO2 peak (1568.02 cm-1, 1380.94 cm-1), shifting of NH
As depicted in Figure 1 (A) and (B), DTA thermogram of RNH- bend secondary amine (1591.16 cm-1), conjugated C=C stretch
PVP blend stored at 25 ± 30C showed small endothermic peak (1620.09 cm-1) to lower wavenumber (1571.88 cm-1 and
at 144.460C which corresponds to melting point of RNH, one 1612.38 cm-1, respectively) compared to RNH and phenolic OH
broad endothermic peak at 255.520C corresponds to thermal (3394.48 cm-1 to broad peak 3271.05 cm-1) of BHA. Shifting of
decomposition of RNH or its associated impurity with one NH peak could be due to hydrogen bonding between the hy-
broader exothermic peak at 161.300C and DSC thermogram drogen atom of the NH group of RNH and OH group of BHA or
showed several endothermic peaks at 81.760C corresponding phenoxy free radicals associated with BHA may involve in deg-
to loss of adsorbed moisture, 144.160C corresponds to melting radation of RNH. As reported earlier, BHA induces physical and
point of RNH with two new additional endothermic peaks at chemical changes in the mixture of atenolol [18].
213.440C and 321.090C which may be associated with for-
mation of new compounds suggests some physical interaction
between RNH and PVP. However, as shown in Figure 2 (B), DSC
thermogram of blend RNH-PVP exposed at 40 ± 20C/75 ± 5%
RH showed shifting of RNH melting peak to lower temperature
from 145.33 to 132.260C with new endothermic peaks at
215.170C and 286.210C that could not be correlated directly
either with PVP or RNH. As reported earlier similar alterations
in the thermogram of glipizide and PVP was observed [12].
Shifting of drug peak to lower temperature may be due to sim-
ple mixing of drug and excipient which lowers the purity of
each component [11, 17].
FTIR Analysis (A)
FTIR spectrum of RNH exhibited entire characteristic peaks
when compared with reported reference spectra. RNH stored
at 50 ± 20C and 25 ± 30C for 3 months showed all peaks as
compared with RNH, indicated no chemical changes. FTIR
spectrum of RNH showed multiple bands around 3300-2400
cm-1 characteristic of peaks NH stretching and CH stretching.
These bands were broaden when exposed to 2 - 80C but retain
functional group peaks at same wavenumber as for RNH, indi-
cated slight changes in RNH on following its storage at 2 - 80C
whereas these bands were broaden as well as peaks for func-
tional group shifted slightly when exposed to 40 ± 20C/75 ±
5% RH which may be associated with higher humidity condi-
(B)
tion, suggests some changes in exposed RNH.
Figure 3: Overlain of FTIR spectrum of RNH, (A)
As demonstrated in Figure 3 (A), comparison of FTIR spectrum BHA, RNH-BHA blend and (B) HPMC, RNH-HPMC
of RNH, BHA and exposed RNH-BHA blend exhibited changes blend stored at 50 ± 20C, 25 ± 30C, 2 - 80C and 40 ±
in spectral pattern in exposed RNH-BHA and disappearance of 20C/ 75 ± 5% RH for 3 months.
NO2 peak (1568.02-1380.94 cm-1), shifting of NH bend sec-
ondary amine, conjugated C=C stretch (1591.16 cm-1, As observed in Figure 3 (B), the functional groups associated
1620.09 cm-1) to lower wavenumber (1575.73 cm-1, 1616.24 with the HPMC polymer were CH, CH2, CH3, C–O–C, C–O, and
cm-1) associated with RNH, phenolic OH (3394.48 cm-1 to H–O–H. The CH, CH2 and CH3 stretching absorption bands were
3247.90 cm-1) associated with BHA which indicated some of found in the 1250–1460 and 2850–2980 cm-1 region. The C–
chemical changes in RNH-BHA following its storage at 50 ± O–C and C–O stretching alcohol absorption bands occurred at
20C whereas RNH-BHA stored at 25 ± 30C demonstrated 1000 cm−1. The absorption band at 1648 cm-1 corresponded to
changes in spectral pattern as well as area of peak with disap- absorbed water (H–O–H). The broad absorption band in the
pearance of NO2 peak (1568.02 cm-1), shifting of NH bend 3500 cm-1 region represented hydrogen bonding in the poly-
secondary amine, conjugated C=C stretch (1591.16 cm-1, mer [19]. In present study, RNH-HPMC stored at 25 ± 30C and
1620.09 cm-1) to lower wavenumber (1577.66 cm-1, 1616.24 2 - 80C showed changes in spectral pattern with disappear-
cm-1) associated with RNH and phenolic OH (3394.48 cm-1 to ance of NH bend secondary amine peak (1591.16 cm-1) sug-
3244.05 cm-1) associated with BHA indicates chemical gests possibility of hydrogen bonding between NH of RNH and

International Journal of Pharmaceutical Research | January-March 2013 | Volume 5 | Issue 1 | 87

 Kotagale et al / Compatibility Study of Ranitidine with Pharmaceutical Excipients
OH from HPMC. Similarly, comparison of FTIR spectrum of
RNH, HPMC and exposed RNH-HPMC blend showed disappear-
ance in NH bend secondary amine peak (1591.16 cm-1) and
decreased in area of OH bond associated with HPMC in IR ab-
sorption which indicates the chemical interaction between
RNH and HPMC at 50 ± 20C whereas RNH-HPMC exposed to
40 ± 20C/75 ± 5% RH demonstrated changes in spectral pat-
tern or area of peak in exposed RNH-HPMC disappearance of
NH bend secondary amine peak (1591.16 cm-1), shifting of
secondary amine CN stretch (1132.14 cm-1) to lower wave-
number (1120.56 cm-1) associated with RNH and C-O peak
from 1024.22 cm-1 to 1066.56 cm-1 associated with HPMC.
