Advanced Powder Technology 23 (2012) 814–823

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Advanced Powder Technology

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

Original Research Paper

Compactibility improvement of metformin hydrochloride

by crystallization technique
Bhavesh S. Barot a,⇑, Punit B. Parejiya a, Tushar M. Patel b, Rajesh K. Parikh b, Mukesh C. Gohel b
a
Department of Pharmaceutics, K.B. Institute of Pharmaceutical Education and Research, Sector 23, Gandhinagar 382 023, India
b
Department of Pharmaceutics and Pharmaceutical Technology, L.M. College of Pharmacy, Navrangpura, Ahmedabad 380 009, India

a r t i c l e i n f o a b s t r a c t

Article history: The objectives of the present study were to address the issues of poor flow and inadequate compressibil-
Received 4 July 2011 ity of metformin HCl by adopting particle engineering technique. Meformin HCl was crystallized in the
Received in revised form 9 November 2011 presence of polyvinylpyrrolidone (PVP K30). A 32 full factorial design (FFD) was employed for optimiza-
Accepted 15 November 2011
tion of the processing parameters. Percentage PVP K30 in solution (X1) and crystallization time (X2) were
Available online 29 November 2011
chosen as the independent variables. Percentage yield (Y1), Carr’s index (Y2) and tensile strength of com-
pacts (Y3) were selected as dependent variables. Mathematical models were evolved and contour plots
Keywords:
were drawn. Metformin HCl particles crystallized in the presence of 2% PVP K30 with crystallization time
Metformin
Direct compression
of four hours (CryMet), showed impressive improvement in flow property, compressibility as well as
Crystallization compactibility as compared to untreated metformin HCl (XMet). The derived compaction parameters
Response surface analysis ‘a’, ‘1/b’ and ‘Py’, obtained using Kawakita and Heckel equations were 0.369, 15.34 and 198.54 MPa for
Heckel analysis XMet; and 0.249, 11.05 and 143.33 MPa for CryMet respectively. Compressibility evaluation of the sam-
Kawakita analysis ples revealed poor compressibility of XMet while CryMet was directly compressible. DSC and FTIR exper-
iments showed that CryMet particles did not undergo chemical modifications during crystallization.
Ó 2011 The Society of Powder Technology Japan. Published by Elsevier B.V. and The Society of Powder
Technology Japan. All rights reserved.

1. Introduction from laboratory to production scale smoothly. Majority of the for-

Tablets are still the most commonly used dosage form because
of the ease of manufacturing, convenience in administration,
accurate dosing and excellent stability. Direct compression is the
preferred method for the preparation of tablets. However, it has
been estimated that less than 20 percent of the active pharmaceu-
tical ingredients (API) can be processed into tablets via direct
compression since the majority of API lack the flow, cohesion or
lubricating properties required for direct compression [1]. There-
fore, the formulator has to resort to (wet) granulation techniques
to obtain API/excipient agglomerates with suitable compression
properties. Wet granulation involves several processing steps
(dry mixing, granulation, drying), different equipments, and exten-
sive downstream testing for powder homogeneity/segregation [2].
Direct compression, although simple in terms of unit process
involved; is highly influenced by powder characteristics such as
flowability, compressibility and dilution potential. Not a single
drug substance or excipient possesses all the desired physico-
mechanical properties required for the development of robust
direct-compression manufacturing process, which can be scaled
⇑ Corresponding author. Tel.: +91 79 23245270; fax: +91 79 23249069.
E-mail address: bhaveshbarot83@gmail.com (B.S. Barot).
mulations (70–80%) contain excipients at a higher concentration
than the active drug [3]. But this concept could be erroneous for
drugs with high dose and poor compactibility, as it might increase
the final weight of tablet beyond acceptable limits. Metformin HCl
is a typical example of this type of drugs [4].
Metformin HCl is an oral anti-hyperglycemic agent of the bigua-
nide class used in the treatment of non-insulin dependent diabetes
mellitus (NIDDM) [5]. Metformin HCl is highly water soluble
(>300 mg/ml at 25 °C), hygroscopic and presents stability prob-
lems, which poses serious problems during tableting. Vijai Kumar
obtained a US patent for preparing directly compressible metfor-
min HCl by using excipients in powder form to improve flow and
compaction properties of the drug and tableting mix [4]. Moreover,
the tableting behavior of the drug could be modified by making
changes in its crystal habit [6]. Crystal habit could be modified
by the presence of impurities in the crystallizing solution. The
presence of small amounts of an effective additive in the crystalli-
zation medium can dramatically change the crystal size and shape
[7]. Several attempts have been made to change the crystal habit of
substances in the presence of additives during crystallization pro-
cess [8–14]. Polyvinylpyrrolidone (PVP) has been utilized as a crys-
tal growth inhibitor and an effective additive during crystallization
of paracetamol for improving its compression properties [8,15].

