Int J App Pharm, Vol 16, Issue 4, 2024, 114-120Original Article
DEVELOPMENT AND OPTIMIZATION OF COATED TABLET CONTAINING AMLODIPINE AND VALSARTAN FOR HYPERTENSION TREATMENT
DUYEN THI MY HUYNH1, TRUONG PHU VINH1, TRAN DUNG TAM1, MINH-NGOC T. lE1, PHUOC-VINH NGUYEN2*
1University of Medicine and Pharmacy, 179 Nguyen Van Cu Street, An Khanh, Ninh Kieu, Can Tho. 2School of Medicine, Vietnam National University Ho Chi Minh City
*Corresponding author: Phuoc Vinh Nguyen; Email: npvinh@medvnu.edu.vn
Received: 28 Mar 2024, Revised and Accepted: 15 May 2024
ABSTRACT
Objective: To develop and optimize the formulation of coated tablets containing these Active Pharmaceutical Ingredients (APIs) with in vitro equivalence to that of the original drug.
Methods: Design Expert and BCPharSoft OPT softwares were applied in the development and optimization of film-coated tablets of amlodipine 5 mg and valsartan 80 mg, in order to obtain a tablet formulation with in vitro equivalence to the original drug in three dissolution testing environments. Evaluating through appearance, identification, medium hardness, weight uniformity, in vitro equivalence, assay.
Results: An optimized formulation of film-coated tablets with in vitro equivalence to the referent drug was obtained. For the tablet core, it is composed of amlodipine besylate 6.94 mg (equivalent to 5 mg amlodipine) and valsartan 80 mg with excipients of 9.77% crospovidone XL, 2% aerosil, 2.75% magnesium stearate, 42.01% avicel PH 112, with a hardness of 70-90 N. The film-coating suspension comprises 4.75% Hydroxypropyl Methylcellulose 6cps (HPMC 6cps), 0.42% polyethylene glycol 6000 (PEG 6000), 0.84% talc, 1.77% titanium dioxide (TiO2), 0.12% yellow iron oxide, in 92.1% ethanol 96%-water (2:1).
Conclusion: In the current study, a film-coated tablet formulation with in vitro equivalence of two APIs to the original drug in all three environments was successfully developed and optimized. The obtained results are an important premise for the development of related generic drugs in the pharmaceutical market of developing countries, which not only reduces the product price but also help less wealthy patients in developing countries to better control hypertension disease.
Keywords: Amlodipine, Valsartan, Film-coated tablets, In vitro equivalence, Hypertension
© 2024 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/)
DOI: https://dx.doi.org/10.22159/ijap.2024v16i4.50984 Journal homepage: https://innovareacademics.in/journals/index.php/ijap
INTRODUCTION
According to a report of the World Health Organization (WHO), there will be about 1.28 billion people aged 30-79 with hypertension around the world in 2021 [1, 2]. Combining multiple groups of drugs in the treatment of hypertension is a new trend for many pharmaceutical manufacturers. The combination of amlodipine and valsartan gives patients many advantages during treatment, such as enhancing treatment effectiveness [3], improving the stabilization of daily blood pressure levels that helps to significantly enhance the tolerability during the administration of separate medications, and minimizing side effects. Indeed, comparative analysis has suggested a reduction in peripheral edema occurrence compared to the utilization of elevated doses of amlodipine [4]. In the current pharmaceutical market, numerous products incorporating such active ingredients are available. However, they frequently fail to adequately address medical needs of vulnerable population, particularly in socioeconomically difficult regions where access to original drugs is normally limited. Consequently, there is a high demand of research for generic drugs containing these compositions.