The absorption band at 1648 cm-1 corresponded to absorbed
water (H–O–H) associated with HPMC and NH secondary
amine peak associated with RNH disappeared in all conditions
which may be due to hydrogen bonding. As reported, the ad-
sorption band at 3500 cm-1 corresponding to hydrogen bonding
is also shifted significantly to a lower field in mixture of HPMC
and Calcum lactate pentahydrate. Moreover hydrogen bond
formation between carboxylic acid group of indomethacin and
OH groups of HPMC have been depicted involving similar
changes in FTIR spectrum [20].
(A)
(B)
Figure 4: Overlain of FTIR spectrum of RNH, (A)
MCC and RNH-MCC blend and (B) MS, RNH-MS
blend stored at 50 ± 20C, 25 ± 30C, 2 - 80C and 40 ±
20C/75 ± 5% RH for 3 months.
As shown in Figure 4 (A), the blend of RNH-MCC stored at 50
± 20C illustrated changes in IR absorption with shifting of sec-
ondary amine CN stretch peak (1132.14 cm-1 to 1163 cm-1) and
blend stored at 2 - 80C revealed changes in spectral pattern as
well as area of peak in exposed RNH-MCC, disappearance of
NO2 peak (1568.02 cm-1) which indicates the some chemical
changes in RNH-MCC. In addition RNH-MCC blend stored at 25
± 30C demonstrated changes in spectral pattern in exposed
RNH-MCC, disappearance of NH bend secondary amine peak
(1591.16 cm-1), shifting of secondary amine CN stretch
(1132.14 cm-1), OH group of MCC (3398.34 cm-1) to lower
88 | International Journal of Pharmaceutical Research | January-March 2013 | Volume 5 | Issue 1
wavenumber (1120.56 cm-1, 3265.26 cm-1) which indicated
some of chemical interaction might be associated with hydro-
gen bonding interaction. RNH-MCC exposed to 40 ± 20C/75 ±
5% RH exhibits diminished peak area, disappearance of NH
bend secondary amine (1591.16 cm-1); shifting of conjugated
C=C stretch, NO2 , tertiary amine CN stretch peaks (1620.09
cm-1, 1568.02 cm-1, 1224.71 cm-1) to lower wavenumber
(1612.38 cm-1, 1542.95 cm-1, 1205.43 cm-1) of RNH, OH peak
(3363.62 to 3263.33 cm-1) of MCC; secondary amine C-N
stretch (1132.14 cm-1) to 1157.21 in exposed RNH-MCC sug-
gests possibility of hydrogen bonding indicated prominent
chemical changes prominent interaction between MCC with
RNH. As reported earlier, spectrum of MCC is characterized by
five strong peaks, which were identified at 3365.51, 2904.05,
1373.44, 1166.47 and 1058.84 cm-1. Mc (porcine mucin) and
Mc-MCC showed only one strong peak each at 1654.67 and
1060.97 cm-1, respectively. The characteristic differences be-
tween the spectrum of Mc-MCC and those of Mc and MCC fur-
ther indicate that a new polymer type was formed [21]. As ob-
served in Figure 4 (B), FTIR spectrum of exposed RNH-MS at
50 ± 20C and 25 ± 30C revealed difference in IR absorption,
peaks of RNH diminished while peak of COO- at 1577 cm-1 in
MS shifted to 1542.95 cm-1 which indicates the chemical
changes in RNH-MS blends. RNH-MS stored at 2 - 80C exhib-
ited disappearance of peaks conjugated C=C stretch (1620.09
cm-1), NO2 peak (1568.02-1380.94 cm-1), secondary amine CN
stretch (1132.14 cm-1); shifting of –COO- peak (1577 cm-1 to
1541.02 cm-1) which might be associated with moisture ab-
sorption at storage relates to hydrogen bonding of secondary
NH of RNH with –COO- of MS indicates prominent interaction
between MS and RNH. Similarly, exposed RNH-MS blend to 40
± 20C/75 ± 5% RH demonstrated decreased in area of peaks
in exposed RNH-MS as well as disappearance of conjugated
C=C stretch (1620.09 cm-1), NO2 peak (1568.02-1380.94 cm-
1
) and secondary amine CN stretch peak (1132.14 cm-1) which
may be associated with higher water content that accelerate
the interaction of MS with RNH through hydrogen bonding,
leading to a marked appearance of this unique IR peak at
