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269
CHAPTER -7
270
7.1 PREFORMULATION STUDIES
7.1.1 Determination of Valganciclovir solubility
Solubility assessment of Valganciclovir in various media of different pH
was carried as per the procedure described in the section 3.3.5 of Chapter 3.
7.1.2 Construction of Standard Calibration curve for Valganciclovir
Standard curve of Valganciclovir was calibrated according to the
general procedure described in the section 3.3.7 of Chapter 3.
7.1.3 Multimedia dissolution of Valganciclovir Marketed Formulations
Valganciclovir conventional marketed formulations were characterized
for drug release rate as per the method specified in the section 4.1.3 of
Chapter 4.
7.1.4 Fourier Transforms Infrared Radiation (FT-IR) Studies
The FT-IR spectrum was taken for pure Valganciclovir powder, initial
formulation and stability study samples according to the method described in
the 3.3.8 of chapter 3.
7.1.5 Differential scanning Calorimetry (DSC) Studies
Pure Valganciclovir powder, Initial formulation and stability samples
were characterized for thermal properties as per the method described in the
section 3.3.9 of chapter 3.
7.1.6 Analytical Methods
271
Ultraviolet Spectroscopy126
A novel, sensitive and precise UV spectroscopic method for
Valganciclovir was developed four different media to estimate the solubility,
dissolution and drug content in the designed formulations as per the
analytical method described in the 3.3.6 of chapter 3. Quantity of
Valganciclovir required was calculated from the relative regression equation of
the standard calibration curve.
7.1.7 Scanning Electron Microscopic (SEM) Studies
Morphological characterization of the prepared Valganciclovir
GRF Bilayered tablets was done by using Scanning electron microscope as
per the method given in the section 3.3.17 of Chapter 3. Valganciclovir GRF
Bilayered tablets prior to invitro dissolution assessment only were subjected
to SEM study.
7.2 Formulation of Non-Effervescent GRF Bilayered Tablets of
Valganciclovir
7.2.1 Characterization of Designed Formulations
In the present investigation Valganciclovir bilayered GRF tablets are
designed in order to retain in the stomach for prolonged time and release the
desired amount of Valganciclovir effectively with enhanced absorption by
maintaining effective plasma levels at the rate dictated by the needs of the
body with increased MRT.
272
Formulation and evaluation of Bilayered Valganciclovir Tablets includes
the following stages of its development.
1. Formulation and optimization of controlled release layer using various
polymers in different proportions by direct compression technique.
2. Formulation and optimization of gastric layer using various potential
polymers in different proportions by wet granulation technique.
3. Compression of Bilayered (Controlled release layer & Gastric layer) tablets
4. Evaluation of the prepared Bilayered tablet of Valganciclovir for various
properties like Drug content, Angle of repose, Bulk Density, Tapped
Density, Carr‘s Index...etc.
5. Evaluation of bilayered Valganciclovir tablets for buoyancy characteristics
like floating lag time and floating time.
6. Performance of in vitro dissolution studies of the bilayered Valganciclovir
tablet and to optimize the best formulation.
7.2.2 Moisture Uptake Studies of Lamivudine Formulations
In order to assign the desired environmental condition during the
manufacturing and storage, the designed and optimized Valganciclovir GRF
Bilayered tablets were subjected to moisture uptake study at different relative
humidity (RH) conditions100 like 33%, 54% and 90% RH as per the
methodology described in section 3.3.12 of Chapter 3.
7.2.3 Formulation of Controlled Release Layer of Valganciclovir
Various formulations (CF1-CF11) were prepared for controlled layer of
Bilayered tablet employing direct compression technique by taking
273
appropriate quantities of the ingredients as mentioned in the Table 7.5. All
ingredients are mixed intermittently by geometric dilutions and subjected to
compression using standard tabletting procedures as described in the section
3.3.4 of Chapter 3.
7.2.4 Formulation of Gastric Layer of Valganciclovir
Various formulations (GF1-GF8) were designed and prepared for the
gastric layer of Valganciclovir bilayered tablet by the standard wet
granulation technique with all the required ingredients as mentioned in the
Table 7.7. All the ingredients are mixed thoroughly by geometric dilutions and
subjected to compression using standard tabletting procedures as described
in the section 3.3.5 of Chapter 3.
7.2.5 Formulation of Non-Effervescent GRF Bilayered Tablets of
Valganciclovir
Optimized controlled release layer formulations and gastric layer
formulations were subjected to compression of bilayered tablets using
standard tabletting procedures. For distinguishing purpose opadry red dye of
low concentration was incorporated in gastric layer.
Controlled layer formulation was tabletted initially, to which the gastric
layer formulation granules were added and compressed. Caplet shaped
distinguished bilayered tablets were compressed and evaluated for the
required compendia parameters.
7.2.6 in vitro Buoyancy Studies82
in vitro buoyancy Studies were conducted for the evaluation of floating
lag time and floating duration time as per the method described in the section
3.3.13.2 of Chapter 3.
The results of in vitro Buoyancy Studies carried for Valganciclovir bilayered
GRF tablets are given in Table 7.9, 7.11, 7.13 and 7.15.
