Indo American Journal of Pharmaceutical Research, 2016
ISSN NO: 2231-6876
FORMULATION AND EVALUATION OF ATOMOXETINE HCL SUSTAINED RELEASE TABLETS P. Sambasiva Rao*, R. Naresh Babu, G. Srinivasa Rao Vijaya College of Pharmacy, Hayath Nagar-501511, Telangana, India. Nirmala College of Pharmacy, Atmakuru-522503, Andhra.Pradesh., India. Research and development Formulations, Hetero Labs Ltd, Jeedimetla-5000055, Telangana, India. ARTICLE INFO ABSTRACT Atomoxetine hydrochloride was formulated as sustained release tablet employing tamarind Article history Received 14/05/2016 seed polysaccharide, Guar gum, PVP, magnesium stearate, micro crystalline cellulose the Available online sustained release tablets were investigated. The Sustained release matrix tablets contain 10/07/2016 atomoxetine hydrochloride were developed using a different drug polymer concentration of tamarind seed polysaccharide, guar gum. The tablets were prepared by directly using micro crystalline cellulose. The formulation was optimized on the basis of acceptable tablet Keywords Atomoxetine, properties and in-vitro drug release. The resulting formulation produced robust tablets with Sustained Release, optimum hardness, thickness consistent weight uniformity and low friability. All tablets but Guar Gum, one exhibited gradual and near completion sustained release for atomoxetine hydrochloride PVP, and 98.6% and 97.5 released at the end of 12 hrs. The results of dissolution studies indicated Magnesium Stearate, that formulation F8, the most successful of the study. The results suggest that the developed Micro Crystalline Cellulose. sustained release tablets of atomoxetine hcl could perform better than conventional dosage forms, leading to improved efficacy and better patient compliance.
Copy right © 2016 This is an Open Access article distributed under the terms of the Indo American journal of Pharmaceutical Research, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Please cite this article in press as P. Sambasiva Rao et al. Formulation and Evaluation of Atomoxetine HCL Sustained Release Tablets. Indo American Journal of Pharmaceutical Research.2016:6(06).
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Corresponding author P. Sambasiva Rao Associate Professor, Vijaya College of Pharmacy, Hayath Nagar-501511, Telangana, India.
[email protected] 09492686832
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INTRODUCTION Sustained release technology is a relatively new field and as a consequence, research in the field has been extremely fertile and has produced many discoveries. New and more sophisticated sustained release drug delivery system constantly being developed and tested. The oral route of administration of sustained release systems has received greater attention because of more flexibility in dosage form design. The design of oral sustained release delivery systems is subjected to several interrelated variables of considerable importance, such as the type of delivery system, the disease being treated, the patient, the length of therapy and the properties of the drug [1]. The pharmaceutical dosage forms having several approaches are available to include the loading of a drug to the maintenance dose of a drug for sustained action [2]. Atomoxetine was a norepinephrine reuptake inhibitor and it is used for the treatment of attention deficit hyperactivity disorder (ADHD) [3]. Atomoxetine selective inhibition of the pre-synaptic transporter, as determined through in-vitro studies. Solid dosage forms and capsules are most popular and preferred drug delivery system because they have a high patient compliance. Many patients find difficult to swallow tablet and hard gelatin capsule, consequently they do not take medication as prescribed. It is estimated that 50% of the population are affected by this problem which result the high incidence of non‐compliance and ineffective therapy. The difficulty is experienced in particular by pediatric and geriatric patients, but it is applicable to people who are ill in bed and those active working patients who are busy or traveling, mentally ill, developmentally disable and patients who are uncooperative. To overcome this problem fast dissolving tablet is prepared. On the basis of these considerations, the present study was an attempt to formulate and evaluation of atomoxetine hydrochloride sustained release to increase its bioavailability. EXPERIMENTAL Materials Atomoxetine hydrochloride was a gift sample from MSN Labs (Hyderabad, India). All of the chemicals used for analytical grade. Methods Preparation of matrix tablets of atomoxetine hcl: The atomoxetine hcl sustained release tablets were prepared by direct compression method. Different concentrations of TSP and MCC for F1 to F6 and Guar gum for F7 to F12 were used. TSP used as matrix forming material, MCC used as diluent. Magnesium state incorporated as a lubricant. All ingredients passed through a # 100 sieve, weighed and blended. The lubricated formulations were compressed using Rotary tablet machine with 12.00 mm flat punch. Tablet weight was (500mg) kept constant. Pre formulation studies: To study the compatibility of various formulation excipients with Atomoxetine hcl, solid mixtures were prepared by mixing the drug with each formulation excipient separately in the ration of 1:1 and it was filled enclosed vial sand placed instability chamber 0 at 30±2 C/65±5%RH. The solid admixtures were characterized using Fourier transform infrared spectroscopy (FT-IR). Development of analytical method of drug Determination of λ max of atomoxetine hcl in phosphate buffer pH 7.4: A solution of Atomoxetine hcl in phosphate buffer pH7.4 was scanned in UV range between 200 to 350 nm (LabIndiaUV1601 spectrophotometer, India). Atomoxetine hcl showed maximum absorbance at 274 nm in phosphate buffer pH7.4.