1541.02 cm-1. As reported earlier, the appearance of the peaks
at 1562, 1556 or 1541 cm-1 might be related to the participa-
tion of water in the ground mixture. The mixture of captopril
with MS showed unique peak at 1541cm-1 indicating water
contents is key factor for acceleration of solid–state interaction
at the interface. Diminished area of peaks observed in the
RNH-MS blends may be due to prominent interaction.
Figure 5: Overlain of FTIR spectrum of RNH, PVP
and RNH blend with PVP stored at 50 ± 20C, 25 ± 30C,
2 - 80C and 40 ± 20C/ 75 ± 5% RH for 3 months.
As depicted in Figure 5, the FTIR analysis of exposed RNH-PVP
blend showed spectral changes with disappearance of NO2
peak (1568 cm-1) at 50 ± 20C, 25 ± 30C and 2 - 80C whereas
 Kotagale et al / Compatibility Study of Ranitidine with Pharmaceutical Excipients
RNH-PVP exposed to 40 ± 20C/75 ± 5% RH showed disappear-
ance of peaks of conjugated C=C stretch (1620 cm-1), NH bend
secondary amine (1591.16 cm-1), NO2 peak (1568 cm-1) and
additional peak of –C=O stretch (1670 cm-1) associated with
PVP shifted to lower wavenumber (1623 cm-1) indicating the
involvement of NH group in hydrogen bonding with C=O of PVP
as a result of prominent interaction between RNH and PVP. PVP
is capable of forming a hydrogen bond either through the ni-
trogen or carbonyl group on the pyrrole ring. However, stearic
hindrance precludes the involvement of nitrogen atom in inter-
molecular interactions, thus making the carbonyl group more
favorable for hydrogen bonding [22]. If the drug and PVP inter-
act, then the functional groups in the FTIR spectra of blend
shows shifts and broadening of band compared to the spectra
of the pure drug. Moreover similar hydrogen bonding has been
depicted due to broadening and shifting of –C=O stretch at
1670 cm−1 to lower wave numbers in the blends of acetamino-
phen and PVP [23].
CONCLUSION
The present paper demonstrated the investigation of interac-
tion of RNH with BHA, HPMC, MCC, MS, and PVP using UV
spectrophotometry, DTA, DSC and FTIR techniques which is
dependent on the condition of exposure. While increased hu-
midity/temperature indicates the physical changes in RNH
whereas chemical changes were not observed. The RNH blend
with excipients exposed to higher temperature/humidity con-
ditions suggested chemical interaction associated with degra-
dation of RNH. In FTIR analysis, the numbers of binding sites
were determined and hydrogen bonding was shown to be
source of intermolecular attraction responsible for interaction.
In all, the blends of RNH with BHA, PVP, HPMC, MCC and MS
demonstrated prominent interaction at all storage conditions
could be incompatible with RNH. Therefore, this study sug-
gests that the RNH-excipient interactions, including stability
testing protocol, for products containing hygroscopic drugs
RNH and excipients should include the study of the rate of
moisture gain as well as effect of temperature. This is particu-
larly specify the environmental conditions are responsible for
interactions of RNH with excipients and to prevent such inter-
actions requirement of proper storage condition in a airtight
amber colored container for RNH containing products are nec-
essary which is also important for products distributed in trop-
ical countries, which have hot and humid environments. This
study also demonstrated that RNH is most hygroscopic com-
pound and represents high vulnerability to degradation in pres-
ence of BHA, HPMC, MCC, MS, PVP, relative humidity, and el-
evated temperature.
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90 | International Journal of Pharmaceutical Research | January-March 2013 | Volume 5 | Issue 1

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