0921-8831/$ - see front matter Ó 2011 The Society of Powder Technology Japan. Published by Elsevier B.V. and The Society of Powder Technology Japan. All rights reserved.
doi:10.1016/j.apt.2011.11.002
 B.S. Barot et al. / Advanced Powder Technology 23 (2012) 814–823
Hence, PVP was selected as a crystal modifier in the present inves-
tigation considering its wide spread use in the pharmaceutical
industry and wide regulatory acceptance around the globe. As
the process of crystallization is influenced by many variables, the
response surface methodology (RSM) was adopted and was pre-
ferred over traditional ‘trial and error’ approaches of one-variable
at a time (OVAT). The major advantages of response surface analy-
sis over OVAT are determination of interaction between factors and
location of optimum factor settings. RSM is a widely practiced ap-
proach in the development and optimization of drug delivery sys-
tems [16]. Several researchers have portrayed the significance of
experimental design and discussed their set up and data interpre-
tation, which has now become an integral part of the drug product
development [17,18].
There is a need to develop directly compressible metformin, as
it is a high dose drug which is hard to compress directly into tab-
lets [19]. The primary objective of present investigation was to de-
velop directly compressible metformin HCl by crystallizing it in the
presence of PVP. The secondary objectives of the present study
were to demonstrate the application of RSM for the development
of directly compressible metformin HCl, characterize the product
in terms of flow (Carr’s index) and compressibility (tensile
strength, Kawakita and Heckel analysis) and to cut down the pro-
cessing steps as compared to wet granulation in manufacture of
metformin tablets.
2. Materials and methods
2.1. Materials
Metformin HCl was a gift from Lincoln Pharmaceuticals (Gandh-
inagar, India). PVP K30 was obtained from Laser Laboratories
(Ahmedabad, India). Acetone was purchased from Finar Chemicals
Pvt. Ltd. (Ahmedabad, India). Iodine, potassium iodide and anhy-
drous citric acid were obtained from S.D. Fine Chemicals Ltd.
(Mumbai, India).
2.2. Crystallization procedure
Metformin HCl (10 g) was dissolved in 50 ml aqueous solutions
containing 0%, 1% or 2% w/v PVP K30. The drug solutions were rap-
idly added to 50 ml previously cooled acetone (3 °C). The resultant
solutions were thoroughly mixed for 15 min employing a magnetic
stirrer. The mixtures were maintained at 3 ± 1 °C in an ice-water
bath for different time durations (crystallization time – 1, 2.5
and 4 h). After the desired crystallization time, the dispersions
were filtered using sintered glass funnel No. 3 under vacuum.
The crystals were dried in an oven at 45 °C. The dried crystals were
then weighed to calculate the % yield [8].
% Yield ¼ ðWeight of crystallized drug=Weight of drug
before crystallizationÞ  100
The crystals of metformin HCl were subsequently stored in a desic-
cator, over silica gel at room temperature before use.
2.3. Moisture content
The moisture content of the crystallized metformin HCl was
determined gravimetrically on a Sartorius MA-40 moisture balance
(Sartorius, Gottingen, Germany). Four gm of accurately weighed
sample was uniformly placed onto the sample pan, and the heating
cycle was started (105 °C for one hr). The percentage moisture con-
tent was calculated from the weight loss of the sample on heating.
The experiment was done in triplicate. The instrument was
allowed to cool between the tests.
815
2.4. Preparation and evaluation of compacts
Crystallized metformin HCl was passed through 40# sieve and
evaluated for flow properties. The bulk density was determined
as a quotient of weight to volume of the sample. The tapped den-
sity was determined using USP tap density tester (ETD – 1020,
Electrolab Pvt. Ltd., India). The Carr’s index (percentage compress-
ibility) was determined as one hundredth times the ratio of differ-
ence between the tapped density and bulk density to the tapped
density [20].
Tablets with round shape and flat faces were formed by direct
compression technique containing 97% of the crystallized metfor-
min HCl (500 mg), 1% talc and 2% magnesium stearate in a single
punch tablet machine (Cadmach Machinery Pvt. Ltd.) with
12.85 mm diameter die cavity at constant compression pressure.
Crushing strength of three randomly selected tablets was deter-
mined using Dr. Schleuniger tablet hardness tester (Pharmatron
8, Germany). Tensile strength measurement was calculated using
Fell and Newton method [21], which can be directly co-related to
the crushing strength, and is given by the mathematical function
shown below:
2F
rt ¼ ð2Þ
pdt
where, ‘rt’ denotes the tensile strength, ‘F’ is the diametric crushing
force, ‘t’ and ‘d’ are the thickness and diameter of the compacts
respectively.
2.5. Experimental design
A 32 full factorial design was used for the optimization of the
processing variables in crystallization. Amount of PVP K30 in solu-
tion (X1, % w/v), and crystallization time (X2, h) were the two inde-
pendent variables. The levels of X1 and X2 were chosen in
accordance with preliminary data and were representative of the
entire range of the operating conditions. The level of PVP K30
was kept below 2% since at higher concentrations crystal growth
is hindered due to high viscosity. The yield of the crystal is time
dependent. Insufficient time (e.g., 10 min) may not favour crystal
growth while excess time (e.g., 8 h) may not be beneficial because
the crystal growth stops when the supersaturated solution is con-
verted to saturated solution. The responses (dependent variables)
studied were amount of metformin HCl obtained after crystalliza-
tion i.e. yield (Y1, %), Carr’s index of the crystallized metformin HCl
(Y2, %) and tensile strength of tablets (Y3, MPa). Table 1 summarizes
independent and dependent variables along with their levels.
Experimental runs are listed in Table 2.
2.6. Statistical analysis of the data and validation of the model
Computations were performed employing Design-ExpertÒ Soft-
ð1Þ ware (Version 7.1.1, Stat-Ease Inc., Minneapolis, MN). Linear, cross-
product contribution (2FI) and quadratic models were generated
for the three response variables using multiple linear regression
Table 1
Factors (independent variables), factor level and responses (dependent variables)
used in 32 full factorial experimental design.
Factors Factor Responses
levels used
1 0 1
X1 = Amount of PVP K30 in 0 1 2 Y1 = Yield (%)
solution (% w/v)
X2 = Crystallization time (h) 1 2.5 4 Y2 = Carr’s index
Y3 = Tensile strength (MPa)
816 B.S. Barot et al. / Advanced Powder Technology 23 (2012) 814–823