Few studies have developed the formulation of these two active ingredients [6, 7]. In those studies, the wet granulation was used to prepare tablets. Nevertheless, it should be noted that amlodipine is susceptible to occasional degradation by humidity and heat. Therefore, this granulation method in large-scale industrial production presents potential risks. In terms of valsartan-an API with poor solubility (Biopharmaceutics Classification System Class II), in general, an additional method, such as solid dispersion technique, is commonly required to enhance its solubility [8, 9]. Nevertheless, this technique required a sophisticated fabrication method and not adequate to commercialize in developing countries. Furthermore, in such developing countries, no research on the preparation of tablets containing the above two active ingredients has been published. This study was conducted to formulate immediate-release tablets containing amlodipine and valsartan with an in vitro drug release rate equivalent to that of original drug, using a conventional method of dry granulation in combination with design of experiment. This is also the first study which combined design of experiments and dry granulation methods to prepare a complexe tablet of such APIs. The results obtained from the current study is a solid base for the industrial production of this kind of tablet that is helpful for better management of hypertension for related patients.
MATERIALS AND METHODS
Materials
Reference substances: Amlodipine besylate, batch number QT145 120122, content 100.3% calculated on anhydrous preparation; valsartan, batch number QT323 020122, content 99.4% based on anhydrous product provided by Ho Chi Minh City Drug Testing Institute. Allopathic drugs: Exforge® (Siegfried Barbera Company, SL-Spain) batch number BCXN8, expiry date 02-2025.
Solvents and chemicals: Acetonitrile (ACN) and methanol meet HPLC standard. Triethylamine (TEA), phosphoric acid and solvents used in analysis meet prescribed analytical standards. Ingredients amlodipine besylate, valsartan, avicel PH 112, crospovidone XL, aerosil, magnesium stearate, HPMC 6cps, TiO2, yellow iron oxide, talc, macrogol-PEG 6000, distilled water and 96% alcohol met standards for pharmaceutical uses.
Equipments: Rimek 10-punch tablet compressing machine (India), Diode Array Detector (DAD) probe HPLC machine with ZORBAX Eclipse Plus C18 reversed-phase chromatography column (Agilent-USA), ERWEKA granulate flow tester, Pharmatest PTB hardness testing machine, Pharmatest PTF E Abrasion testing machine, Pharmatest PTWS 120D dissolution testing machine, Kern ABS 220-4 electrical scale (Germany).
Method
Dissolution investigation of Exforge®control tablets (amlodipine 5 mg and valsartan 80 mg)
The dissolution test of Exforge® control tablets was performed by a paddle-type dissolution tester (type 2), medium volume is 1000 ml, pH 1.2, 4.5, 6.8, and the stirring speed is 50 rpm [10]. Samples are takend at 10, 15, 30, 45, 60 minutes with a volume of 10 ml, filtered through 0.45 µm RC membrane before performing chromatography. The samples were assayed by HPLC using PDA with the following chromatography conditions: ZORBAX Eclipse Plus C18 chromatography column (4.6 x 250 mm; 5 µm), detection wavelength 237 nm, flow rate 1 ml/minute, sample injection volume 20 µL, mobile phase: ACN-0.7% TEA solution (adjusted to pH 3.0 with 0.05% phosphoric acid) at a ratio of 40:60, isocratic elution.
Design and optimization of immediate-release tablets’ formulation containing amlodipine 5 mg and valsartan 80 mg
Our previous studies indicated that the drug release rate was influenced by the content of crospovidone, HPMC 6cps, and tablet hardness in the tablet formulation. Consequently, three parameters, including crospovidone ratio, HPMC 6cps concentration, and tablet hardness, were used as independent variables in our design.
The design of the experiment was established using Design-Expert software with three independent variables x1 for the crospovidone content, x2 for tablet hardness, and x3 for HPMC 6cps content. Each formulation was prepared with a quantity of 200 coated tablets.
Selection of the dependent variable: The dependent variable is the similarity coefficient (f2 value) between amlodipine and valsartan in three distinct dissolution media at three pH levels of 1.2, 4.5, and 6.8, in comparison to the referent tablet. In which:
y1, y2, y3: f2 value for amlodipine of the formulation and control drug at pH 1.2; 4.5; 6.8.
y4, y5, y6: f2 value for valsartan of the formulation and control drug in pH 1.2; 4.5; 6.8.
f2 value
……. (1)
n is the number of sampling points, Rt is the average of the percentage of control drug dissolved at time t since the start of the test; Tt is the average of the percentage of reagent dissolved at time t since the start of the test [11].