274
7.2.7 in vitro Drug Release Studies
The in vitro dissolution studies were performed for the Valganciclovir
bilayered tablets up to 12 hours using USP type II dissolution apparatus
(LABINDIA, DISSO-2000, Mumbai, India) at 100 rpm. Dissolution, sampling
and analytical methodology was given in the section 3.3.13.1 of Chapter 3.
in vitro drug release profiles were shown in Tables 7.6, 7.7, 7.11, 7.13
and 7.15
7.2.8 Kinetic Analysis of Release Data
Dissolution data of Valganciclovir bilayered GRF tablets was fitted to
five popular release linear and non linear models like Zero Order, First Order,
Higuchian Models, Erosion Model and Power Law to characterize the kinetics
of drug release from dosage forms. Curve fitting was done as described in
section 3.3.15 of Chapter3.
7.2.9 Statistical Comparison of Dissolution Profiles 103
Dissolution profiles were characterized and the similarity factor (f2
factor) was calculated to compare the dissolution profiles of different
formulations with the stability samples by the method described in the
section 3.3.16 of chapter 3.
7.2.10 Compatibility Studies By IR and DSC
7.2.10.1 Drug Excipient Compatibility Studies by IR Spectroscopy
Valganciclovir, Optimized Polymer, Valganciclovir + Optimized Polymer
- Physical mixture, Valganciclovir + optimized Polymer formulation discs were
prepared for FT-IR measurement as per the procedure described in the
section 3.3.8 of Chapter 3. The FTIR Spectra were given in Fig. 7.12 to 7.18.
275
7.2.10.2 Differential Scanning Calorimetry (DSC) Studies78
DSC study was carried out for Valganciclovir bilayered GRF tablets to
check if any incompatibility which occurs between the drug and the polymer.
The study was carried out for the optimized formulation and compared with
that of the standard as per the procedure given in section 3.3.9 of Chapter 3..
The DSC Thermograms are shown in Fig 7.19 to 7.25.
7.2.11 Accelerated stability studies on the prepared formulations102
Optimized formulations of prepared Valganciclovir GRF Bilayered
tablets were filled in HDPE containers and stored at the following conditions
like 40°C/75% RH for about 3 months as per ICH guidelines. The samples
were characterized for % drug content, FTIR and DSC study.
7.3 RESULTS AND DISCUSSIONS
7.3.1 Valganciclovir Solubility Determination
In pre-formulation studies, drug solubility assessment at different pH
conditions is the prime most consideration, as it directly simulates the drug
absorption throughout the GI tract106-108.
Valganciclovir has shown highest solubility in 0.1 N HCl and in pH 6.8
Phosphate buffer. The solubility of Valganciclovir in water is 124.81 mg/ml
where as in case of acetate buffer pH 6.8 the solubility is 189.37 mg/ml.
(Table 7.1) indicating the peak solubility of the drug in the pH range of 1 to 7.
Table 7.1: Solubility data of Valganciclovir in various pH media
Media
Solubility (mg/ml)
Water 124.81
0.1 N HCl 216.06
pH 4.5 Acetate buffer 76.48
pH 6.8 phosphate buffer 189.37
276
R² = 0.997
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0 5 10 15
Ab
sorb
an
ce
Conc (mcg)
CALIBRATION CURVE OF VALGANCICLOVIR
Fig: 7.1 Comparative Solubility Profiles of Valganciclovir in
Various pH Media
7.3.2 Construction of standard calibration curves for Valganciclovir126
Standard calibration curve was constructed by scanning the 20μg/ml
of Valganciclovir in 0.1N HCl. The standard graph of Valganciclovir in 0.1N
HCl has shown a good linearity with R2 of 0.997, in the concentration range
of 2-10 μg/ml.
Table – 7.2 Standard Calibration
Values of Valganciclovir Fig 7.2 Standard plot of Valganciclovir
0
50
100
150
200
250
Water 0.1 N HCl pH 4.5 Acetate buffer
pH 6.8 phosphate
buffer
Solu
bili
ty (m
g/m
l)
Media
Conc.(mcg) Absorbance
0
2 0.092
4 0.145
6 0.206
8 0.267
10 0.317
277
0
20
40
60
80
100
120
0 10 20 30 40 50
Cu
mu
lati
ve %
Dru
g R
elea
sed
Time (Minutes)
Dissolution Profile of Valganciclovir Tablets In Various Media
Water
0.1N Hcl
pH 4.5 Acetate BufferpH 6.8 Phosphate Buffer
7.3.3 Multimedia Dissolution of Valganciclovir Marketed Formulations
Multimedia dissolution assessment of Valganciclovir marketed
conventional formulations among different pH media (Table 8.2) has shown
similar release profiles with good correlation (Fig- 8.2) by releasing more than
90 % of drug within 10 minutes, clearly indicating the availability of drug at
the specific absorption site.
Table 7.3 in vitro Dissolution Profiles of Valganciclovir Tablets 100 mg
in Various pH Media
Fig. 7.3 Drug Release Rate of Marketed Valganciclovir Tablets
in Various pH Media
Time
(min)
Water
0.1 N HCl pH 4.5
Acetate buffer
pH 6.8
Phosphate buffer
5 86 ± 2.31 88 ±2.89 92 ±2.96 87 ±2.56
10 92 ±2.12 99 ±3.15 99 ±2.56 96 ±3.15
15 100 ±3.12 100 ±1.56 100 ±2.14 100 ±2.36
30 100 ±3.56 100 ±2.36 100 ±1.24 100 ±1.16
45 100 ±1.12 100 ±1.01 100 ±0.99 100 ±0.92
278
7.3.4 Fourier Transforms Infrared Radiation measurement (FT-IR) of
Pure Valganciclovir Drug
The FT-IR spectrum was taken for pure Valganciclovir powder.
as per the method described in the section 3.3.8 of Chapter 3.