Table 2
Experimental runs as per 32 full factorial experimental design with factors X1 = Amount of PVP K30 in solution (% w/v) and
X2 = Crystallization time (hours); and responses Y1 (Yield, %), Y2 (Carr’s index) and Y3 (tensile strength, MPa).

Experimental run of crystallization X1 (% w/v) X2 (h) Y1a (%) Y2a Y3a (MPa)
1 0 1 52.33 ± 1.15 37.33 ± 0.58 0.10 ± 0.03
2 1 1 48.67 ± 0.58 27.33 ± 2.08 0.46 ± 0.03
3 2 1 46 ± 1.73 25.33 ± 1.53 0.58 ± 0.03
4 0 2.5 63.33 ± 2.52 35.33 ± 2.52 0.11 ± 0.03
5 1 2.5 55.33 ± 2.52 24.33 ± 2.08 0.52 ± 0.03
6 2 2.5 21.33 ± 1.53 18.67 ± 2.52 0.81 ± 0.03
7 0 4 83.33 ± 1.15 35.33 ± 1.53 0.13 ± 0.03
8 1 4 77.33 ± 2.52 23.33 ± 2.52 0.84 ± 0.04
9 2 4 71.67 ± 1.53 16.33 ± 2.52 1.18 ± 0.04
a
Mean of 3 ± SD.

analysis. Significance of the model was determined by comparisons consists of the term ‘n’ (tap number) instead of applied pressure.
of statistical parameters like standard deviation (SD), R2, adjusted Tapping of powder, as such simulates the axial pressure applied
R2, predicted R2, and predicted residual error sum of squares onto the tablets during compaction.
(PRESS). The best model was decided on the basis of higher values XMet and CryMet powders containing 1% talc and 2% magne-
of adjusted R2 and predicted R2. Moreover, adjusted R2 and pre- sium stearate were tapped on USP tap density tester (ETD –
dicted R2 should be within 0.2 of each other to ensure the validity 1020, Electrolab Pvt. Ltd., India). The initial bulk volume of the
of the model. PRESS value should be small for the best model. powders in the measuring cylinder (before tapping) was taken as
PRESS demonstrates how well the model fits the data. Three ‘V0’. The data were analyzed using Kawakita equation:
dimensional response graphs were constructed using the software.
n 1 n
To validate the chosen experimental design and equations, the ¼ þ ð3Þ
c ab a
tests corresponding to four additional random crystallization con-
ditions were carried out in the experimental matrix. Subsequently, where,
the resultant experimental data of the response properties were V 0  V inf
quantitatively compared with those of the predicted values. Also, a¼ ð4Þ
V0
the linear regression plots between observed and predicted values
of the response properties were drawn using MS-ExcelÒ. V0  Vn
C¼ ð5Þ
V0
2.7. Quantitative determination of PVP K30 in CryMet
in which ‘C’ is degree of volume reduction, ‘a’ and ‘b’ are constants,
The amount of PVP K30 was determined by photometric analy- and, ‘Vn’, and ‘Vinf’ are the powder bed volumes after nth tapping (5,
sis of the PVP-iodine complex. Accurately weighed 10 mg of the 10, 15, 20, 25, 50, 75, 100, 200, 300 and 400) and at equilibrium
CryMet (obtained from experimental batch with optimum process- state (500th tap) respectively (13). The constant ‘a’ is equivalent
ing conditions) was dissolved in 100 ml volumetric flask contain- to the value of initial porosity of the powder bed which corresponds
ing 100 ml 0.4 M citric acid solution. Ten ml of analyte was to the total portion of the reducible volume at the nth tapping and
withdrawn from the flask into a test-tube kept in an ice-bath. thus determines the degree of volume reduction for the bed of par-
Two milliliters of 0.006 N iodine solution was added in a test-tube. ticles at infinite number of taps (applied pressure); while ‘b’ is the
The intensity of color was measured by determination of absor- constant of proportionality which is inversely related to the yield
bance of the solution using water as a blank at 500 nm in UV/Vis- strength of particles. Mathematically, ‘1/b’ is the pressure needed
ible Spectrophotometer (Shimadzu 1700, Japan). Three batches of to compress the powder to one half of its total volume [23].
CryMet, using optimized process parameters, were made on three
consecutive days, and average PVP K30 content was noted. The PVP 2.9.2. Heckel analysis
K30 content was determined from a calibration curve obtained The Heckel equation provides a method of converting force and
previously [22]. displacement signals to a linear relationship for materials undergo-
ing compaction. The equation assumes that dependence of densifi-
2.8. True density and particle size measurement cation on pressure is of first order, with the interparticulate pores
as the reactant and the densification of the powder bed as the
The true density of the CryMet and untreated metformin HCl product.
(XMet) was determined by helium pycnometer (Pycno 30, Smart  
1
Instruments, Mumbai, India) in triplicate at room temperature. ln ¼ KP þ A ð6Þ
1D
Particle size of the CryMet and XMet was measured by optical
microscopy (DMLP microscope, Leica Microsystems, Wetzlar, where ‘D’ is the solid fraction (the ratio of tablet density to true den-
Germany). Eye piece was fitted with round glass disc with grooved sity of powder) at applied pressure ‘P’; ‘K’ is the material-dependent
markings. Calibration of eye-piece was done using a standard constant (the slope of the straight line portion of the Heckel plot),
calibrated slide. Sample was put on the slide and the size of at least and the reciprocal of ‘K’ is the mean yield pressure (Py) which can
100 particles was determined. be obtained by regression analysis of the linear portion of the plot.
Intercept ‘A’ gives the densification of the powder bed as a result of
2.9. Compaction studies initial particle rearrangement (DA).
 