The main composition of the tablet core includes 6.94 mg of amlodipine besylate (corresponding to 5 mg of amlodipine), 80 mg of valsartan, 4 mg of aerosil, 5.5 mg magnesium stearate, crospovidone (x1), avicel 102 sufficient for 200 mg of tablet core. The film-coating contained HPMC 6cps (x2), 0.44 mg PEG 6000, 0.88 mg talc, 1.84 mg TiO2, and 0.12 mg yellow iron oxide for the coating layer of 103.68 mg. The solvent used for coating suspension was 96% ethanol-water (2:1). The design of the experiments is presented in table 2.
Table 1: Independent variables and ranges
| Independent variable | Symbol | Variation level | ||
| Upper level | Base level | Lower level | ||
| Crospovidone ratio (%) | x1 | 15 | 10 | 5 |
| Pellet hardness (N) | x2 | 90-110 | 70-90 | 50-70 |
| HPMC ratio 6cps (%) | x3 | 5 | 4 | 3 |
Table 2: Design of experiments for coated tablets containing amlodipine and valsartan (5/80 mg)
| Formula | Tablet core (mg/tablet) | Coating suspension (mg/tablet) | |
| Crospovidone XL (x1) | Hardness (x2) | HPMC 6cps (x3) | |
| F1 | 10 | 50-70 | 3.11 |
| F2 | 10 | 50-70 | 4.15 |
| F3 | 10 | 50-70 | 5.18 |
| F4 | 10 | 70-90 | 3.11 |
| F5 | 10 | 70-90 | 4.15 |
| F6 | 10 | 70-90 | 5.18 |
| F7 | 10 | 90-110 | 3.11 |
| F8 | 10 | 90-110 | 4.15 |
| F9 | 10 | 90-110 | 5.18 |
| F10 | 20 | 50-70 | 3.11 |
| F11 | 20 | 50-70 | 4.15 |
| F12 | 20 | 50-70 | 5.18 |
| F13 | 20 | 70-90 | 3.11 |
| F14 | 20 | 70-90 | 4.15 |
| F15 | 20 | 70-90 | 5.18 |
| F16 | 20 | 90-110 | 3.11 |
| F17 | 20 | 90-110 | 4.15 |
| F18 | 20 | 90-110 | 5.18 |
| F19 | 30 | 50-70 | 3.11 |
| F20 | 30 | 50-70 | 4.15 |
| F21 | 30 | 50-70 | 5.18 |
| F22 | 30 | 70-90 | 3.11 |
| F23 | 30 | 70-90 | 4.15 |
| F24 | 30 | 70-90 | 5.18 |
| F25 | 30 | 90-110 | 3.11 |
| F26 | 30 | 90-110 | 4.15 |
| F27 | 30 | 90-110 | 5.18 |
Tablet-core preparation’s process
(1) Weigh the necessary amount of amlodipine, valsartan, avicel PH 112, crospovidone XL, 80% of aerosil, 60% of magnesium stearate and mix these components homogeneously; (2) Precompression of pellets with a weight of about 350 mg and hardness around 60 N; (3) Dry granulation through 0.8 mm sieve; (4) Screen pellets through 0.45 mm sieve; (5) Recalculate the necessary amount of aerosil, sieve through 0.45 mm sieve, and mix with the above mixture; (7) Compression of tablet core with a weight of about 200 mg; hardness N (x3); and a diameter of 7.5 mm.
Film-coating process
Prepare the film coating suspension: (1) 60 ml of 96% ethanol-distilled water (2:1) (solution A); (2) Dispersion of HPMC 6cps into solution A, mix thoroughly until total swelling; (3) dissolution of PEG 6000 into HPMC solution (solution B). (4) TiO2 and yellow iron oxide was weighted and grinded. Slowly add 5 ml of solution A. Dilute the paste with the remaining amount of solution A (solution C). (5) Add the solution (C) into the solution (B). Disperse the talc into the final mixture and stir slowly for 60 min.
