DESIGN AND EVALUATION OF GUANFACINE EXTENDED RELEASE FORMULATION

Abstract

Objective: The present study was aimed to develop of the Guanfacine Hydrochloride Extended-release tablets for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). The dosage regimen of Guanfacine Hydrochloride is 4 mg at every 6 h. The concentration of Guanfacine in plasma is fluctuating. Hence, to control the plasma fluctuation and to avoid toxicity problem, Guanfacine Hydrochloride was chosen as a drug with an aim to develop an extended release system for 20 to 24 h. Methods: The design of the system was based on the use of pH-dependent polymer (Hydroxypropyl Methyl Cellulose), pH-independent polymer (Eudragit L 100-55), along with microenvironment modifiers such as organic acid (Fumaric acid) were used in the formulation. Drug-excipient compatibility was studied by FTIR. Before compression, the granules were evaluated for precompression parameters such as bulk density, tapped density, an angle of repose, compressibility index and Hausner’s ratio. After compression, evaluation tests of tablets such as general appearance, hardness, thickness, weight variation, friability, content uniformity, in vitro release studies and stability studies were performed. Results: Out of 9 formulations, the drug release was found to be within the innovator formulation F9. The stability study of formulation F9 revealed there was no significant change in physical and chemical properties of drug stored at 40 °C/75 % RH, 30 °C/65 % RH, 25 °C/60 % RH for 2 mo. Conclusion: Optimized formulation batch F9 showed highest F2 value which indicates similarity with innovator product. The study indicates that Guanfacine Hydrochloride Extended-release tablet was successfully developed.