1
2.9.1. Kawakita analysis A ¼ ln þB ð7Þ
The Kawakita equation, as shown below describes the relation- 1  DA
ship between the degree of volume reduction of the powder
column and the applied pressure. The equation shown below DA ¼ 1  eA ð8Þ
 B.S. Barot et al. / Advanced Powder Technology 23 (2012) 814–823
where ln (1/1-DA) is related to initial die filling, while ‘B’ demon-
strates the densification due to slippage and rearrangement of
primary and fragmented particles, which corresponds to ‘D0’, which
is powder density at zero pressure. ‘D0’ represents the densification
as a result of die filling and initial powder packing.
D0 ¼ 1  eB
DB ¼ DA  D0 ð10Þ
For Heckel analysis, pressure required for compressibility of the
powder could be estimated by in-die or at pressure and out-of die
or zero pressure after the compaction. In-die measurements are af-
fected by elastic deformation due to pressure [24,25], which de-
creases the porosity. Hence, out-of-die or zero pressure is
considered as a reliable method to study the powder behavior
accurately [26,27]. XMet and CryMet powder mixtures, were com-
pressed in a KBr press (Wika Quality Systems, Germany) using
12.85-mm flat faced punches and matching die. Eight hundred
mg of each powder mixture consisting of 97% of drug powder, 1%
talc and 2% magnesium stearate was taken and the pressure was
exerted on the tablets up to 270 MPa by KBr Press. Tablets were
stored in an air-tight container for 24 h to enable the elastic recov-
ery to occur. Diameter and thickness of tablets were determined.
The data were processed using the Heckel equation [27–29].
2.10. Characterization of CryMet
2.10.1. Scanning electron microscopy (SEM)
Electron micrographs of XMet and CryMet particles were taken
employing SEM (JSM T200, Japan). The specimens were coated un-
der vacuum with gold in an argon atmosphere prior to observation.
The instrument was operated at an acceleration voltage of 30 kV.
2.10.2. Differential scanning calorimetry (DSC)
DSC study of XMet and CryMet samples were carried out on dif-
ferential scanning calorimeter (model DSC7, Perkin Elmer, Bacons-
field, UK). Two mg samples; each of XMet and CryMet were hold
for 1 min at 50 °C and then heated gradually at 10 °C min1 in
crimped aluminum pans under nitrogen atmosphere from 50 °C
to 270 °C. The onsets of melting points and enthalpies of fusion
of samples were noted.
2.10.3. Fourier-transform infrared spectroscopy (FTIR)
FTIR study was performed on treated samples to determine the
interaction between metformin hydrochloride and PVP K30 or any
change in the structure of the drugs upon treatment employed.
XMet and CryMet were mixed separately with IR grade potassium
bromide (KBr). This mixture was scanned over a wave number
range of 4000 to 400 cm1 using Fourier Transform Infrared spec-
trophotometer (Model FTIR-8400S, Shimadzu, Japan) and overlay
spectra was recorded.
3. Results and discussion
3.1. Moisture content
It is worthwhile to note that moisture plays a critical role in
compression. One of the most common causes of capping in tablets
is inadequate moisture in the blend ready for compression. Mois-
ture may also affect the flow characteristics of the powder. At
25 °C, PVP K30 absorbs approximately 40% moisture when exposed
to 80% RH [30]. The moisture content of the crystallized metformin
HCl was found to be around 3%, which could be due to the hygro-
scopic nature of PVP K30 that retains residual moisture, even after
drying. It is recommended that the crystallized metformin HCl and
817
the tablets prepared from them should be stored in air-tight
containers.
3.2. Experiments of 32 FFD
Following the addition of PVP K30 solutions containing metfor-
ð9Þ
min HCl in acetone, the crystals were collected after stipulated per-
iod of times as shown in the experimental design. The percentage
yield (%) and Carr’s index of the crystallized metformin HCl; and
tensile strength of the tablets are shown in Table 2.
Percentage yield of crystallized metformin HCl decreased with
increase in concentration of PVP K30 in the solution but increased
with increase in crystallization time. Nearly all the batches show
yield more than 50%. Carr’s index of crystallized drug decreased
with increase in both concentration of PVP K30 and crystallization
time. Gohel et al. [31] mentioned that for directly compressible
powder, Carr’s index should be less than 20. Tensile strength of
tablets increased with increase in both% of PVP K30 and crystalli-
zation time.
Crystallization involves the steps of nucleation and crystal
growth. The number of nuclei formed depends on the operating
conditions such as temperature, presence of absence of seeds, etc.
The cooling of the supersaturated solution leads to formation of
more number of nuclei. The cooled acetone solution in the present
investigation facilitates nucleation. The crystal growth is governed
by diffusion, which is adversely affected by the viscosity of the dis-
persion medium, which is dependent on the PVP K30 concentration.
The value of the Carr’s index mainly depends on the size and shape
of the crystals. Both the factors X1 and X2 favoured lowering of
Carr’s index. XMet exhibits poor flow characteristics (Carr’s index:
40, angle of repose: 45). It is inferred that agglomerate formation
due to PVP K30 favoured sphericity, which leads to improved flow.
The tensile strength is dependent on the strength of the bond be-
tween particles of the metformin HCl. PVP K30 is a known binder
and therefore Y3 increases by increase in X1 as well as X2.
3.3. Mathematical modeling
Mathematical relationship was established between the factors
(independent variables) and responses (dependent variables) using
the statistical package Design-ExpertÒ. A second order polynomial
equation that fitted to the data is as follows:
Y ¼ b0 þ b1 X 1 þ b2 X 2 þ b3 X 1 X 2 þ b4 X 21 þ b5 X 22 ð11Þ
where b0 is the intercept representing the arithmetic averages of all
the quantitative outcomes of nine runs; b1 to b5 are the coefficients
computed from the observed experimental values of Y; and X1
(amount of PVP K30 in solution) and X2 (crystallization time) are
the coded levels of factors. The term X1X2 and Xi2 (i = 1 and 2) rep-
resents the interaction and quadratic terms, respectively. The wide
range in the responses (Y1: 21 to 83, Y2: 16 to 37, and Y3: 0.1 to 1.18)
indicates that the selected independent variables have strong effect
on the responses. Therefore, it is worthwhile to go for further data
analysis. The equations of the responses are given below:
Yield ðY 1 Þ ¼ 55:93  5X 1 þ 14:22X 2  1:33X 1 X 2 þ 0:97X 21 þ 6:64X 22
Carr’s index ðY 2 Þ ¼ 24:64  7:94X 1  2:50X 2  1:75X 1 X 2
þ 2:71X 21 þ 1:04X 22
Tensile strength ðY 3 Þ ¼ 0:53 þ 0:37X 1 þ 0:17X 2 þ 0:14X 1 X 2
 0:11X 21 þ 0:086X 22
The equation represents the quantitative effects of factors (X1
and X2) upon the responses (Y1, Y2 and Y3). Coefficients with one
818 B.S. Barot et al. / Advanced Powder Technology 23 (2012) 814–823