The coating process was conducted on CALEVA equipment (CALEVA-UK), including (1) Assemble the spray system, opening the compressed air system; (2) Put tablet core into coating pan, turn on the air blower at 15 m/s, adjust the pan vibration speed to 20 Hz, with a temperature of 60 °C. Blow the dust and dry the tablets for 10 minutes. Weigh dried tablet cores; (3) Spray the coating suspension for 10-15 minutes. Dry tablets for 10 minutes; (4) Weigh coated tablets. (5) Dry the tablets after coating for 10 minutes; (6) Keep coated tablets in a moisture-free environment for one day before dissolution tests.
RESULTS
The results of the solubility survey of Exforge®tablets
Dissolution tests were conducted for the original drugs-Exforge® at three different pH 1.2, 4.5, and 6.8. The results were presented in the table 3.
Optimization of the formulation of immediate-release coated tablets containing amlodipine 5 mg and valsartan 80 mg using dry granulation
f2 value of amlodipine (y1, y2, y3) and valsartan (y4, y5, y6) of each formula in the design of experiments and the control drug at pH 1.2, 4.5, and 6.8 was determined and presented in table 4.
Table 3: Dissolution test results of Exforge® tablets in three pH environments (n = 6)
| Time (min) | Release of active compounds (%) | |||||
| Amlodipine | Valsartan | |||||
| pH 1.2 | pH 4.5 | pH 6.8 | pH 1.2 | pH 4.5 | pH 6.8 | |
| 10 | 65.22±0.03 | 3.20±0.02 | 15.66±0.03 | 20.36±0.04 | 55.24±0.06 | 85.84±0.03 |
| 15 | 68.56±0.02 | 5.57±0.03 | 27.69±0.05 | 28.03±0.05 | 68.96±0.01 | 89.88±0.05 |
| 30 | 70.75±0.04 | 11.32±0.07 | 49.19±0.03 | 39.35±0.03 | 77.19±0.08 | 90.01±0.03 |
| 45 | 73.85±0.05 | 22.16±0.05 | 57.34±0.02 | 46.97±0.02 | 82.54±0.03 | 90.51±0,02 |
| 60 | 80.05±0.04 | 23.51±0.05 | 68.30±0.03 | 52.57±0.02 | 84.36±0.06 | 90.58±0.05 |
Data is given as mean±SD, n=6
Table 4: f2 value of amlodipine and valsartan in each formula in the design of experiments compared to the control drug
| No | x1 | x2 | x3 | y1 | y2 | y3 | y4 | y5 | y6 |
| 1 | 5 | 1 | 3 | 30.61 | 25.71 | 28.22 | 35.97 | 35.04 | 35.57 |
| 2 | 5 | 1 | 4 | 28.94 | 24.92 | 27.28 | 34.25 | 34.03 | 34.11 |
| 3 | 5 | 1 | 5 | 27.69 | 23.84 | 26.74 | 33.29 | 32.24 | 32.31 |
| 4 | 5 | 2 | 3 | 26.12 | 22.45 | 24.53 | 31.36 | 31.18 | 31.26 |
| 5 | 5 | 2 | 4 | 26.47 | 20.43 | 23.45 | 30.49 | 29.33 | 30.07 |
| 6 | 5 | 2 | 5 | 23.85 | 19.24 | 20.16 | 29.04 | 28.41 | 28.64 |
| 7 | 5 | 3 | 3 | 14.73 | 12.97 | 13.02 | 19.44 | 17.36 | 18.74 |
| 8 | 5 | 3 | 4 | 13.21 | 11.86 | 12.01 | 17.98 | 15.22 | 17.03 |
| 9 | 5 | 3 | 5 | 12.89 | 10.09 | 10.75 | 17.46 | 14.54 | 16.31 |
