Design of Experiment Approach for Enhancing the Dissolution Profile and Robustness of Loratadine Tablet Using D-α-Tocopheryl Polyethylene Glycol 1000 Succinate
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
2.2. Design of Experiment and Statistical Data Analysis
2.3. Preparation of Granules and Tablets
2.4. Evaluation of Granules
2.4.1. Granules Size Distribution
2.4.2. Flowability of Granules
2.4.3. Bulk and Taped Density
2.5. Evaluation of Tablets
2.5.1. Weight Variation
2.5.2. Uniformity of Drug Content
2.5.3. Hardness and Friability
2.5.4. Disintegration Time
2.5.5. In Vitro Dissolution
3. Results
4. Discussion
4.1. Influence of Key Variables on Average Granules Size (D50)
4.2. Influence of Key Variables on Granules’ Bulk Density
4.3. Influence of Key Variables on Granules’ Flowability
4.4. Influence of Key Variables on Tablet Strength
4.5. Influence of Key Variables on Disintegration Time
4.6. Influence of Key Variables on Tablet Dissolution
4.7. Lack-of-Fit Test
4.8. Optimization and Validation of Design
4.9. Scale-Up Considerations and Commercial Viability
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Run | TPGS (% w/w) | SSG (% w/w) |
---|---|---|
1 | 2 | 2 |
2 | 2 | 5 |
3 | 2 | 8 |
4 | 4 | 2 |
5 | 4 | 5 |
5 * | 4 | 5 |
5 * | 4 | 5 |
5 * | 4 | 5 |
6 | 4 | 8 |
7 | 6 | 2 |
8 | 6 | 5 |
9 | 6 | 8 |
Ingredients | Function | % w/w |
---|---|---|
Loratadine | Drug | 5 |
TPGS | Surfactant | 2–6 |
Sodium starch glycolate | Superdisintegrant | 2–8 |
* Microcrystalline cellulose PH-102 | Filler | Up to 100 |
* Lactose monohydrate | Filler | Up to 100 |
Magnesium stearate | Hydrophobic lubricant | 1 |
Total | - | 100 |
Responses | Suggested Model | p-Value | R2 | Adjusted R2 | Predicted R2 | Adequate Precision |
---|---|---|---|---|---|---|
Y1: * D50 | Quadratic | <0.0001 | 0.9950 | 0.9908 | 0.9759 | 47.31 |
Y2: Bulk density | Linear | <0.0001 | 0.8979 | 0.8753 | 0.8172 | 17.74 |
Y3: Angle of repose | Linear | <0.0001 | 0.9846 | 0.9812 | 0.9779 | 43.16 |
Y4: Crushing strength | Quadratic | <0.0001 | 0.9920 | 0.9853 | 0.9336 | 28.52 |
Y5: Disintegration time | Quadratic | <0.0001 | 0.9892 | 0.9803 | 0.9715 | 30.58 |
Y6: Percent release after 30 min | Linear | <0.0001 | 0.9331 | 0.9183 | 0.8529 | 25.05 |
Formula | Mean Granule Size (µm ± SD) | Bulk Density (g/mL ± SD) | Tapped Density (g/mL ± SD) | Angle of Repose (Degree ± SD) | Carr’s Index | Hausner’s Ratio |
---|---|---|---|---|---|---|
1 | 206.13 ± 0.35 | 0.413 ± 0.014 | 0.510 ± 0.005 | 36.21 ± 0.321 | 19 | 1.23 |