Table 3 Table 5
Model summary statistics of the measured responses Y1 (Yield, %), Y2 (Carr’s index) SME of the factors on the responses Y1 (yield, %), Y2 (Carr’s index) and Y3 (tensile
and Y3 (tensile strength, MPa). strength, MPa).

Response Model SD R2 Adjusted Predicted PRESS Standardized main effects (SME)a

R2 R2
Y1 Y2 Y3
Y1 Linear 4.22 0.9161 0.8921 0.8311 251.45
X1 11.62 22.68 18.33
Quadratic 1.05 0.9971 0.9934 0.9715 42.46
X2 33.06 7.14 8.29
2FI 4.43 0.9209 0.8813 0.6933 456.54
X1X2 – 4.07 5.63
Y2 Linear 2.32 0.9167 0.8929 0.79 95.31 X12 – 4.75 3.23
Quadratic 0.86 0.9934 0.9852 0.9528 21.43 X22 9.623 – –
2FI 2.06 0.9437 0.9155 0.697 137.51 R2 99.71% 99.34% 99.12%
Y3 Linear 0.13 0.889 0.8573 0.7038 0.33 p-Value of lack of fit 0.1459 0.6611 0.2728
Quadratic 0.05 0.9912 0.9803 0.9340 0.075
a
2FI 0.08 0.9584 0.9377 0.9018 0.11 Only the terms with statistical significance are included.

Quadratic model is suggested for equations of all the three responses.