| 10 | 10 | 1 | 3 | 35.12 | 32.46 | 34.25 | 36.17 | 34.52 | 35.55 |
| 11 | 10 | 1 | 4 | 41.99 | 40.16 | 41.45 | 43.54 | 41.26 | 42.68 |
| 12 | 10 | 1 | 5 | 45.35 | 41.94 | 43.07 | 46.82 | 45.11 | 46.05 |
| 13 | 10 | 2 | 3 | 45.76 | 42.14 | 43.61 | 47.23 | 45.67 | 46.56 |
| 14 | 10 | 2 | 4 | 46.55 | 44.42 | 45.57 | 51.03 | 48.95 | 49.26 |
| 15 | 10 | 2 | 5 | 49.41 | 46.82 | 48.17 | 52.23 | 50.07 | 50.62 |
| 16 | 10 | 3 | 3 | 59.78 | 56.94 | 59.11 | 65.02 | 59.27 | 62.72 |
| 17 | 10 | 3 | 4 | 64.13 | 59.12 | 62.15 | 76.23 | 64.50 | 70.01 |
| 18 | 10 | 3 | 5 | 64.02 | 58.89 | 61.96 | 76.11 | 64.19 | 69.45 |
| 19 | 15 | 1 | 3 | 12.46 | 9.48 | 10.15 | 17.24 | 14.47 | 16.43 |
| 20 | 15 | 1 | 4 | 13.99 | 11.42 | 11.77 | 18.35 | 16.03 | 17.95 |
| 21 | 15 | 1 | 5 | 15.42 | 12.78 | 13.06 | 20.01 | 18.21 | 19.37 |
| 22 | 15 | 2 | 3 | 15.07 | 14.02 | 14.79 | 16.67 | 15.23 | 16.11 |
| 23 | 15 | 2 | 4 | 17.22 | 16.58 | 17.1 | 20.54 | 19.47 | 20.21 |
| 24 | 15 | 2 | 5 | 21.09 | 19.79 | 20.94 | 24.89 | 23.44 | 24.86 |
| 25 | 15 | 3 | 3 | 29.27 | 28.65 | 29.06 | 33.89 | 32.64 | 33.35 |
| 26 | 15 | 3 | 4 | 35.08 | 33.47 | 34.95 | 37.88 | 36.19 | 37.66 |
| 27 | 15 | 3 | 5 | 41.35 | 40.37 | 41.18 | 44.61 | 43.68 | 44.41 |
Table 5: Optimized parameters and predicted results for the coated tablet using BCPharSoft OPT software
| Parameters | y1 | y2 | y3 | y4 | y5 | y6 |
| R2 training | 0.90 | 0.90 | 0.93 | 0.90 | 0.93 | 0.98 |
| R2 testing | 0.90 | 0.93 | 0.90 | 0.95 | 0.90 | 0.90 |
| R2 | 0.92 | 0.94 | 0.93 | 0.92 | 0.94 | 0.96 |
R2 training and R2 testing values in the range of 80-100% showed that the used model was significant and there was a significant correlation between the independent variables and the dependent variable. The graphs representing correlation of independent variables on dependent variable were presented in fig. 1-3.
a |
b |
c |
d |
e |
f |
Fig. 1: Effects of independent variables x1 and x2 on the dependent variable (a) y1, (b) y2, (c) y3, (d) y4, (e) y5, (f) y6
a |
b |
c |
d |
e |
f |
Fig. 2: Effects of independent variables x1 and x3 on the dependent variable (a) y1, (b) y2, (c) y3, (d) y4, (e) y5, (f) y6
a |
b |
c |
d |
e |
f |
Fig. 3: Effect of independent variables x2 and x3 on dependent variable (a) y1, (b) y2, (c) y3, (d) y4, (e) y5, (f) y6
In fig. 1, the results showed that to obtain all y1; y2; y3; y4; y5; y6 value superior to 50%, the crospovidone content should be in the range of 8-12% and the tablet hardness should be 80-110 N.
The fig. 2, showed that to obtain the required value of the dependent variables, the crospovidone content should be in the range of 6-8.5% and the HPMC 6cps content should be 4.5-5%.