Full text

Original Article
DESIGN AND EVALUATION OF GUANFACINE EXTENDED RELEASE FORMULATION
*SANJEEVANI DESAI1, DURGACHARAN BHAGWAT2, SUNITA SHINDE1, JOHN DISOUZA1
1Tatyasaheb Kore College of Pharmacy, Warananagar, 416113, Maharashtra, India. 2
Received: 31 Oct 2018, Revised and Accepted: 30 Jan 2019
Bharati Vidyapeeth College of Pharmacy, Kolhapur,
Maharashtra, India.
Email: srdesai.tkcp@gmail.com
ABSTRACT
Objective: The present study was aimed to develop of the Guanfacine Hydrochloride Extended-release tablets for the treatment of Attention Deficit
Hyperactivity Disorder (ADHD). The dosage regimen of Guanfacine Hydrochloride is 4 mg at every 6 h. The concentration of Guanfacine in plasma is
fluctuating. Hence, to control the plasma fluctuation and to avoid toxicity problem, Guanfacine Hydrochloride was chosen as a drug with an aim to
develop an extended release system for 20 to 24 h.
Methods: The design of the system was based on the use of pH-dependent polymer (Hydroxypropyl Methyl Cellulose), pH-independent polymer
(Eudragit L 100-55), along with microenvironment modifiers such as organic acid (Fumaric acid) were used in the formulation. Drug-excipient
compatibility was studied by FTIR. Before compression, the granules were evaluated for precompression parameters such as bulk density, tapped
density, an angle of repose, compressibility index and Hausner’s ratio. After compression, evaluation tests of tablets such as general appearance,
hardness, thickness, weight variation, friability, content uniformity, in vitro release studies and stability studies were performed.
Results: Out of 9 formulations, the drug release was found to be within the innovator formulation F9. The stability study of formulation F9 revealed
there was no significant change in physical and chemical properties of drug stored at 40 °C/75 % RH, 30 °C/65 % RH, 25 °C/60 % RH for 2 mo.
Conclusion: Optimized formulation batch F9 showed highest F2 value which indicates similarity with innovator product. The study indicates that
Guanfacine Hydrochloride Extended-release tablet was successfully developed.
Keywords: Extended-release, Solubility, pH-dependent polymer, In vitro study
© 2019 The Authors. Published by I nnovare Academic Sciences Pvt Ltd. This is an open-ac cess article u nder the CC BY license (http://creativeco mmons.org /licenses /by/4.0/)
DOI: http://dx.doi.org/10.22 159/ijap.2019v11i3.30578
INTRODUCTION
Oral drug delivery has been known for decades as the most widely
utilized route of administration for delivery of drugs via different
dosage forms due to its ease of administration, high patient
compliance and flexibility in the desi gn of dosage form. The goal of
any drug delivery system is to provide a therapeutic amount of drug
to proper site in the body to achieve promptly and then maintain,
the desired drug concentration. The design of a proper dosage
regimen is an important element in accomplishing this goal [1, 2].
Conventional oral drug delivery systems are slowly fading away
in the market owing to disadvantages. These delivery systems
produce fluctuation of drug plasma level that either exists at a
safe therapeutic level or quickly falls below the minimum
effective level. This effect is usually totally dependent on the
particular agent’s biological half-life, the frequency of
administration and release rate. It is recognized that many
patients can benefit from drugs intended for chronic
administration by maintaining the plasma level within a safe
effective range [3]. Extended oral drug delivery systems are
highly recognized today for their benefits, improving the
disadvantages of conventional drug delivery systems.
To be a successful, extended-release [ER] products the drug must be
released from the dosage from at a predetermined rate in
gastrointestinal fluids, maintain sufficient gastrointestinal residence
time and be absorbed at a rate that will replace the amount of drug
being metabolized and excreted. Extended drug delivery systems are
used in the treatment of chronic rather than the acute condition, and
they process a good margin of safety [4-6].
While psychostimulant medications have large effect sizes for
treatment of attention-deficit/hyperactivity disorder (ADHD)
symptoms. Guanfacine is a selective alpha2-agonist that shares some
pharmacological properties with the non-selective alpha2-agonist
clonidine [7].
The aim of this research work was to formulate guanfacine
hydrochloride (HCl) ER tablet which delivered drug for 24 h.
MATERIALS AND METHODS
Materials
Guanfacine HCl was supplied by Intas Pharmaceutical. H. P. M. C,
Methacrylic Acid (Eudragit L100-55), Microcrystalline Cellulose PH-
102, Lactose Monohydrate, Fumaric Acid, Glyceryl Behenate, Lake Of
Indigo Carmine, Ferric Oxide Yellow from Evonik Signet Chemical
Corporation Pvt. Ltd. Industries, Mumbai. All other chemicals used
were of analytical grade.
Methods
Preformulation study
Organoleptic properties
The drug samples were evaluated for its colour, odour, taste and
appearance. The result was mentioned in table 3.
Melting point
The melting point was determined by the melting point apparatus.
The temperature at which drug melted was recorded the result was
mentioned in table 3.
Solubility
For the determination of solubility, an excess amount of drug was
added in the solvent (water, 0.1N HCl, Acetate buffer pH 4.5,
Phosphate Buffer pH 6.8) at room temperature and kept for 48 h
with occasional shaking. The supernatant was taken and analyzed by
using Shimadzu UV 1800 double beam spectrophotometer. The
results were mentioned in table 4.
Differential scanning calorimetry (DSC)
The DSC study was carried out for the obtained sample of guanfacine
HCl to confirm its purity. The DSC patterns were recorded on a
METTLER TOLEDO STARe System. 1.5 mg of drug was heated in
crimped aluminium pans at a scanning rate of 400 °C/min in an
atmosphere of nitrogen gas flow 40 ml/min using the range of 40-
350 °C. The DSC curve was shown in fig. 1.
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Int J App Pharm, Vol 11, Issue 3, 2019, 43-48
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Formulation development
The primary aim of this development work was to produce a stable
and bioequivalent formulation as compare to that of reference
formulation. The formulation development work was undertaken
considering the following approaches [8-11].
Direct compression
The range of concentration of release modifier was also based on
the patent of the innovator’s product. i.e. Concentration of
hydroxypropyl methylcellulose (HPMC) as shown in the
following table.
Table 1: Batch formula
S. No.
Ingredients
Batch codes (Quantity in mg/tab)
F1
F2
F3
F4
F5
F6
F7
F8
F9
1.
Guanfacine HCl
4.59
4.59
4.59
4.59
4.59
4.59
4.59
4.59
4.59
2.
Microcrystalline cellulose
50
82
38.21
38.21
47.21
47.21
41.21
75.21
41.2
3.
Methacrylic acid
60
40
60
60
65
70
70
70
70
4.
HPMC
49
55
60
60
35
30
30
30
30
5.
Lactose monohydrate
52.20
52.20
57
57
49
49
-
-
-
6.
Lake of Indigo Carmine
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
7.
Ferric oxide yellow
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
8.
Fumaric acid
10
12
13
13
18
18
-
18
18
9.
Glyceryl behenate
36
20
26
26
40
40
40
26
40
10.
Ludipress
-
-
-
-
-
-
60
50
40
Compatibility study of drugs with Excipients
FTIR
FTIR spectra of pure drug and conventional and ready base
approach formulations of these excipients with the drug were
recorded on Agilent FTIR spectrophotometer. The instrument was
operated under dry air purge and the scans were collected with a
resolution of 4 cm-1 over the region 4000-650 cm-1.
Evaluation of granules
Bulk density
Bulk Density is the ratio of the weight of powder to the volume it
occupies. It is expressed as g/ml.
Flow property
Compressibility is indirectly related to the relative flow rate,
cohesiveness and particle size distribution of the powder. Tapped
and untapped bulk density measurements can estimate the
compressibility of a material
Selection of dissolution media
Dissolution media was selected based on the dissolution database
published in literature available and based on the solubility and
stability of the dosage form and considering the intended use of
the dosage form. The HCl Buffer pH 2.2, Acetate Buffer pH 4.5,
Phosphate Buffer pH 6.8 media were selected for dissolution
profile.
Characterization of an innovator product
Physical characterization
The reference product for guanfacine HCl is INTUNIV Tablets
manufactured by Shire Inc. The developmental work was done
considering innovator product i.e. INTUNIV 4 mg Tablets. The
physical characteristics of the INTUNIV 4 mg Tablets are given in.
Table 2: Product details of intuniv 4 mg
S. No. Description Intuniv 4 mg tablet
1
Name of Product
Intuniv Tablets 4 mg
2
Label Claim
Contains Guanfacine HCl eq. to 4 mg of Guanfacine
4
Manufactured By
Shire US Inc, Wayne, PA 19087, Made in USA
5
Market
US
6
Dosage form details
6.1
Dosage form
ER Tablet
6.2
Shape
Capsule-shaped, Biconvax
6.3
Color
Green
6.4
Size (Length X Width)
12.31 X 6.10 mm
6.5
Thickness
4.15 mm
6.6
Average weight
268 mg
Comparison of dissolution profiles for selection of optimized batch
The similarity factor (f2) given by SUPAC guidelines for a modified
release dosage form was used as a basis to compare dissolution
profiles. The dissolution profiles are considered to be similar when
f2 is between 50 and 100. The dissolution profile of products were
compared using a f2 which is calculated from the following formula,
Where n is the dissolution time and Rt and Tt are the reference (here
is the theoretical dissolution profile of guanfacine HCl) and test
dissolution value at time t48. All Factorial design batches (F1 to F8)
were compared with the theoretical profile for calculati on of
similarity factor.
Stability study
The stability study is performed to check the physical-chemical
integrity of the product. For performing the stability study storage
condition was determined based on ICH Guidelines. The selected F9
batch was subjected to stability study [12-15].
RESULTS AND DISCUSSION
Preformulation study
The received samples were identified by various tests. The results
are as shown below.