Fig: 7.4 IR Spectrum of Valganciclovir Pure Drug
7.3.5 DSC Studies of Pure Valganciclovir Drug
Thermal characterization of pure Valganciclovir drug was done by by
Differential Scanning Calorimetry (DSC) studies as described in the section
3.3.9 of Chapter 3. DSC Thermogram of pure Valganciclovir drug was shown
in Fig: 7.5.
279
Fig No-7.5 DSC Thermogram of Valganciclovir
7.3.6 Analytical methods
UV spectra of Valganciclovir have show different absorption maxima in
varied media (Fig-4.6). A standard concentration of Valganciclovir in different
media was prepared and stored for 24 hours to assess the stability of the
Valganciclovir. Similar absorption spectra were observed among them with
similar λmax indicating the stable nature of the drug. (Table 7.4)
Table 7.4 λmax values of Valganciclovir in different pH media
Time Water 0.1NHCl pH 4.5 acetate
buffer
pH 6.8 phosphate
buffer
Initial 253.75 254.65 254.60 251.29
24 Hours 254.08 254.47 255.43 251.18
280
7.3.7 Formulation and Optimization of Controlled Release Layer of
Valganciclovir
Bilayered tablets are specialized dosage forms where in combination of
two or more drugs in a single unit having different release profiles at a
controlled fashion, which improves patient compliance, prolongs the drug(s)
action, avoid saw tooth kinetics resulting in effective therapy along with better
control of plasma drug levels.
Bilayered tablet formulations of Valganciclovir were optimized based
upon the release characteristics of controlled release layer and gastric layer in
addition to buoyancy characteristics.
Controlled release formulations CF1 to CF11 were prepared with the
aid of various potent acrylic polymers like Eudragit RS 100, Eudragit RL100,
Eudragit EPO, PEG 1000, PEG 6000, Eudragit S 100, and Eudragit L 100. All
the formulations were prepared by direct compression methods.
Table-7.5 Compositions of Valganciclovir Controlled Release Layer
Formulations (CF1- CF11)
INGREDIENTS
(mg) CF1 CF2 CF3 CF4 CF5 CF6 CF7 CF8 CF9 CF10 CF11
Valganciclovir 225 225 225 225 225 225 225 225 225 225 225
Eudragit RS100 50 -- -- -- -- -- -- -- -- --
Eudragit RL100 -- 50 -- -- -- -- -- -- 40 -- --
Eudragit EPO -- -- 50 -- -- -- -- 40 -- -- --
PEG 1000 -- -- -- 50 -- -- -- -- -- -- --
PEG 6000 -- -- -- -- 50 -- -- -- -- -- --
Eudragit S100 -- -- -- -- -- 50 -- -- -- -- 40
Eudragit L100 -- -- -- -- -- -- 50 -- -- 40 --
HPMC K4M 18 18 18 18 18 18 18 28 28 28 28
Microcrystalline
Cellulose 152.5 152.5 152.5 152.5 152.5 152.5 152.5 152.5 152.5 152.5 152.5
Magnesium
stearate 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5
281
0
20
40
60
80
100
120
0 5 10 15
% C
DR
TIME (Hours)
COMPARATIVE DRUG RELEASE PROFILE OF FORMULATIONS CF1-CF11 F1
F2F3F4F5F6F7F8F9F10F11
Table 7.6: Drug Release Profile of Valganciclovir Controlled Layer Formulations CF1 – CF11
Time CF1 CF2 CF3 CF4 CF5 CF6 CF7 CF8 CF9 CF10 CF11
0 0 0 0 0 0 0 0 0 0 0 0
0.5 31.32±0.20 31.32±0.56 31.08±0.32 36.12±0.11 58.32±0.32 37.2±0.63 41.64±0.82 20.28±0.43 30.12±0.88 24.24±0.73 25.2±0.53
1 39.24±0.28 42.35±0.45 54.12±0.55 53.52±1.11 60±0.36 50.64±0.21 45.6±0.54 30±0.31 46.32±1.02 40.2±0.42 33.36±0.61
2 43.36±0.45 53.4±0.91 78.84±0.22 85.68±0.64 85.2±0.21 73.08±0.53 79.92±0.25 46.8±0.58 60.6±0.43 62.16±0.49 72.84±0.37
4 56.21±0.83 59.04±0.56 83.28±0.68 90±0.41 89.4±0.10 90.84±0.56 91.5±0.85 70.56±0.75 66.72±0.87 72.44±1.43 76.2±1.32
6 61.2±0.85 64.12±0.27 95.44±0.33 91.44±0.82 94.56±1.11 95.76±0.84 92.96±1.32 71.92±0.92 72.04±0.36 88.64±0.76 87.62±0.29
8 74.64±0.36 78.24±0.66 98.12±0.21 96.24±0.82 97.44±1.24 95.62±0.46 80.16±0.34 84.36±0.55 96.37±0.22 91.43±1.12
10 80.69±0.48 82.2±0.43 90.58±0.22 88.27±0.66 93.67±0.53
12 90.17±0.86 93.39±0.77 94.43±0.59 92.23±1.32
Fig: 7.6 Comparative Drug Release of Valganciclovir Controlled Layer Formulations CF1-CF11
282
All the controlled release formulations CF1 to CF11 were assessed for
invitro drug release characteristics by standard dissolution testing
procedures through USP XXIV Dissolution Apparatus-II ( Model: Disso 2000,
M/s. Lab India). 900 ml of 0.1 N Hcl was used as dissolution medium,
maintained at a temperature of 37±0.5oC and the paddle was rotated at 50
RPM.