The results presented in the fig. 3 indicated that there is no independent variable value x2; x3 in the survey range that made the dependent variables reach over 50%.
Taking all of these results into consideration, to obtain all dependent values over 50%, the crospovidone content, the HPMC 6cps content and the tablet core’s hardness should be in the range of 8-12%, 4.5-5% and 80-110 N, respectively.
Table 6: Optimal parameters for the coated tablet
| Optimal parameters | Predicted value | ||||
| x1 | 9.772% | y1 | 54.565 | y4 | 53.719 |
| x2 | 70-90 N | y2 | 50.006 | y5 | 54.364 |
| x3 | 4.748% | y3 | 50.307 | y6 | 50.015 |
In order to validate the optimal results predicted by BCPharSoft OPT software, three batches of 1,000 tablets with crospovidone XL content of 9.772%, tablet hardness in the range of 70-90 N and HPMC 6cps content of 4.748%.
Table 7: Validation of optimal formulation through experimentation (n=6).
| Independent variable | Experiment | Average value | Predicted value | ||
| Batch 1 | Batch 2 | Batch 3 | |||
| y1 | 53.65 | 53.13 | 52.72 | 53.17±0.47 | 54.565 |
| y2 | 50.08 | 50.06 | 50.15 | 50.09±0.05 | 50.006 |
| y3 | 53.12 | 52.39 | 52.91 | 52.81±0.38 | 53.307 |
| y4 | 52.35 | 52.98 | 52.23 | 52.52±0.40 | 53.719 |
| y5 | 54.03 | 52.94 | 53.64 | 53.54±0.55 | 54.364 |
| y6 | 50.14 | 50.21 | 50.22 | 50.19±0.04 | 50.015 |
The experimental results was compared to predicted one using one-factor ANOVA without repetition, the result was F=0.343<Fcrit.=4.964, so there is no significant difference between experimental results and the predicted results by using BCPharSoft OPT software.
Table 8: Quality test of the optimized coated tablet containing amlodipine and valsartan (5/80 mg)
| Quality attribute | Requirement | Results | ||
| Batch 1 | Batch 2 | Batch 3 | ||
| Appearance (n = 10) | Yellow film-coated tablets, smooth and non-crumble surface | Correct | Correct | Correct |
| Identification (n = 10) | The chromatogram of the tested sample includes two peaks with retention times corresponding to the retention time of the standard sample. | Correct | Correct | Correct |
| Medium hardness (n = 20) | 70-90 N | Pass (80.8±0.31 N) |
Pass (85.3±0.15 N) |
Pass (79.3±0.32 N) |
| Weight uniformity (n = 20) | Not more than two units' weight deviate from the 7.5% difference limit, and no unit's weight is superior to 15% of the average weight. | Pass (203.3±0.23 mg) |
Pass (204.1±0.39 mg) |
Pass (201.6±0.59 mg) |
| In vitro equivalence (n = 6) | f2 value (of amlodipine and valsartan in all three pH environments)>50% | Pass (f2>50%) |
Pass (f 2>50%) |
Pass (f 2>50%) |
| Assay (n =6) | 95-105% | Pass (100.2%) | Pass (101.9%) | Pass (102.5%) |
DISCUSSION
Valsartan has poor water solubility and poor flowability nature. This property can affect the control of weight and hardness of tablets during tablet compression. Therefore, an improvement of flowability of the powder before the compression step is required. In addition, due to the sensitivity of amlodipine to moisture [12], wet granulation is not applicable for the related formulation. To improve the flowability of the powder, dry granulation method was chosen with avicel PH 112 as a diluent [12]. The weight of the tablet core was fabricated with a hardness of about 60 N. Using avicel PH 112 and application of appropriate hardness for the tablet core were proven to be helpful for the granulation. Crospovidone XL, a super disintegrant excipient, was also added into the optimized formulation and was showed to be crucial to ensure the release rate of the active ingredients. The obtained results revealed that the addition of this super disintegrant should be at the beginning of the fabrication process as it could lead to gradual swelling and capillary action, and help to prevent the excessive release of the active ingredient [13]. Similar benefits of using crospovidone XL as super disintegrant in immediate-release tablets containing amlodipine was also observed by Behin Sundara Raj et al. in 2012 [14].