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45
Table 3: Organoleptic properties of guanfacine HCl
S. No.
Organoleptic properties
Observations
Specification
1.
Colour
White or off white
White or off white
2.
Odour
Odourless
Odourless
3.
Description
Crystalline powder
Crystalline powder
4.
Melting Point
226 °C
225 °C-227 °C
Table 4: Solubility profile of guanfacine HCl
S. No.
pH solubility profile
Solubility (mg/ml)
1
Water
0.163
2
0.1 N HCl
0.420
3
Acetate buffer pH 4.5
1.265
4
Phosphate buffer pH 6.8
1.302
Based on Organoleptic properties and solubility studied drug was
characterized for the above parameters which were found to be
similar and complies with the standard specification. Hence the
guanfacine HCl was identified and considered to be pure.
Fig. 1: DSC thermogram of guanfacine HCl
Differential scanning calorimetry (DSC)
The DSC spectrum of guanfacine HCl was obtained and is given in fig.
1. Drug shows Sharp melting endotherm at 225 °C, which is the
melting point of the drug.
Thermal analysis showed a characteristic sharp endothermic peck at
225.67 °C indicating the melting point of the drug. The fact
confirmed the obtained drug was pure and in crystalline form.
Analytical methods
UV spectroscopy
Calibration curves of guanfacine HCl were carried out in different
media like methanol, 0.1 N HCl and Phosphate buffer pH 6.8
Calibration curve in Methanol, 0.1N HCl and Phosphate buffer pH 6.8
were found to be linear having R2 value 0.9992, 0.9907, 0.9992
respectively as shown in fig. 2.
FTIR compatibility study
To check the interaction between drug and excipients used in the
formulations, FTIR studies were performed.
These peaks were not affected and prominently observed in FTIR
spectra given in fig. 3 Thus, we can say that there was no significant
interaction between drug and excipients were observed.
Fig. 2: Calibration curve in Methanol, 0.1N HCl, Phosphate buffer pH 6.8