Controlled Formulations CF1 and CF2 comprising Eudragit RS 100
and Eudragit RL 100 had exhibited potential retardation by releasing
88.17% and 93.39% of drug respectively at the end of 12 hours.
CF3 formulation designed by Eudragit EPO has shown 95% of the
drug release 6 hours itself, which may not be desirable in view of the
objective to control the drug release up to 12 hours.
Controlled layer formulations CF4 to CF7 prepared by PEG 1000, PEG
6000, Eudragit S100, and Eudragit L100 has shown drug release of more
than 95%, but the polymers had retarded the release of drug only up to 8
hours, which is not desirable according to the objective of study to prolong
the drug release up to 12 hours.
Concentrations of Eudragit RL100, Eudragit EPO, Eudragit S100, and
Eudragit L100 were decreased and HPMC K4M concentration was slightly
increased in CF8, CF9, CF10 and CF11 respectively and subjected to
dissolution testing. Drug release was found to be increased in all the
formulations compared with that of high concentrations. Formulation CF8
and CF9 had retarded more than 90% of drug successfully upto 12 hours,
but the drug release was found to be highly inconsistent w.r.t dissolution
profiles, which may not meet the objective of the study that drug to be
released at a rate controlled and efficient manner.
By comparing the drug release profiles of all controlled layer
formulations CF 1 to CF11, formulation CF2 designed employing Eudragit
RL 100 was finally optimized as the best formulation for the controlled layer
283
of the bilayered tablet, as it had shown superior characteristics with respect
to drug release and rate retarding ability too.
7.3.8 Formulation and Optimization of Gastric Layer of Valganciclovir
Apart from controlled release layer optimization, suitable polymers
and their desired proportions are to be optimized towards gastric release
layer, since gastric layer plays predominant role in maintaining the required
buoyancy characteristics for the bilayered tablet of Valganciclovir. Various
formulations (GF1-GF8) were prepared for gastric layer of bilayered tablet
employing standard wet granulation technique and compressed as per the
standard tabletting procedures.
Various potential rate controlling polymers like HPMC K4M, HPMC
K100M, HPMC K15M, Eudragit RS100, Eudragit RL 100, Eudragit S100,
Eudragit L 100 and Eudragit EPO in equal proportions were employed along
with Carbopol 934 and Sodium alginate for Gastric formulations GF1 to
GF8.
Table7.7 Compositions of Valganciclovir Gastric Release Layer
Formulations (GF1- GF8)
INGREDIENTS (mg) GF1 GF2 GF3 GF4 GF5 GF6 GF7 GF8
Valganciclovir 225 225 225 225 225 225 225 225
HPMC K4M 30 -- -- -- -- -- -- --
HPMC K100M -- 30 -- -- -- -- -- --
HPMC K15M -- -- 30 -- -- -- -- --
Eudragit RS100 -- -- -- 30 -- -- -- --
Eudragit RL100 -- -- -- -- 30 -- -- --
Eudragit S100 -- -- -- -- -- 30 -- --
Eudragit L100 -- -- -- -- -- -- 30 --
Eudragit EPO -- -- -- -- -- -- -- 30
Carbopol 934 20 20 20 20 20 20 20 20
Sodium Alginate 15 15 15 15 15 15 15 15
Microcrystalline
Cellulose
155.5 155.5 155.5 150.5 155.5 155.5 155.5 155.5
Magnesium Stearate 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5
284
0
20
40
60
80
100
120
0 2 4 6 8 10 12 14
% C
DR
TIME ( Hours)
COMPARATIVE DRUG RELEASE PROFILE OF FORMULATIONS GF1-GF 8
F1
F2
F3
F4
F5
F6
F7
F8
Table 7.8 Cumulative % Drug Release Profile of Valganciclovir Gastric Layer
Formulations GF1-GF8
Time GF1 GF2 GF3 GF4 GF5 GF6 GF7 GF8
0 0 0 0 0 0 0 0 0
0.5 9.32±0.65 11.21±0.53 10.37±0.36 21.96±0.37 14.95±0.94 13.86±0.52 14.68±1.26 13.35±0.21
1 14.66±0.58 18.36±0.21 13.59±0.12 27.84±0.21 21.38±0.63 23.28±0.36 22.69±0.63 21.52±0.45
2 26.32±1.10 29.85±0.83 23.75±0.64 41.49±0.73 36.28±0.26 43.31±0.72 35.77±0.28 32.95±0.68
4 41.25±0.93 38.29±0.63 28.16±0.35 52.4±0.86 47.76±0.44 54.27±0.53 46.2±1.27 43.22±0.98
6 52.21±0.64 47.32±0.25 34.43±0.43 61.96±1.32 58.92±0.26 59.42±0.84 59.98±0.62 58.64±0.433
8 59.73±0.41 56.13±0.96 48.74±0.53 74.24±0.39 66.35±1.52 61.39±0.47 63.36±1.46 61.37±1.21
10 66.38±0.27 62.35±0.77 53.38±0.40 83.29±1.05 70.38±0.94 77.81±0.82 71.12±0.53 69.34±0.87
12 79.27±0.85 72.11±0.28 67.71±0.68 95.41±0.47 89.44±0.24 88.22±1.42 82.06±0.37 78.28±0.94s
Fig: 7.7 Comparative Drug Release Profiles of Valganciclovir Gastric Layer
Formulations GF1-GF8
285
All the respective polymers in the gastric layer formulations GF1 to
GF8 in association with Carbopol934 and Sodium alginate had successfully
retarded the drug up to 12 hours. Among all the formulations that were
subjected to dissolution characterization, GF4 designed by employing
Eudragit RS100 had shown good release characteristics of about 95% in 12
hours, which provides the basis for its optimization as the best gastric layer
formulation apart from its buoyancy characters.