2 | 224.71 ± 0.32 | 0.431 ± 0.006 | 0.502 ± 0.009 | 35.89 ± 0.423 | 14.1 | 1.16 |
3 | 262.15 ± 0.21 | 0.452 ± 0.032 | 0.518 ± 0.019 | 35.57 ± 0.127 | 12.7 | 1.14 |
4 | 311.56 ± 0.26 | 0.463 ± 0.034 | 0.542 ± 0.007 | 33.46 ± 0.615 | 14.5 | 1.17 |
5 | 331.25 ± 0.21 | 0.461 ± 0.007 | 0.533 ± 0.015 | 33.54 ± 0.247 | 13.5 | 1.15 |
5 * | 346.11 ± 0.65 | 0.458 ± 0.033 | 0.521 ± 0.0024 | 33.11 ± 0.442 | 12.1 | 1.13 |
5 * | 344.21 ± 0.24 | 0.456 ± 0.008 | 0.513 ± 0.017 | 33.78 ± 0.361 | 11.1 | 1.12 |
5 * | 343.54 ± 0.32 | 0.486 ± 0.047 | 0.561 ± 0.031 | 33.61 ± 0.431 | 13.3 | 1.15 |
6 | 359.11 ± 0.45 | 0.501 ± 0.019 | 0.568 ± 0.003 | 32.84 ± 0.392 | 11.8 | 1.13 |
7 | 401.75 ± 0.64 | 0.532 ± 0.020 | 0.587 ± 0.012 | 30.77 ± 0.331 | 9.3 | 1.10 |
8 | 412.55 ± 0.25 | 0.528 ± 0.022 | 0.579 ± 0.043 | 30.11 ± 0.214 | 8.8 | 1.09 |
9 | 423.64 ± 0.81 | 0.533 ± 0.110 | 0.591 ± 0.027 | 30.23 ± 0.325 | 9.8 | 1.11 |
Run | Weight (mg ± SD) | Drug Content (% ± SD) | Crushing Strength (N ± SD) | Friability (% ± SD) | Disintegration Time (S ± SD) | %Release at 30 min (% ± SD) |
---|---|---|---|---|---|---|
1 | 200.6 ± 0.951 | 100.12 ± 1.31 | 68.352 ± 0.215 | 0.09 ± 0.03 | 7.11 ± 1.13 | 74.53 ± 1.15 |
2 | 201.03 ± 0.624 | 96.70 ± 0.13 | 68.058 ± 0.133 | 0.02 ± 0.06 | 4.15 ± 1.33 | 77.24 ± 1.14 |
3 | 200.59 ± 0.943 | 101.23 ± 1.12 | 61.095 ± 0.139 | 0.03 ± 0.02 | 2.35 ± 1.28 | 78.04 ± 1.13 |
4 | 201.0 5 ± 0.701 | 100.66 ± 1.6 | 68.254 ± 0.235 | 0.03 ± 0.01 | 7.5 ± 1.63 | 79.25 ± 2.36 |
5 | 200.96 ± 0.829 | 98.3 ± 1.61 | 69.431 ± 0.211 | 0.17 ± 0.05 | 5.38 ± 1.61 | 83.47 ± 1.82 |
5 * | 200.81 ± 0.853 | 101.54 ± 0.88 | 68.745 ± 0.210 | 0.04 ± 0.03 | 4.25 ± 1.32 | 82.79 ± 2.41 |
5 * | 200.47 ± 0.683 | 100.88 ± 1.63 | 67.568 ± 0.237 | 0.09 ± 0.02 | 5.33 ± 2.18 | 83.14 ± 2.84 |
5 * | 201.08 ± 0.755 | 98.76 ± 2.01 | 67.764 ± 0.209 | 0.06 ± 0.01 | 4.35 ± 0.57 | 82.91 ± 1.21 |
6 | 200.77 ± 1.06 | 100.93 ± 0.76 | 68.745 ± 0.342 | 0.15 ± 0.03 | 4.14 ± 0.81 | 85.63 ± 2.17 |
7 | 200.79 ± 0.871 | 100.4 ± 0.8 | 41.286 ± 0.233 | 0.08 ± 0.01 | 12.31 ± 0.36 | 83.52 ± 2.33 |
8 | 200.84 ± 0.739 | 101.3 ± 1.7 | 41.776 ± 0.257 | 0.16 ± 0.03 | 11.02 ± 0.84 | 85.11 ± 3.11 |
9 | 200.61 ± 0.828 | 100.1 ± 1.5 | 43.836 ± 0.353 | 0.12 ± 0.01 | 11.45 ± 0.68 | 91.52 ± 1.98 |
Variables | Coefficient Estimate | Sum of Squares | Standard Error | * F-Value | p-Value |
---|---|---|---|---|---|
Granule size (Quadratic model) | |||||
Intercept | 339.49 | - | 2.05 | - | - |
X1 | 90.82 | 49,495.08 | 2.73 | 1109.18 | <0.0001 |