3.4. Standardized main effects (SME) and reliability of the models

factor represents the effect of that particular factor while the coef-
ficients with more than one factor and those with second order
terms represents the interaction between those factors and the
quadratic nature of the phenomena, respectively. Positive coeffi-
cients indicate synergistic effects while the negative coefficients
indicate antagonistic effect of the factors.
Suitable mathematical models of the 32 FFD such as linear, qua-
dratic and 2FI models were analyzed by the software. Table 3 rep-
resents the model summary statistics of the responses. Quadratic
model showed a superior fit for all the three responses, as their ad-
justed R2 and predicted R2 were comparatively higher than other
models. Moreover, PRESS value of quadratic model for the three re-
sponses was smallest. In Table 4, factor effects of 32 FFD model and
associated p-values for the responses Y1, Y2 and Y3 are presented. A
factor is considered to influence the response if the effects signifi-
cantly differ from zero and the p-value is less than 0.05. Data in Ta-
ble 5 shows that the response Y1 (Yield) was significantly affected
by X2 (crystallization time, p-value < 0.0001), X1 (% w/v of PVP K30
in the crystallizing solution, p-value 0.0003) and the quadratic
term X22 (p-value 0.0006). The reasons for synergistic effect of
factor X2 (b2 = 14.22) and antagonistic effect of factor X1 (b1 = -5)
are due to increased probability of crystal growth and increased
resistance to diffusion respectively. Significant factors affecting
the response Y2 were X1 (p-value < 0.0001), X2 (p-value 0.0021),
interaction term X1X2 (p-value 0.0155) and quadratic term X12
(p-value 0.0087). Agglomerated crystals exhibit better flow as
compared to finer particles. The reason for antagonistic effect of
factors X1 (b1 = -7.94) and X2 (b2 = -2.50) is formation of agglomer-
ated crystals. Significant response affecting Y3 were similar to Y2
viz., X1 (p-value < 0.0001), X2 (p-value 0.0012), interaction term
X1X2 (p-value 0.0049) and quadratic term X12 (p-value 0.0320).
Better flow will result in uniform die filling and hence better par-
ticle–particle bond formation will be observed. Tensile strength
is dependent on particle–particle bond formation.
Table 5 presents SME values which were calculated by dividing
the main effects with the standard error of the main effects. Only
statistically significant (p-value < 0.05) values are included in the
table. The larger SME value of X2 for Y1 suggested the paramount
effect of crystallization time on the yield, while larger values of
X1 for Y2 and Y3 suggest the prime importance of % w/v of PVP
K30 in crystallizing solution on Carr’s index and tensile strength.
R2 value signifies the percentage of variability in responses that
are fitted to the models. In the present study, higher R2 value
of > 99% represents the reliability of the design. Additionally, the
p-value of lack of fit more than 0.05 for the three responses
strengthened the reliability of the quadratic model and suggested
the absence of any lack-of-fit [32].
3.5. Response surface analysis
The three dimensional response surface plots were drawn to
visualize the effect of independent variables on each response.
Fig. 1 shows the effect of % w/v of PVP K30 in crystallizing solution
(X1) and crystallization time (X2) on % yield (Y1), Carr’s index (Y2)
and tensile strength (Y3).
Fig. 1a represents the decrease in % yield (Y1) with increase in %
of PVP K30 in the crystallizing solution (X1); where it is supposed
to have suppressing effect on recovery of metformin HCl by PVP
K30. But, this effect is counteracted by increase in crystallization
time, which increases the yield. The relative decrease of yield with
increase in % of PVP K30 is at the cost of increase in flowability and
Carr’s index. Fig. 1b represents the decrease in Carr’s index (Y2)
with increase in % of PVP K30 in the crystallizing solution (X1)
and crystallization time (X2). The plot shows the optimum range
of Carr’s index (15–20) when both the factors are at the maximum
level. Fig. 1c represents the non-linear relationship between % of
PVP K30 in the crystallizing solution (X1) and crystallization time
(X2). It also depicts direct proportionality between tensile strength

Table 4
Summary of each factor effect and its p-values for the measured responses Y1 (yield, %), Y2 (Carr’s index) and Y3 (Tensile strength, MPa).

Factor Y1 Y2 Y3
Factor effect p-Value Factor effect p-Value Factor effect p-Value
X1 5.00 0.0003 7.94 <0.0001 0.37 <0.0001
X2 14.22 <0.0001 2.50 0.0021 0.17 0.0012
X1X2 1.33 0.0636 1.75 0.0155 0.14 0.0049
X12 0.97 0.2282 2.71 0.0087 0.11 0.0320
X22 6.64 0.0006 1.04 0.1387 0.086 0.0577
Refined regression equations of the fitted modela
Y1 = 55.93 – 5X1 + 14.22X2 + 6.64X22
Y2 = 24.64 – 7.94X1 – 2.50X2 – 1.75X1X2 + 2.71X12
Y3 = 0.53 + 0.37X1 + 0.14X2 – 0.11X1X2 + 0.086X12
a
Only the terms with statistical significance are included.
 B.S. Barot et al. / Advanced Powder Technology 23 (2012) 814–823 819

parameters were % PVP K30 in crystallization solution (X1) 2%

and crystallization time (X2) 4 h (CryMet: batch with experimental
run 9). CryMet showed % yield (Y1) 71.67 ± 1.53, Carr’s index (Y2)
16.33 ± 2.52 and tensile strength (Y3) 1.18 ± 0.04 MPa.

3.6. Validation of response surface model

In order to assess the reliability of the developed mathematical

model, crystallization process corresponding to random crystalli-
zation conditions which cover the entire range of experimental do-
main was performed. For each of these test runs, responses were
estimated by use of general mathematical model and general
experimental procedures. Table 6 lists the crystallizing conditions
of the random check points (A, B, C and D); their experimental
and predicted values for both the response variables. Fig. 2 shows
linear correlation plots between the observed and predicted re-
sponse variables. The graphs demonstrate high values of R2 (>0.9)
indicating excellent goodness of fit. Therefore, it can be concluded
that, model functions Y1, Y2 and Y3 well interpreted the variable
data of crystallizing conditions. A model is considered as most suit-
able if the difference between percentage prediction error and zero
is low. The lower magnitude of percentage prediction error (-8.19
to 4.88 for Y1, -8.23 to 6.41 for Y2; and -7.14 to 1.33 for Y3) as well
as significant values of R2 (>0.9) in the current study indicate the
robustness of the mathematical model and high prognostic ability
of the RSM. The footnote of Table 6 shows the equation to calculate
the percentage prediction error.