The obtained results with the design of experiments showed a significant impact of all tested independent variables on the release rate of amlodipine and valsartan, thereby affecting the in vitro equivalence of the resulted film-coated tablets. Nevertheless, the impact level was showed to be different. Indeed, Crospividone XL demonstrated the greatest impact on the release level of the tablet’s APIs. This important influence may be due to the fact that its positive impact on the flowability and compactibility of granules as well as its ability to form complexes with amino groups in valsartan, enhancing the solubility of valsartan [13, 15]. A similar result was also observed in the study of Ramirez et al., in which a ratio of crospovidone XL at 10% produced the maximal release rate of API [15]. Secondly, the tablet’s hardness also presented a significant impact on the release level of APIs but less important than that of crospovidone XL. Specifically, a softer tablet makes it easier to release the APIs. On the contrary, an increase in the hardness makes tablets more solid but harder, and takes more time to be disintegrated. In terms of HPMC 6 cps, the obtained results showed that there was the less significant impact on the release of APIs. Indeed, HPMC 6cps only creates a low-viscosity film when the tablets come into contact with the dissolution testing environment, that does not greatly affect the release ability of the tablets but only to protect against moisture that was similar to the results obtained by Chulhun Park et al.,[16].
From the above results, an equilibrium between these two parameters, as showed in the results, is indispensable to obtain a maximized dissolution rate of tablets, which was determined and validated using the design of experiment. This finding again highlighted the benefits of design of experiment softwares, such as BCPharSoft OPT, in the drug formulation, as it is considered a great forward step in the pharmaceutical industry, especially in developing countries. Such supporting tool can bring many advantages in formula research process, especially in shortening the time and number of tested formulas, and finally help saving time and wasted ingredients.
CONCLUSION
An optimal film-coated formulation was successfully developed for hypertension treatment, including 6.94 mg amlodipine besylate (3.47%) (equivalent to 5 mg of amlodipine), 80 mg valsartan (40%), 19.54 mg crospovidone XL (9.77%), 4 mg aerosil (2%), 5.5 mg magnesium stearate (2.75%), and 84.02 mg avicel PH 112 (42.01%) for the tablet core. Tablet core’s hardness was in the range of 70-90 N. The film-coating layer comprises 4.92 mg HPMC 6cps (4.75%), 0.44 mg PEG 6000 (0.42%), 0.88 mg talc (0.84%), 1.84 mg TiO2 (1.77%), 0.12 mg yellow iron oxide (0.12%), and 95.48 mg ethanol 96%-water (2:1) (92.1%). Optimized tablets met the in vitro equivalence in comparison to the reference drug, with f2 values for amlodipine recorded at 53.17 (pH 1.2), 50.09 (pH 4.5), and 52.81 (pH 6.8), and for valsartan at 52.52 (pH 1.2), 53.54 (pH 4.5), and 50.19 (pH 6.8). Results obtained from the current study reconfirmed the potential of using mathematical models in drug formulation to obtain desired properties and may be used as an example for the quality by design in the pharmaceutical industry. Further studies on clinical trials for bioequivalence test will be conducted in order to commercialize this optimized formulation.
ACKNOWLEDGEMENT
The authors would like to acknowledge the Can Tho University of Medicine and Pharmacy for research support.
AUTHORS CONTRIBUTIONS
D. T. M. H: Methodology, Conceptualization, Writing-original draft, Project administration, Resources, Supervision, Other authors: Methodology, Conceptualization, Writing-original draft, Datacuration, Resources, M. N. T. l: Resources, Data curation, Phuoc-Vinh Nguyen: Writing-original draft, Data curation, Resources, Writing-Review and editing.
CONFLICT OF INTERESTS
The authors declare no competing interests.
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