All the gastric layer formulations GF1 to GF8 were subjected to invitro
buoyancy studies at agitation conditions for evaluation of buoyancy lag time
and duration of floating characteristics. Results of buoyancy studies were
tabulated as Table 7.9
Table 7.9: Buoyant Characteristics of Valganciclovir Gastric Layer
Formulations GF1 –GF8
GASTRIC
FORMULATION
BUYOYANCY
LAG TIME
(Minutes)
DURATION OF
FLOATING
GF 1 40 >12 Hours
GF 2 50 4.5 Hours
GF 3 40 > 8 Hours
GF 4 22 >12 Hours
GF 5 34 >12 Hours
GF 6 -- --
GF 7 42 6-7 Hours
GF 8 -- --
GF1, GF4 and GF5 formulations had exhibited excellent buoyancy
characteristics by maintaining their integrity for more than 12 hours, which
shows the consistent floating ability of the respective polymers by hydrogel
formation upon wetting.
GF2 and GF3 formulations had shown poor floating characteristics by
being buoyant only up to 4.5 hours and 8 hours respectively.
GF6 and GF8 formulations failed to exhibit their buoyancy ability, as
they failed to float even after a long lag of observation.
286
Since no effervescent or gas generating agents were used, all the
gastric formulations has shown buoyancy lag time from minimum of 22
minutes to maximum of 50 min, as the study pertains to the development of
non-effervescent dosages forms basing on the hydrogel forming ability of the
potential polymers selected.
7.3.9 Formulation and Optimization of Non-Effervescent Bilayered
Tablets of Valganciclovir
Among the controlled release formulations [CF1 – CF11] prepared,
Formulation CF2 with the aid of Eudragit RL 100 polymer is selected as
optimized formulation basing on its controlled release retarding ability.
Among the Gastric release formulations [GF1 – GF11] prepared,
formulation GF4 with the Eudragit RS 100 is selected as optimized
formulation basing on its controlled release retarding ability and better
buoyancy characteristics.
Bilayered tablets were prepared by direct compression procedure
employing the standard tabletting methods.
Table-7.10 Composition of Valganciclovir Bilayered Formulation (BLF)
CONTROLLED LAYER GASTRIC LAYER
INGREDIENTS
(mg)
COMPOSITION
(mg)
INGREDIENTS
(mg)
COMPOSITION
(mg)
Valganciclovir 225 Valganciclovir 225
Eudragit RL 100 50 Eudragit RS 100 30
HPMC K4M 18 Carbopol 934 20
Microcrystalline
Cellulose 152.5 Sodium Alginate 15
Magnesium Stearate 4.5 Microcrystalline
Cellulose 155.5
Magnesium Stearate 4.5
287
Table 7.11 Drug Release Data, Buoyant Characteristics of
Valganciclovir Bilayered Formulation (BLF)
TIME %DRUG
RELEASE
BUOYANCY
LAG TIME
DURATION OF
FLOATING
0 0
Not Floating --
30 20.28±0.31
1 31.13±0.56
2 46.87±0.84
4 54.62±1.22
6 71.92±0.32
8 81.16±0.88
10 86.24±1.59
12 92.66±0.63
Bilayered Formulation (BLF) compressed employing CF2 Formulation
of controlled release layer and GF5 Formulation of Gastric layer were
subjected to invitro dissolution studies and invitro buoyancy studies. BLF
had shown good release characteristics of more than 92% at the end of 12
hours but the buoyancy characteristics were found to be totally poor
without any floating behavior, which claims the necessity to optimize the
Bilayered formulation for its floating characteristics.
Optimization of Bilayered Formulation
Table – 7.12 Composition of Valganciclovir Bilayered Formulation (BLF 1)
CONTROLLED LAYER GASTRIC LAYER
INGREDIENTS
(mg)
COMPOSITION
(mg)
INGREDIENTS
(mg)
COMPOSITION
(mg)
Valganciclovir 225 Valganciclovir 225
Eudragit RL 100 50 Eudragit RS 100 30
HPMC K4M 18 Carbopol 934 22
Microcrystalline
Cellulose 152.5 Sodium Alginate 18
Magnesium Stearate 4.5 Microcrystalline
Cellulose 150.5
Magnesium Stearate 4.5
288
Table-7.13 Drug Release Data, Buoyant Characteristics of
Valganciclovir Bilayered Formulation (BLF1)
TIME %DRUG
RELEASE
BUOYANCY
LAG TIME
DURATION
OF
FLOATING
0 0
38
Minutes
More than
12 Hours
30 24.24±0.74
1 28.92±0.83
2 30.12±0.32
4 46.32±1.05
6 60.6±0.63
8 80.04±0.49
10 84.36±0.39
12 89.96±1.16
Carbopol and Sodium alginate concentrations were slightly increased
in BLF and designed as BLF1 formulation and subjected to invitro
dissolution studies and invitro buoyancy studies. BLF 1 had shown around
89% of drug release at the end of 12 hours, which is slightly less than that
of BLF. Buoyancy characteristics were found to be better with a buoyancy
floating lag time of 38 min and duration of floating being more than 12
hours, which might be due to the gelling ability of Carbopol and Sodium
alginate in addition to the hydrogel formed by Eudragit RL 100 and Eudragit
RS 100.