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Fig. 3: FTIR spectrum of drug and physical mixture
Table 5: Physical evaluation of granulation batches
Batch code
F1
F2
F3
F4
F5
F6
F7
F8
F9
Bulk density (g/ml)
0.428
0.457
0.604
0.667
0.646
0.626
0.410
0.528
0.475
Tap density (g/ml)
0.545
0.592
0.760
0.771
0.729
0.724
0.508
0.624
0.552
Carr’s Index (%)
21.46
22.80
20.54
13.48
13.02
13.52
19.29
15.31
13.92
Hausner’s Ratio
1.27
1.29
1.25
1.15
1.12
1.15
1.23
1.18
1.16
Evaluation of granules
Physical Evaluation of granulation batches was indicated in table 5.
The Carr’s Index and Hausner’s Ratio was indicated blend showed
good physical property and did not show any issue regarding weight
variation and indicates that direct compression method was
suitable.
Formulation development
Physical characteristics
Physical characteristics data such as average weight, hardness,
thickness, assay, friability were mentioned in table 6. Results
revealed that assay has a more significant effect on the dissolution
profile of guanfacine HCl ER formulation.
Table 6: Physical evaluation of tablet
Physical parameter
Batches
Average Weight (mg)
Hardness (N)
Thickness (mm)
Friability (%)
Assay (%)
F1
265
10±6.05
4.30-4.40
0.89±0.011
85.50
F2
265
50±7.8
4.60-4.70
0.65±0.012
92
F3
260
90±2.25
4.35-4.45
0.213±0.018
79.82
F4
260
110±2.06
4.45-4.55
Nil
89
F5
260
100±2.54
4.45-4.55
0.132±0.018
99
F6
265
110±3.05
4.20-4.30
0.215±0.021
98.5
F7
267.20
100±6.52
4.40-4.50
0.220±0.017
99.66
F8
265
110±7.52
4.45-4.465
0.154±0.022
99.2
F9
265
110±6.22
4.36-4.42
0.142±0.025
98.4
Dissolution study
Dissolution Profile of Intuniv tablet 4 mg. (innovator) was carried
out in a different solvent. Comparative study were carries out
between formulated batches F1-F9 and Intuniv tablet. From the
above result, it was observed that Intuniv 4 mg tablet showed
more release in a phosphate buffer solution having pH 6.8 The
above-mentioned results of F1-F9 batch % cumulative drug
released in 6.8 pH phosphate buffer with USP apparatus type II
indicates F1-F3 batch showed less released after 24 h compared to
remaining batches. Batch F9 showed good similarity with the
innovator product.
Statistical treatment of dissolution data
The values of similarity factor (f2) for the batch F9 showed
maximum f2 value 85.42 as shown in table 7.
Hence, formulation batch F9 was considered as an optimum batch.

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Fig. 4: Dissolution profile of intuniv 4 mg tablet
Fig. 5: Dissolution profile of intuniv 4 mg tablets and F1-F9 batch
Table 7: Similarity factor (f2) for F1-F9
Batch
F1
F2
F3
F4
F5
F6
F7
F8
F9
Similarity Factor
40.5
46.75
33.1
51.02
59.37
67.97
74.24
71.87
85.42
Table 8: Stability evaluation of optimized batches
Batch No.
F9
Test
Condition
40 °C/75 % RH
30 °C/65 % RH
25 °C/60 % RH
Initial
1 Mo
2 Mo
1 Mo
2 Mo
1 Mo
2 Mo
Description
Light Green Oval Shaped
Assay
99.5 %
98.9 %
99 %
98.2 %
99.4%
99.3%
99.2%
Hardness
90 N
82 N
85 N
80 N
86 N
90 N
87 N
Avg. Wt. (mg)
265
264. 8
264.8
265
265
265
265
Time (Hrs)
% DR in Phosphate 6.8
1
9.21
8.56
7.98
8.41
7.64
8.47
8.1
4
34.42
37.52
38.24
36.45
39.14
38.42
37.2
8
64.22
66.41
62.45
63.25
65.12
61.45
69.75
12
84.65
86.14
82.14
84.12
81.85
85.45
86.58
18
91.56
92.45
94.12
90.12
91.46
92.84
92.56
24
96.14
97.12
97.52
95.6
96.42
97.46
96.12
Stability study
Stability study of optimized batch F9 was carried out and results as
shown in table 8.
The above table shows that there was no considerable changes in
appearance, physical parameter and chemical parameters of the
formulation after stability study. From observed results, it was
stated that the prepared tablet was found to be stable.
CONCLUSION
The focus of the current study was to develop the extended-release
tablet of guanfacine HCl using a direct compression method. In this
developed formulation pH-dependent and pH-independent
polymers such as Hydroxy Propyl methylcellulose and Eudragit
L100–55 were utilized to prepare matrix tablets.
Incompatibility study IR, it was observed that the drug was in pure
form and there were no major interactions with other polymers. The
in vitro dissolution study revealed that the batch F9 was best among
nine batches been prepared and showed a similar release pattern
with innovator product. Stability study of the optimized batch was
carried out at 40 °C/75 % RH, 30 °C/65 % RH, 25 °C/60 % RH. It
was found that there was no statistically significant difference in in
vitro drug release before and after stability study. Thus, from the
above conclusion, it is summarized that the formulation and
evaluation of guanfacine HCl extended-release tablet was
successfully prepared by using a direct compression method.
AUTHORS CONTRIBUTIONS
All the author have contributed equally
CONFLICT OF INTERESTS
Declared none
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