Tapped density 10 gms of powder were introduced into a clean, dry100 ml measuring cylinder. The cylinder was then tapped 100 Ts from a constant height and tapped volume was read. Compressibility index: The compressibility of the powder was determined by the Carris’s compressibility index.
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Evaluation Parameters[5-6] Pre compression parameters Bulk density It is the ratio of powder to bulk volume. The bulk density depends on particle size distribution, shape and the cohesiveness of particles. Accurately weighed quantity of powder was carefully poured into a graduated measuring cylinder through a large funnel and volume was measured which is called initial bulk volume.
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Calibration curve for atomoxetine hcl: Accurately weighed quantity of Atomoxetine hcl (50mg) was dissolved in phosphate buffer pH 7.4 in 50 ml volumetric flask (SSI). From SSI, 10ml solution was transferred to 50 ml volumetric flask and volume was made up with phosphate buffer pH 7.4 (SSII). From SSII, 10 ml solution was transferred to 50 ml volumetric flask and volume was made up with phosphate buffer pH 7.4 (SSIII). 1, 2, 3, 4 and 5ml from SSIII were transferred to 10 ml volumetric flasks and diluted up to the mark to give 5, 10, 15, 20 and 25 μg/ml solutions respectively. The absorbance of these solutions was determined in a UV spectrophotometer at 274 nm and calibration curve was plotted.
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Angle of repose It is the maximum angle possible between the surface of the pile of the powder and the horizontal plane. Post compression parameters: Thickness and diameter: Control of the physical dimension of the tablet such as thickness and diameter is essential for consumer acceptance and tablet uniformity. The thickness and diameter of the tablet were measured using Vernier calipers. It is measured in mm. Hardness: The monsanto hardness tester was used to measure the tablet hardness. Friability (F): Tablet strength was tested by Roche friabilator. Pre weighed tablets were allowed for 100 revolutions (4mint), taken out and were deducted. The percentage weight loss was calculated by rewriting the tablets. Weight variation: Randomly selected twenty tablets were weighed individually and together in a single pan balance. The average weight was noted and standard deviation calculated. Uniformity of drug content: Accurately weighed quantity of the powder, tablet equivalent to 100 mg of the drug was transferred to 100 ml volumetric flask. 50 ml of buffer solution of pH-7.4 was added. Mix with the aid of ultrasound for 10 min, and then the volume were made up to 100 ml with the same buffer solution, mixed solution was filtered through the membrane filter disc with an average pore diameter not greater than 0.45µm. 5ml of the filtrate was diluted to100 ml with same buffer solution and examined under U.V Spectrophotometry at 274 nm. FTIR study: FTIR spectra of the polymers were taken and compared with the spectrum of the pure drug. The characteristic peaks of the drug were checked in the polymer spectra. First, we determine the Spectroscopy of pure Atomoxetine Hcl. Swelling index: The swelling index of the dosage form is conducted by using the USP dissolution apparatus-I in 900 ml of pH 7.4 phosphate buffer which is maintained at 37±0.5°C, rotated at 50 rpm. At selected regular intervals, the tablet is withdrawn the excess water was blotted with tissue paper. Stability Studies o 0 Selected formulations were stored at different storage conditions at elevated temperatures such as 25 C±2 C/60%±5%RH, 0 0 0 0 30 C±2 C/65%±5%RH and 40 C± 2 /75%±5% RH for 90days. The samples were withdrawn at intervals of 15 days and checked for physical changes, hardness, friability, drug content and percentage drug release. RESULTS AND DISCUSSION Preformulation studies of pure drug Drug selection After oral administration, atomoxetine hcl is rapidly and completely absorbed as unchanged drug. Peak plasma concentrations are reached approximately 1.25 to 3.00 hr following ingestion. Atomoxetine hcl, where the concentration reaches approximately 57% of those in plasma. The volume of distribution is approximately 25 Lit
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Dosage form selection Classically simple matrix delivery systems exhibit first order or SQRT release kinetics. Matrix tablets are resistant to dose dumping. Due to the simple nature of the formulation and being robust they are unaffected by variations in ingredients. Matrix tablets containing hydrophilic polymers are common and commercially successful means of prolonging the oral drug delivery and hence patient compliance.