38 minutes of floating lag time is too long and tedious, which may not
be considerable aspect with respect to the objective of the present study.
289
Table -7.14 Composition of Valganciclovir Bilayered Formulation BLF -02
CONTROLLED LAYER GASTRIC LAYER
INGREDIENTS
(mg) COMPOSITION(mg)
INGREDIENTS
(mg) COMPOSITION(mg)
Valganciclovir 225 Valganciclovir 225
Eudragit RL 100 50 Eudragit RS 100 30
HPMC K4M 18 Carbopol 934 25
Microcrystalline
Cellulose 152.5 Sodium Alginate 12
Magnesium
Stearate 4.5
Microcrystalline
Cellulose 153.5
Magnesium
Stearate 4.5
Table- 7.15 Drug Release Data, Buoyant Characteristics of
Valganciclovir Bilayered Formulation (BLF2)
TIME %DRUG
RELEASE
BUOYANCY
LAG TIME
DURATION
OF
FLOATING
0 0
29
Minutes
More than
12 Hours
30 21.63±0.48
1 30.12±1.28
2 48.74±0.73
4 61.92±0.21
6 69.61±1.32
8 78.76±0.11
10 86.53±0.36
12 91.38±0.51
290
0
10
20
30
40
50
60
70
80
90
100
0 5 10 15
% C
DR
Time ( Hours)
COMPARATIVE DRUG RELEASE PROFILES OF BILAYERED FORMULATIONS
BLF
BLF1
BLF2
In BLF 2, Carbopol concentration was slightly increased and Sodium
alginate concentration was slightly decreased, subjected to invitro
dissolution studies and invitro buoyancy studies. Drug release was found to
be increased up to 94% and floating lag time was decreased to 29 minutes,
which is encouraging compared to that of previous BLF and BLF1
formulations.
29 minutes of floating lag time is bit high in floating drug delivery
systems which may result in the dosage form to get emptied from stomach
to the intestine region, but the presence of Carbopol 934 in the Bilayered
formulation due to its bio adhesive nature, it may assist the dosage form to
adhere to the gastric lining there by blocking the possibility of bilayered
tablet from getting emptied to the intestine from stomach region.
Fig: 7.8 Comparative Drug Release Profiles of Valganciclovir Bilayered
Formulations BLF, BLF1, BLF2
291
0 10 20 30 40 50
GF1
GF2
GF3
GF4
GF5
GF6
GF7
GF8
BLF
BLF1
BLF2
BUOYANCY LAG TIME
Fig- 7.9 Buoyancy Lag Time Details of Gastric Layer Formulations and
Bilayered Formulation
7.3.10 ANALYSIS OF RELEASE DATA
Dissolution data of all the designed formulations were fitted to
popular model dependent approaches viz. Zero Order, First Order,
Higuchian Model, Erosion Model and Power Law (Korsemeyer Pappas Model)
in order to assess the drug release kinetics.
Time (Min)
292
0
0.5
1
1.5
2
2.5
0 5 10 15L
OG
% U
ND
ISSO
LV
ED
TIME (Hours)
REGRESSION PLOT-FIRST ORDER (CF1 - CF11)CF1
CF2
0
50
100
150
200
0 5 10 15
CU
MU
LATI
VE
DR
UG
R
ELEA
SE (
CD
R)
TIME
REGRESSION PLOT-ZERO ORDER (CF1 - CF11)
CF1
CF2
0
50
100
150
200
0 1 2 3 4
CU
MU
LA
TIV
E D
RU
G
RELEA
SE (
CD
R)
SQRT TIME
REGRESSION PLOT-HIGUCHIAN MODEL (CF1 - CF11)
CF1
CF2
REGRESSION PLOTS OF CONTROLLED RELEASE FORMULATIONS
Fig: 7.10 Regression Plots of Valganciclovir
Controlled Release Formulations (C1-C11)
REGRESSION PLOTS –
CONTROLLED RELEASE FORMULATION
(CF1 TO CF11)
0
2
4
6
8
10
12
0 5 10 15
1-[
1-Q
]1/
3
TIME (hrs)
REGRESSION PLOT- EROSION MODEL(CF1 - CF11)
CF1
CF2
CF3
CF4
CF5
CF6
0
0.5
1
1.5
2
2.5
0 0.5 1 1.5
LO
G C
DR
LOG TIME
REGRESSION PLOT-POWER LAW (CF1 - CF11)
CF1
CF2
Table – 7.16 Relative Regression Coefficient Values of
Valganciclovir Controlled Release Formulations (CF1-CF11)
CONTROLLED
FORMULATIONS
ZERO
ORDER
(r)
FIRST
ORDER
(r)
HIGUCHI
(r)
EROSION
(r)
POWER LAW
(n)
CF1 0.913 0.854 0.969 0.405 0.635
CF2 0.924 0.825 0.953 0.387 0.729
CF3 0.841 0.632 0.931 0.414 0.590
CF4 0.955 0.604 0.872 0.407 0.556
CF5 0.826 0.603 0.811 0.489 0.661
CF6 0.932 0.711 0.929 0.305 0.596
CF7 0.881 0.807 0.890 0.386 0.702
CF8 0.939 0.876 0.977 0.280 0.568
CF9 0.948 0.864 0.935 0.375 1.635
CF10 0.952 0.722 0.979 0.455 0.626
CF11 0.943 0.897 0.911 0.421 0.723
294
REGRESSION PLOTS OF GASTRIC LAYER FORMULATIONS
Fig : 7.11 Regression Plots of Valganciclovir Gastric Layer
Formulations (GF1-GF8)
REGRESSION PLOTS –