3.7. Quantitative determination of PVP K30 in CryMet

The amount of PVP K30 taken up by CryMet was 8% w/w. The

compressional characteristic of CryMet is dependent on the
amount of PVP since it plays an important role in bond formation
between metformin particles. In order to have minimum fluctua-
tion in the functionality of CryMet, it is recommended that PVP
K30 content shall be considered as an important quality control
test. A lower value might result into a friable tablet and a higher
value might result in hindered disintegration and dissolution.

3.8. Compaction studies

3.8.1. Kawakita analysis

The volume reduction process changes from powder to powder
due to differences in particle size and inter-particulate friction.

Fig. 1. Response surface plots showing effect of % w/v of PVP K30 in crystallizing Table 6
solution (X1) and crystallization time (X2) on (a) % yield (Y1), (b) Carr’s index (Y2) The experimental and predicted values for the responses Y1 (Yield, %), Y2 (Carr’s
and (c) tensile strength (Y3). index) and Y3 (tensile strength, MPa) of check points (A, B, C and D).

Check Crystallization Response Experimental Predicted Percent

points conditionsa X1 value value prediction
(Y3) and factors. The plot depicts the maximum tensile strength
(% w/v)/X2 (h) errorb
when both the factors are at the maximum level. The unit opera-
A 1.5/4 Y1 74 74.29 0.39
tion of crystallization involves the use of concentrated drug solu-
Y2 19 17.97 5.37
tions at the beginning. The mother liquor usually contains some Y3 0.94 0.9275 1.33
amount of drug after completion of the crystallization step. There-
B 1.5/2 Y1 52 49.46 4.88
fore, the yield of crystals is less than 100%. The amount of drug left Y2 24 22.46 6.41
behind in the mother liquor is dependent on the crystallization Y3 0.612 0.6083 0.60
conditions. C 1/3 Y1 62 61.35 1.05
With the help of the overlay plot, the crystallization process Y2 22 23.81 8.23
was optimized for all the three responses. The optimum parame- Y3 0.565 0.5861 3.73
ters were selected on the basis of the criteria for maximum % yield D 0.5/1 Y1 47 50.85 8.19
(>70), Carr’s index (<20) [33] and tensile strength (>0.91 MPa) Y2 30 30.91 3.03
[34]. The desired tensile strength is equivalent to crushing Y3 0.203 0.2175 7.14

strength of 70 N. Overlaying of the contour plots was done in the a

X1, Amount of PVP K30 in solution (% w/v), and X2, crystallization time (hours).
Design-ExpertÒ software. All the criteria were at the optimum le- b
Percentage error was calculated using the formula (Experimental value – pre-
vel when the X1 and X2 are at the maximum level. The optimal dicted value)/experimental value  100.
820 B.S. Barot et al. / Advanced Powder Technology 23 (2012) 814–823

Kawakita parameters were obtained by linear regression analysis
(Fig. 3a). The R2 value for both XMet and CryMet was 0.999. The
parameter ‘a’ explains the initial porosity at zero pressure which
is corresponding to the total portion of reducible volume at maxi-
mum pressure. It also describes the relative volume reduction at
the maximum number of taps. Here, XMet has higher ‘a’ value
(0.369) than CryMet, which could be attributed to needle shape
structure of primary metformin particles, possessing large amount
of voids between them. The less ‘a’ value of CryMet (0.249) is due
to the smaller size and spherical shape of the particles, which
would facilitate efficient packing. The mean particle size of CryMet
(184 lm) was lesser than XMet (462 lm). The ‘1/b’ values for XMet
and CryMet are 15.39 and 11.05 respectively. Thus, XMet requires
greater force to reduce to one half of its original volume than
CryMet, as needle shape crystals of metformin get packed with
high amount of rearrangement, which requires higher force. The
larger ‘b’ value of CryMet (0.091) than XMet (0.0655) implies that
comparatively less resisting forces could occur for CryMet during
compression [35,36].
3.8.2. Heckel analysis
Heckel reported that linear portion of the plot (Fig. 3b)
represents the densification process by particle deformation
after interparticle bonding. Heckel parameters were thus derived