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Matrix tablets The objective of the present study is the formulation and in-vitro evaluation of matrix tablets of atomoxetine hcl using natural polymers. Atomoxetine hcl widely used in the anti depressant. TSP and guar gum used as a release retardant in the present research work. The retardant materials that are commonly used include hydrophilic and hydrophobic polymers. Hydrophilic polymers are becoming very popular in formulating oral sustained release tablets. As the fluid or media penetrates the matrix tablet, the polymer swells and drug diffuses from the system at a rate determined by the nature and composition of the polymer. Tablets were prepared by direct compression method with polymers, with compressible vehicles (micro crystalline cellulose), binder (PVPK30) and lubricants (Mg. Stearate) to improve compaction, flow and release properties of tablets. Melting point determination Melting point of Atomoxetine Hcl was found to be in the range of which is almost the standard value of indicate the purity of the drug sample. Drug - polymer compatibility studies 0 0 Drug excipients compatibility studies were carried out at an accelerating condition 30 C ± 2 C/60%±5%RH. A small quantity of each mixture was evaluated by FTIR with the control, the pure atomoxetine hcl and the excipient was studied. It was found that all peaks corresponding to different functional groups of pure drug were present in the polymers, this shows the absence of interaction between the drug and polymers. Post compression parameters The formulated tablets were subjected to post- compression evaluation such as thickness, hardness, weight variation, friability, drug content, swelling studies, and in vitro dissolution studies. Tablet thickness The results of thickness for formulated tablets were determined using a screw gauge and results are shown in Table 4. Hardness test The mean values of hardness of tablets are shown in Table 4. The hardness of all formulations was in the range of 5.6±0.13 to6.4±0.34 kg/cm2. Hardness test will be done by the Monsanto Hardness Tester. Friability test The friability values of prepared tablets are given in Table 4. The values ranged from 0.163± 0.13to0.549± 0.11 %. The punches used to compress the tablets were 12.08 mm, spherical shaped. The shape and size of the tablets were found to be within the 2 limit. The hardness of the tablets was found to be in the range of 5.6±0.13 to 6.4±0.34Kg/cm . It was within the range of monograph specification. Thickness of the tablets was found to be in the range of 3.74±0.03 to 3.96±1.6mm. The friability of the tablets was found to be less than 1% and it was within the range of standard specification Weight variation test Twenty tablets were randomly selected from each formulation and evaluated. The average weight of each formulation was recorded. The values were almost uniform. The average values of tablets ranged from 501.0 to 501.5mg. Swelling index The swelling index of the dosage form is conducted by using the USP dissolution apparatus-II in 900 ml of pH 7.4 phosphate buffer which is maintained at 37±0.5°C, rotated at 50rpm.
Stability studies There was no significant changes in drug content, physical stability, hardness, friability and drug release (Table 28-32) for the o 0 0 0 0 0 selected formulations F5 and F12 after 60 days at 25 C ± 2 C/60% ±5%RH, 30 C ±2 C/65%±5%RH and 40 C±2 /75%±5%RH. Therefore the main objective of the study to formulate and evaluate the matrix tablets of a atomoxetine hcl drug using TSP and Guar gum as a retardant were achieved.
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In- vitro dissolution studies In-vitro release studies were carried out for all the formulations as per USP-II tablet dissolution test employing a rotating paddle at 50 rpm using 900 ml of phosphate buffer of pH 7.4 as dissolution medium. The results were evaluated for 12hr. As per the results (Table 23,24) of dissolution study formulations F1, F2, F3, F4, F5, F6, F7, F8, F9, F10, F11 and F12 showed 98.62, 96.93, 98.43, 97.68, 98.06, 94.12, 97.87, 99.43, 97.12, 98.50, 96.68 and 97.5 % respectively. This showed that the drug release from the tablet was sustained for 4 to 12 hr. F1 with 10% TSP and F7 with Guar gum as retardant showed 98.62 % and 97.87% release within 5hr. Whereas in formulation F5 with 30%TSP and F12 with 35% guar gum as a retardant showed 98.06% and 97.5% release upto12hr.