GASTRIC LAYER FORMULATION
(GF1 TO GF8)
Table 7.17: Relative Regression Coefficient Values of
0
20
40
60
80
100
120
0 5 10 15
CU
MU
LA
TIV
E D
RU
G
RELEA
SE(C
DR
)
TIME(Hours)
REGRESSION PLOT-ZERO ORDER (GF1 - GF8)
GF1
GF2
0
0.5
1
1.5
2
2.5
0 5 10 15
LO
G%
UN
DIS
SOLV
ED
TIME(Hours)
REGRESSION PLOT-FIRST ORDER (GF1 - GF8)
GF1
GF2
-20
0
20
40
60
80
100
120
0 1 2 3 4CU
MU
LATI
VE
DR
UG
REL
EASE
(C
DR
)
SQRT TIME
REGRESSION PLOT-HIGUCHIAN MODEL
(GF1 - GF8)GF1
GF2
GF3 0
1
2
3
4
5
6
7
0 5 10 15
1-[
1-Q
]1/
3
TIME(Hours)
REGRESSION PLOT-EROSION MODEL (GF1 - GF8)
GF1
GF2
GF3
GF4
GF5
GF6
GF7
0
0.5
1
1.5
2
2.5
0 0.5 1 1.5
LO
G %
DR
UG
RELEA
SE
LOG TIME
REGRESSION PLOT- POWER LAW(GF1 - GF8)
GF1
GF2
GF3
295
Valganciclovir Gastric Layer Formulations (GF1-GF8)
GASTRIC LAYER
FORMULATIONS
ZERO
ORDER
(r)
FIRST
ORDER
(r)
HIGUCHI
(r)
EROSION
(r)
POWER LAW
(n)
GF1 0.960 0.982 0.989 0.581 0.645
GF2 0.944 0.985 0.995 0.530 0.562
GF3 0.968 0.960 0.961 0.560 0.575
GF4 0.932 0.910 0.994 0.932 0.623
GF5 0.932 0.918 0.987 0.520 0.525
GF6 0.893 0.935 0.972 0.497 0.515
GF7 0.920 0.976 0.994 0.520 0.532
GF8 0.925 0.983 0.995 0.511 0.584
Table -7.18 Relative Regression Coefficient Values of
Valganciclovir Bilayered Formulations
BILAYERED
FORMULATION
ZERO
ORDER
(r)
FIRST
ORDER
(r)
HIGUCHI
(r)
EROSION
(r)
POWER LAW
(n)
BLF 0.901 0.766 0.990 0.380 0.532
BLF1 0.919 0.754 0.997 0.500 0.560
BLF2 0.923 0.760 0.985 0.512 0.581
All the formulations were found to have following typical Zero
order kinetics which was clearly indicated by their relatively higher ―r‖
values compared to that of First order regression co efficient values.
All the formulations were found to be accepting Higuchian
diffusion as release model, indicated by their relatively higher ―r‖
values compared to that of Erosion model regression coefficient
values.
296
The dissolution data of all formulations were fitted to the Power
law (Korsemeyer Pappas model) and the entire exponent ―n‖ values
were found to be between 0.5-1, indicating that all the formulations
were following Non-Fickian mode of drug release.
7.3.11 Drug – Excipient Compatibility Study by IR and DSC
7.3.11.1 FTIR Spectroscopic Studies of Optimized Bilayered
Tablets of Valganciclovir
Infrared spectroscopy is a successful analytical technique being
employed to check if any the chemical interactions occur between the
drug and the other excipients used in the formulations.
IR spectra of pure drug, optimized polymers, physical mixture of
optimized formulation and optimized bilayered tablet formulation were
shown in Fig: 7.12, 7.13, 7.14, 7.15, 7.16, 7.17 and 7.18 respectively
Fig: 7.12 IR Spectrum of Valganciclovir Pure Drug
297
Fig: 7.13 IR Spectrum of Eudragit RL 100
Fig: 7.14 IR Spectrum of Eudragit RS 100
298
Fig: 7.15 IR Spectrum of Carbopol 934
Fig: 7.16 IR Spectrum of HPMC K4M
299
Fig: 7.17 IR Spectrum of Drug + Polymer(S) - Physical Mixture
Fig: 7.18 IR Spectrum of Drug + Polymer(S) - Optimized Bilayered
Tablet Formulation
300
By carrying out drug and polymer compatibility studies, it was
assessed and concluded that that there was no interaction between
the drug and polymer, as the principle peaks of the drug were found
to be unaltered and the respective regions of the IR spectra .
7.3.11.2 Differential Scanning Calorimetric (DSC) Studies of
Optimized Bilayered Tablets of Valganciclovir
DSC is an advanced technique by which the heat flows to or
from a reference, which is monitored as a function of temperature or
time, while the samples are subjected to a controlled temperature
program.
Lopinavir+ Ritonavir, Optimized Polymer (Geleol Pastilles+
Myrj52), Physical mixture of Lopinavir+ Ritonavir + Optimized
Polymer( Geleol Pastilles+ Myrj52, Optimized formulation of Lopinavir+
Ritonavir + Optimized Polymer( Geleol Pastilles+ Myrj52 )formulations
were subjected to DSC studies to check the compatibility among
them.
