Vol 3, Issue 2, 2021 (82-87)
http://journal.unpad.ac.id/idjp
*Corresponding author,
e-mail : y.w.wardhana@unpad.ac.id (Y. W. Wardhana)
https://doi.org/10.24198/idjp.v3i2.35312
© 2021 Y. W. Wardhana et al
Phase Transitions Among of Valsartan Polymorphs
Due to Grinding and Humidity Variations
Yoga Windhu Wardhana1, Risanteni Riskasari2, Fikri Alatas2
1Department of Pharmaceutics and Pharmaceuticals Technology, Faculty of Pharmacy,
University of Padjadjaran
2Faculty of Pharmacy, University of Jenderal Achmad Yani
Submitted : 18 August 2021, Revised : 12 November 2021, Accepted : 30 November 2021
Abstract
Phase transition between drugs with polymorphisms needs attention due to
unconscious changes in quality. Valsartan (VAL) is a drug model with polymorphic
events to be studied here. All phase forms originate from recrystallization through
various organic solvents such as acetonitrile and n-butyl acetate. So as a
comparison, this study used starting materials (from the market) that were not
treated. The grinding and humidity variations (RH 75% and 98%) treatment were
studied in a phase transition. The polymorphic changes characterization was
observed by microscope light polarization (PLM), Fourier Transform Infrared
(FTIR), and Powdered X-ray Diffractometer (PXRD). Polymorphic
transformations between VAL treatments were observed using PXRD. There were
significant differences in morphology, IR spectra, and diffractograms pattern.
Found that the untreated VAL was amorphous, whereas the others were in high
crystallinity. The resulting phase of n-butyl acetate shows the behavior of a
metastable phase that tends to change to a stable crystal (like the product phase of
acetonitrile).
Keywords: Valsartan, Phase transition, Polymorphism, Recrystallization
1. Introduction
The ability to find the polymorphism
of pharmaceuticals during manufacturing
pro-cessses is critically important. Since
known the pharmaceuticals compound
exhibits poly-morphism, that means
changing different physicochemical
properties at the site made the industry
more cautious. Crystallization conversion
during unit operations like mill-ing and
granulation is commonly hidden [4,6]. The
pharmaceutical industry is necessary to
ensure that only the polymorph specified in
the regulatory fulfill is immanent in the
formulation so that they must keep the
quality of the product not turn to unaccep-
tance criterion [3].
Valsartan (VAL), N-(1-oxopentyl)-
N-[[2'-(1H-tetrazol-5-yl) [1,1'-bi-phenyl]-
4-yl]-methyl]-L-valine, as selective
angiotensin II type 1 receptor blocker
choose widely for the treatment of
Y. W. Wardhana et al / Indo J Pharm 3 (2021) 82-87
83
hypertension [7]. This pharmaceutical
compound reported having 12 different
polymorphs and amorphous form [1].
Unfortunately, there is a lack of
information regarding the changes in the
properties of these polymorphs, especially
about transition during the manufacturing.
The habit or morphology of crystals
generally is obtained from solution satura-
tion, stirring rate, cooling rate, solvent
mixtu-re, additives, crystal seeds,
temperature, and impurities. Among the
various methods, the variation of the
dielectric constant of the solvent is effective
and practical in obtaining some phase [8].
Caused by finding different polymorphic
forms in pharmaceuticals solid among
commercial products will take much more
time, unrealistic, and inefficient. Therefore,
this study aims to learn polymorphic
changes under mechanical forces like
grinding and humidity variation
environments among phases of VAL.
Meanwhile, all VAL phases were produced
by recrystallizing the selected solvents. The
information resulting useful for pharmaceu-
tical development if there want to be
applied vary of polymorph forms.
Fig. 1. Structure formula of Valsartan [7].
2. MATERIALS AND METHODS
Materials
Valsartan (VAL) was obtained from
Zhejiang Huahai Pharmaceutical Co.,
LTD. (Batch No. C5271-13-196). All
other chemi-cals used were of
analytical grade. The solvents used n-
butyl acetate and acetonitrile was apply
without any purification.
3. Methods
2.1 Polymorphs preparation
The VAL bulk powder from the
market was amorphous form. To earn
different crystal forms of VAL was
obtained with recrys-tallization by two
organic solvents. An amount of VAL was
dissolved in some volumes of solvent (n-
butyl acetate or acetonitrile) at 15 – 20oC
for an hour. Then the solutions (or
suspensions) dried at room temperature.
After several hours the solid phase appears,
collected in a separate container, and
labeled.
2.2 Polarization Light Microscope
The morphology of crystalline habit
may observe firstly by Olympus BX53
model U-LH100-3 microscope with 400 x
magnification.
2.3 Fourier Transform Infrared
(FTIR) Spectroscopy
The sample fingerprints functional
groups were recorded by IR Prestige-21
Shimadzu, Japan. The samples were disper-
sed in KBr powder and compress by a
hydraulic press to form a compact
transparent disc. The spectrum of each
sample was recorded from 400–4000 cm–1.