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Figure 1: Fourier transform infrared spectra of atomoxetine hydrochloride.
Figure 2: Calibration curve of atomoxetine hcl in phosphate buffer solution (pH 7.4).
F1 100 50 − 222 25 03
F2 100 75 −− 197 25 03
F3 100 100 −− 172 25 03
F4 100 125 −− 147 25 03
F5 100 150 −− 122 25 03
F6 100 175 −− 97 25 03
F7 100 −− 50 222 25 03
F8 100 −− 75 197 25 03
F9 100 −− 100 172 25 03
F10 100 −− 125 147 25 03
F11 100 −− 150 122 25 03
F12 100 −− 175 97 25 03
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Ingredients Atomoxetine Hcl Tamarind seed polysaccharide Guar gum Microcrystalline cellulose PVP K 30(5%) Magnesium stearate
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Figure 3: In-vitro dissolution profile of F7 to F12 formulations. Table 1: Formulation of atomoxetine hydrochloride sustained release tablets.
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Table 2: Linearity data of atomoxetine hydrochloride. Concentration(µg/ml)
Absorbence
5 10 15 20 25
0.120 0.232 0.349 0.453 0.576
Table 3: Pre compression parameters of atomoxetine hydrochloride.
Formulation code F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12
Parameters Angle Of Repose 27.22± 1.6 27.15± 1.31 26.22± 1.58 29.45± 1.42 28.12± 1.57 25.90±1.22 24.10± 1.6 23.51± 1.31 27.97± 1.58 29.82± 1.42 28.96± 1.57 26.14±1.22
Bulk Density (g/ml) 0.495±0.004 0.495±0.004 0.470± 0.003 0.470±0.009 0.465± 0.006 0.465± 0.005 0.450± 0.005 0.495±0.004 0.470± 0.003 0.470±0.009 0.465± 0.006 0.465±0.004
Tapped Density (g/ml) 0.547± 0.019 0.555± 0.016 0.526± 0.012 0.520± 0.013 0.536± 0.014 0.512± 0.011 0.520± 0.013 0.512± 0.011 0.536± 0.014 0.526± 0.012 0.555± 0.016 0.547± 0.0018
Compressibility Index (%) 13.29± 0.75 12.10± 1.63 10.64± 1.33 13.40± 1.48 16.21± 0.78 15.16±1.35 13.10± 0.75 14.12± 1.63 12.64± 1.33 16.20± 1.48 15.21± 0.78 14.18± 1.35
Table 4: Post compression parameters of atomoxetine hydrochloride. Formulation code F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12
Thickness (mm) 3.88± 0.16 3.89± 0.18 3.85± 0.32 3.90± 0.03 3.93± 0.16 3.96± 0.14 3.91± 0.16 3.75± 1.31 3.77± 0.58 3.87± 1.42 3.76± 1.57 3.74± 1.22
Hardness (kg/) 5.8±0.10 6.0±0.24 5.7±0.14 5.9±0.12 6.3±0.35 6.2±0.13 6.2±0.25 6.0±0.34 5.9±0.15 6.3±0.44 5.6±0.13 6.4±0.34
Friability (%)(n=10) 0.163± 0.13 0.220± 0.41 0.320± 0.21 0.262± 0.12 0.420± 0.35 0.490± 0.21 0.341± 0.013 0.549± 0.11 0.269± 0.014 0.420± 0.012 0.368± 0.016 0.450± 0.010
F1 0 30.93 50.53 67.87 98.62 −− −− −− −− −− −− −− −−
F2 0 26.06 49.68 66 77.25 96.93 −− −− −− −− −− −− −−
F3 0 23.43 27.56 34.31 44.81 60.18 78.56 82.68 90.93 98.43 −− −− −−
F4 0 21.37 25.5 32.25 38.43 59.06 74.62 79.5 87.56 93.37 97.68 −− −−
F5 0 17.81 20.62 32.81 42.56 49.87 53.43 65.43 70.87 87.18 91.68 93.93 98.06
F6 0 17.81 25.68 32.43 38.25 48.18 61.12 70.31 79.12 83.43 87.18 90.93 94.12
F7 0 29.25 49.31 74.06 87.75 97.87 −− −− −− −− −− −− −−
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F8 0 28.31 48.37 72.93 77.25 95.43 −− −− −− −− −− −− −−
F9 0 27.75 36.93 44.06 53.62 65.62 87.56 97.12 −− −− −− −− −−
F10 0 25.68 32.25 35.81 45.75 54.75 69 86.25 93.18 98.50 −− −− −−
F11 0 22.31 33.18 38.81 46.12 52.12 60.18 67.12 88.12 95.25 96.68 −− −−
F12 0 19.68 21.75 34.12 43.68 50.81 54.75 66.56 72 88.5 92.62 95.06 97.5
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Time (hr) 0 1 2 3 4 5 6 7 8 9 10 11 12
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Table 5: In-vitro dissolution studies of atomoxetine hydrochloride.