DSC Thermograms of pure drug, pure optimized polymers,
optimized formulation physical mixture and optimized bilayered Tablet
formulation were shown in Fig: 7.19, 7.20, 7.21, 7.22, 7.23, 7.24 and
7.25 respectively
Fig : 7.19 DSC Thermogram of Valganciclovir Pure Drug
301
Fig: 7.20 DSC Thermogram of HPMC K4M
Fig: 7.21 DSC Thermogram of Carbapol 934
302
Fig: 7.22 DSC Thermogram of Eudragit RS-100
Fig: 7.23 DSC Thermogram of Eudragit RL-100
303
Fig: 7.24 DSC Thermogram of Optimized Valganciclovir
Formulation Physical Mixture
Fig : 7.25 DSC Thermogram of Optimized Bilayered Tablet
Formulation BF 2
304
7.3.12 Moisture uptake studies of Optimized Bilayered Tablets of
Valganciclovir
Optimized GRF Bilayered tablets of Valganciclovir which were
formulated in different combination and proportions of various polymers
were exposed to different relative humidity (RH) conditions. Comparatively
less moisture uptake was observed in both granules and tablets at 33 % RH
and higher moisture uptake was observed at above 90 % RH. The moisture
uptake by granules and tablets was proportional to that of percent relative
humidity (RH). Due to larger surface area the moisture uptake of granules
was found to be more than tablets (Table 7.19 and Fig 7.26) and later on
after certain time period equilibrium moisture was attained.
Table 7.19 Percent of moisture uptake of Valganciclovir Granules and
Bilayered Tablets Formulation BLF 2
% Humidity Moisture uptake in % w/w
Time 24 Hrs 48Hrs 72 Hrs 96 Hrs 120 Hrs
Granules
33% 0 0.027 0.033 0.045 0.046
54% 0.208 0.32 0.341 0.365 0.365
90% 1.551 1.863 1.982 2.113 2.125
Bilayered
Tablets
33% 0.009 0.012 0.023 0.031 0.039
54% 0.117 0.224 0.256 0.262 0.269
90% 1.145 1.206 1.262 1.291 1.336
305
The results of moisture uptake study reveals and give an idea
about assigning proper storage condition for granules and final
formulation during the manufacturing and further usage.
Fig. 7.26 Percent Moisture Uptake vs. Time Plots of Bilayered
Tablets of Valganciclovir
(G is granules at 33% RH, G is granules at 54% RH, G granules
at 90 % RH, T is tablets at 33 % RH , T is tablets at 54% RH and
T tablets at 90 % RH)
7.3.13 Accelerated Stability Studies of Optimized Bilayered
Tablets of Valganciclovir
Percent assay and dissolution rate of accelerated stability
studies subjected samples at 1, 2, and 3 months of optimized
Valganciclovir bilayered GRF formulation BLF2 had shown
satisfactory results. The similarity factor (f-2) was calculated (Table
7.20) and compared to initial dissolution and it was found to be more
than 77. The comparative dissolution profile plots of stability samples
0
0.5
1
1.5
2
2.5
0 50 100 150
% M
ois
ture
Up
take
Time (Hours)
Moisture Absorption Studies
G-33% RH
G-54% RH
G-90% RH
T-33% RH
T-54% RH
T-90% RH
306
have shown good correlation with initial samples. (Fig 7.27) indicating
the stable nature of the optimized Valganciclovir bilayered GRF
formulation (BLF 2).
7.20 Dissolution and Assay of Bilayered Tablets of Valganciclovir
During Stability (n=3)
Time Stavudine Multi Unit GRFDDS Formulation F-7
0 M 1 M 2 M 3M
2 48.74±0.73 47.63(±1.9) 47.20(±3.1) 47.26(±2.8)
6 69.61±1.32 69.29(±1.1) 67.25(±3.6) 68.19(±2.3)
8 78.76±0.11
79.21(±1.1) 79.41(±2.7) 78.22(±2.7)
10 86.53±0.36
85.16(±2.1) 86.12(±1.1) 85.41(±1.1)
12 91.38±0.51
92.38(±3.1) 92.73(±1.1) 93.61(±3.1)
f-2 - 78(±2.6) 80(±2.2) 79(±1.1)
Assay 99.21 99.56 99.63 100
f-2- similarity factor
Fig. 7.27 Comparative Cumulative Percent Released vs. Time
Plots of Bilayered Tablets of Valganciclovir-
Initial, 1, 2 and 3 months at 40°C/75% RH
0
20
40
60
80
100
0 5 10 15
C%
CD
R
Time (Hours)
Accelerated Stability Studies
BF2- Initial (0 Months)
"BF2- 1 Month @ 40oC / 75% RH
"BF2- 2 Month @ 40oC / 75% RH
"BF2- 3 Months @ 40oC / 75% RH
307
7.3.14 Scanning Electron Microscopy (SEM) Studies
Scanning electron microscopy studies of the present
Valganciclovir BGF tablet formulation was mainly carried out for the
examining the surface of polymeric drug delivery system which may
provide important information about the porosity and microstructure
of the device.
Fig No- 7.28 Scanning Electron Microscope Photographs of
Optimized Valganciclovir Formulation
500 X ( Dry Surface) 500 X ( 4 Hours Swelling)
500 X ( 6 Hours Swelling) 500 X ( 12 Hours Swelling)
From the SEM studies, it was observed that as the time
increases the swelling ability and the porosity of the tablet was found
to be increased, which mainly helps to drug to release from the
bilayered tablet formulation at rate effective and controlled manner.