2.4 Powder X-ray Diffraction
(PXRD)
Powder X-ray diffraction (PXRD)
was conducted by X-ray diffractometer
(X’Pert–Pro PANalytical, Netherland) with
Cu–Kα radiation (1.5 Å), at 40kV, 30 mA,
and fixed divergence slit 0.05o, receiving
slit 0.45 mm. All samples were scanned at
room temperature in the 2θ range of 5–50o
with 0.02 step size and 0.8 s per step, care
was taken to avoid phase transitions during
preparation.
2.5 Polymorphic Transformation
Evaluation
Y. W. Wardhana et al / Indo J Pharm 3 (2021) 82-87
84
Mechanical Forces Influence (Grinding)
Considerable amounts of VAL polymorphs
were ground in Retsch RM 200 at 100 rpm
for 30, 60, and 90 minutes. The phase
transition among polymorphs was
monitored with an X-ray diffractogram.
Humidity Influence
Stored some VAL polymorphs under
humidity-controlled on desiccator at room
temperature with RH 75% (NaCl super-
saturation) and 98% (K2SO4
supersaturation) for a month, and take
samples every a week to observed by
PXRD.
4. RESULT AND DISCUSSION
Polarization Light Microscope
The recrystallization produced
among polymorphs was monitored through
different habit morphology with a
polarization light microscope. From
microscopic images found the habits
modification resulted, as seen in Fig. 2. As
shown in the figure, the crystal habit of a
400 x magnification polymorph of
acetonitrile in smaller rods than the crystals
of n-butyl acetate.
Fourier Transform Infrared (FTIR)
Spectroscopy
To prove that all resulted
polymorphs are the same substance an IR
spectrum from FTIR was analyzed.
The spectrum showed a similar pattern of
functional group fingerprints, which proved
those powders are the same substance. It
looks a little different at 3456 cm–1 bands
as represent of O–H stretch, there found in
untreated VAL has a broad O–H stretches
that indicate as amorphous has a more
hydrophilic group. Other bands such as
those at 2962 and 2360 cm–1 representing
the C–H and C=O bands appear to shift
slightly in different polymorphs. The
fingerprint pattern around 500–2000 cm–1
shows very little shift but is still in the same
spectrums pattern. This variation among
polymorphs indicates that the solvent has
interaction to affect crys-talline
modification among VAL.
3.1 Powder X-ray Diffraction
(PXRD)
Lastly, the powerful distinguishing
among crystals using powdered X-ray diff-
ractogram. As shown in Fig. 4 those
powders have a very disparity ordered
arrangement. The starting materials of VAL
has shown an amorphous form which has to
shorten ordered
85
Fig. 2. Images of PLM in 400 x magnification of (A) starting material of VAL, (B) VAL from
acetonitrile, (C) VAL from n-butyl acetate
Fig. 3. FTIR spectra of (A) starting material of VAL, (B) VAL from n-butyl acetate, (C) VAL
from acetonitrile
than another polymorphic form resulted
from solvent recrystallization. Those looks
that polymorph came from acetonitrile
more crystalline than n-butyl acetate. The
crystal from acetonitrile has 2θ peaks at
10.7˚, 13.8˚, 18.5˚, 20.0˚, and 20.5˚, while
from n–butyl acetate has 2θ peaks at 5.2˚,
9.5˚, 10.4˚, 11.6˚, 12.7˚, 13.8˚, and 14.2˚.
3.2 Polymorphic Transformation
Evaluation
The resulting polymorphs are then
treated in the form of energy variations
such as mechanics through milling and
various humidity environments in storage,
which can cause changes in product quality
in the manufacturing process. The phase
change between the VAL forms was
observed, the acetonitrile product phase
changed to an amorphous form after 90
minutes of milling, while the VAL form
was produced from n-butyl acetate at 30
minutes of milling had a diffractogram
pattern to the polymorphic form of
acetonitrile. Under humidity, the VAL from
acetonitrile is shown unchanged even at RH
98% after a month stored, but the VAL
from n-butyl acetate looks to change easily
into another polymorph form. It means that
VAL from n-butyl acetate was the
metastable form among the polymorphs
compared.
Y. W. Wardhana et al / Indo J Pharm 3 (2021) 82-87
86
Fig. 4. X–ray diffractograms of (A) untreated VAL, (B) VAL from acetonitrile, (C) VAL from
n-butyl acetate
A
B
C
Fig. 5. Monitored of polymorphic transformation within (A) grinding, (B) stored at RH 75%,
and (C) RH 98%
5. CONCLUSION
Phase transitions are usually neglected
factors in the validation of manufactured
products. These factors are common as
hidden quality aspects. So, through this
research, we want to introduce pharmacists
who are concerned carefully. This study
aims to obtain a polymorphic structure from
acetonitrile and n-butyl acetate. These
polymorphs have different properties, but
for pharmaceutical development it shows
that the VAL of n-butyl acetate has been
handled with care, causing the shape to
change easily.
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