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Table 6: Release kinetic parameters of designed sustained release matrix tablets of atomoxetine hcl. Formulation code F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12
Zero order kinetics First order kinetics Higuchi kinetics 0.988 0.982 0.979 0.972 0.984 0.973 0.972 0.965 0.953 0.975 0.973 0.980
0.735 0.832 0.821 0.899 0.870 0.961 0.898 0.89 0.831 0.845 0.819 0.892
0.952 0.991 0.947 0.949 0.971 0.976 0.967 0.966 0.921 0.925 0.937 0.969
Korsmeyer /Pepas kinetics 2 N value R 0.982 0.807 0.992 0.794 0.936 0.729 0.937 0.756 0.974 0.761 0.981 0.729 0.991 0.774 0.984 0.751 0.951 0.797 0.925 0.658 0.964 0.651 0.968 0.727
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CONCLUSION In this study matrix tablet of atomoxetine hcl was prepared by direct compression, using TSP and Guar gum polymers used as release retardant. It was found that increase in the concentration of TSP and Guar gum in polymeric ratio decreases the drug release. TSP is non-carcinogenic, biocompatible and has high drug holding capacity. This led to its application as excipient in hydrophilic drug delivery system. The guar gum swells in gastric fluid to produce a highly viscous layer around the tablet through which the drug must diffuse. This property makes guar gum useful ingredient for sustained release matrix tablet. The formulation F5 and F12 containing 30% and 35% of TSP and guar gum respectively, showed good drug release with good matrix integrity. From the above result, it has been found that the optimized formulation F5 containing 30% of the TSP as drug retarding polymer shows better sustained effect for 12 hour when compared to F11 containing 30% of guar gum having sustained effect for 10 hour. Different parameters like hardness, friability, weight variation, drug content uniformity, in-vitro drug release were evaluated for these formulations. Based on these results, formulations F5 and F12 were found to be the most promising formulations. The optimized formulations F5 and F12 follows Higuch’s plot since the regression coefficient is 0.971 and 0.969 and plots were also found to be linear. This confirms that the drug release through the matrix was diffusion and slope (n) value of Peppa’s plot in the optimized formulations F5 and F12 was found to be 0.761 and 0.727. Thus, non Fickian diffusion was the main mechanism. The regression 2 2 coefficient (R ) values of zero order in the optimized formulation F5 and F12 were greater than the R values of the first order. Thus, the drug release follows zero order kinetics. Stability studies were conducted for the optimized formulations as per ICH guidelines for a period of 90 days, which revealed the stability of the formulations and in vitro drug release was better than other formulations.
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REFERENCESS 1. Beatrice B, Lachmann FM. Infant research and adult treatment. 3 rd ed. New jersey: Hillsdale Publishers; 2002. Pp. 55-57. 2. Patel J, Shah N. Formulation and evaluation of sustained release tablets containing atomoxetine hydrochloride. J P S B R. 2014; 4(3): 196-200. 3. STRATTERA capsules for oral use. Indianapolis, USA: Eli Lilly and company. Retrieved 23 may 2014. 4. Fallon JM. Pharmaceutical preparation for ADD, ADHD and other associated disorder. US patent 2007/0116695 A1, 2007 5. Leon L, Herbert AL. Pharmaceutical dosage forms: Tablets. In: The theory and practices of industrial pharmacy.3 rd ed, New York : Lea and Febiger; 1991, pp. 293-345. 6. Subrahmanyam CVS. Textbook of Physical Pharmaceutics 2nd ed. New Delhi: Vallabh prakashan; 2003. p. 180-234.
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