Fig. 2. Linear co-relation plots between (a) predicted and observed % yield (Y1), (b) predicted and observed Carr’s index (Y2), (c) predicted and observed tensile strength (Y3).
 B.S. Barot et al. / Advanced Powder Technology 23 (2012) 814–823
Fig. 3. (a) Heckel plot of CryMet and XMet, (b) Kawakita plot of CryMet and XMet,
(c) compressibility profile CryMet and XMet.
by linear regression analysis of the straight line portion of the
Heckel plots. The R2 values for XMet and CryMet were 0.942
and 0.984 respectively. XMet powder mix was not able to form
the compacts and extensive capping was seen immediately after
ejection, so the dimensions of the compacts were recorded on
the basis of displacement of punch. Table 7 summarizes the val-
ues of ‘Py’, which states that yield pressure of XMet (196.53)
was greater than CryMet mixture (143.08). A lower value of
‘Py’ of CryMet represents a higher degree of densification as
compared to XMet, while the higher value of ‘Py’ indicates high-
er yield strength, requiring higher force for initiating deforma-
tion. The necessity of such high pressure for forming compacts
is justified by the presence of crystal lattice in XMet, which
resists the densification process [36]. The lower value of ‘Py’
indicates the higher plasticity of CryMet, due to re-bonding of
primary crystals. The CryMet particles underwent a high degree
of fragmentation during compression resulting in formation of
numerous fresh and clean surfaces for particle–particle bonding
[36]. The lower values of ‘DA’, ‘D0’ and ‘DB’ of XMet explain the
821
Table 7
Derived compaction parameters of XMet and CryMet.
Parametersa XMet CryMet
a 0.369 ± 0.002 0.249 ± 0.001
b 0.065 ± 0.003 0.091 ± 0.006
1/b 15.396 ± 0.785 11.05 ± 0.88
ab 0.024 ± 0.001 0.024 ± 0.001
Py 198.54 ± 25.13 143.33 ± 8.19
DA 0.05 ± 0.06 0.915 ± 0.003
D0 0.0024 ± 0.00 0.7916 ± 0.012
DB 0.047 ± 0.06 0.123 ± 0.014
a
Mean of 3 ± SD.
extensive frictional and cohesive forces at zero pressures which
opposes dense packing and relative particle rearrangement at
low force [35,36].
The compacts formed during Heckel analysis were character-
ized using tensile strength and porosity measurements. Compress-
ibility of the samples could be compared on the basis of porosity-
applied pressure measurements. The values of porosity obtained
after 103 MPa were 59.18% and 3.98% for XMet and CryMet respec-
tively, whereas after 200 MPa, the values were 32.27% and 2.12%
for XMet and CryMet respectively (Fig. 3c). The results show that
CryMet possess lower values of porosity and hence it is better com-
pressible than XMet.
3.9. Characterization of CryMet
3.9.1. SEM
SEM micrographs (Fig. 4) indicate needle-shaped and rela-
tively large size crystals of XMet (particle size > 400 lm)
which are responsible for its poor compactibility. While the
micrographs of CryMet shows reduction in size and becomes
almost spherical in shape. The spherical shape of the treated
particles is responsible for good compactibility and flowability.
PVP K30 changes the shape of metformin HCl particles and
deposits on it forming a thin coat over them, so as to cause
the formation of small agglomerates which helps in the con-
version of poorly compressible drug into a directly compress-
ible drug [8].
3.9.2. DSC
Both the samples viz., CryMet and XMet showed a sharp melt-
ing point with a flat base-line which indicated that no events such
as hydration, solvation or polymorphic transition had occurred
during treatment employed. However, Table 8 indicates that the
onsets of melting point (Tm) and enthalpies of fusion (DHf) of trea-
ted drug decreased by 1.4 °C and 25.029 J g1 respectively, as com-
pared to XMet. These reductions in melting point onset and
enthalpies of fusion, may be attributed to the presence of amor-
phous regions in the crystals, or due to weakening and disruption
of the crystal lattice and order, or in this case, may be attributed to
an interaction between metformin HCl and PVP K30 in the crystals
resulting in the change in physical properties. Overlaid DSC ther-
mogram of XMet and CryMet HCl revealed no major change in
the physical properties of the drug or polymorphic transition after
the treatment (Fig. 5).
3.9.3. FTIR
FTIR studies revealed that XMet showed two typical bands at
3369 and 3296 cm1 due to N-H primary stretching vibration
and a band at 3170 cm1 relative to N-H secondary stretching,
and characteristics bands at 1626 and 1567 cm1 assigned to
822 B.S. Barot et al. / Advanced Powder Technology 23 (2012) 814–823

Fig. 4. SEM micrographs of (a) XMet and (b) CryMet.

Table 8 4. Conclusions
Results of DSC study.

Sample DSC parameters

It was found that PVP K30 is an effective additive during crystal-
lization and it significantly affected the process and changed the
Onset of melting Peak Area Enthalpy of fusion
crystal habit of metformin and improved its compactibility. Re-
point Tm (°C) height (mW) (mJ) DHf (J g1)
sponse surface design was used to find the optimum factor settings
XMet 232.092 29.0087 683.615 318.989
and it was achieved by drawing an overlaid contour plot. The opti-
CryMet 230.732 29.5191 574.691 293.960
mum processing parameters were % PVP K30 in crystallization
solution (X1) 2% and crystallization time (X2) 4 h. The optimized
batch showed % yield (Y1) 71.67 ± 1.53, Carr’s index (Y2)
16.33 ± 2.52 and tensile strength (Y3) 1.18 ± 0.04 MPa. The perfor-
C = N stretching. No significant shifts or reduction in intensity of mance of crystallized drug was attributed to the adsorption of
the FTIR bands of metformin hydrochloride were observed in the PVP K30 onto the surfaces of growing crystals. DSC and FTIR exper-
CryMet. Overlaid FTIR spectra of XMet and CryMet HCl revealed iments confirmed that CryMet did not undergo structural modifi-
no major change in the physical properties of the drug or polymor- cations as compared to XMet. CryMet could be used to make
phic transition after the treatment. directly compressible sustained release tablets with high drug

Fig. 5. DSC thermogram of CryMet and XMet.

 B.S. Barot et al. / Advanced Powder Technology 23 (2012) 814–823
loading. The work carried out in this investigation has potential
industrial applications since the classical binders are ineffective
in improving tableting performance of poorly compressible drug.
Acknowledgement
The authors are thankful to Lincoln Pharmaceuticals, Gandhin-
agar, India for providing metformin HCl as gift sample.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.apt.2011.11.002.
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