X2 | 20.91 | 2623.37 | 2.73 | 58.79 | 0.0003 |
X1X2 | –8.53 | 291.21 | 3.34 | 6.53 | 0.0432 |
X12 | –17.28 | 796.49 | –17.28 | 17.85 | 0.0055 |
X22 | –0.5775 | 0.8893 | –0.5775 | 0.0199 | 0.8924 |
Granules bulk density (Linear model) | |||||
Intercept | 0.4762 | – | 0.0041 | – | – |
X1 | 0.0495 | 0.0147 | 0.0058 | 74.08 | <0.0001 |
X2 | 0.013 | 0.0010 | 0.0058 | 5.11 | 0.0501 |
Granule flowability (Linear model) | |||||
Intercept | 33.26 | - | 0.0819 | - | - |
X1 | –2.76 | 45.71 | 0.1158 | 568.48 | <0.0001 |
X2 | –0.30 | 0.54 | 0.1158 | 6.72 | 0.0291 |
Variables | Coefficient Estimate | Sum of Squares | Standard Error | * F-Value | p-Value |
---|---|---|---|---|---|
Crushing strength (Quadratic model) | |||||
Intercept | 7.0 | - | 0.06 | - | - |
X1 | –1.2 | 8.64 | 0.05 | 417.91 | <0.0001 |
X2 | –0.071 | 0.03 | 0.05 | 1.49 | 0.267 |
X1X2 | 0.25 | 0.25 | 0.07 | 12.09 | 0.013 |
X12 | –1.44 | 5.56 | 0.0881 | 268.86 | <0.0001 |
X22 | –0.058 | 0.0092 | 0.0881 | 0.4452 | 0.529 |
Disintegration time (Quadratic model) | |||||
Intercept | 4.87 | - | 0.212 | - | - |
X1 | 3.53 | 74.69 | 0.189 | 345.88 | <0.0001 |
X2 | –1.5 | 13.44 | 0.189 | 62.23 | 0.0002 |
X1 X2 | 0.975 | 3.8 | 0.232 | 17.61 | 0.0057 |
X12 | 2.62 | 18.32 | 0.2846 | 84.84 | <0.0001 |
X22 | 0.856 | 1.96 | 0.2846 | 9.05 | 0.0237 |
Percent release at 30 min (Linear model) | |||||
Intercept | 82.26 | - | 0.37 | - | - |
X1 | 5.06 | 153.42 | 0.52 | 93.19 | <0.0001 |
X2 | 2.98 | 53.34 | 0.52 | 32.4 | 0.0003 |
Response | * F-Value | p-Value | Comment |
---|---|---|---|
d50 | 0.945 | 0.517 | Not significant |
bulk density | 1.02 | 0.537 | Not significant |
Flowability | 0.984 | 0.551 | Not significant |
Crushing strength | 4.24 | 0.133 | Not significant |
Disintegration time | 0.157 | 0.918 | Not significant |
Percent release at 30 min | 27.07 | 0.01 | Significant |
Variables | Target | Range | Weight | Importance Coefficient |
---|---|---|---|---|
Input | ||||
TPGS | In range | 2–6% w/w | 1 | NA |
SSG | In range | 2–8% w/w | 1 | NA |
Output | ||||
Crushing strength (N) | 58.840 | 41.286–69.431 | +++ | |
Disintegration time (Min) | 5 | 2.35–12.31 | 1 | +++ |
Percent release at 30 min (%) | 85 | 74.53–91.52 | 1 | +++ |
Variables | Value | ||
---|---|---|---|
TPGS (2–6% w/w) | 5.02 | ||
SSG (2–8% w/w) | 5.13 | ||
Overall desirability = 0.880 | |||
Responses | Predicted values | Experimental values * | Prediction error (%) |
Crushing strength (N) | 58.84 | 56.094 ± 0.32 | 4.66 |
Disintegration time (Min.) | 7.33 | 7.11 ± 1.08 | 3.001 |
Percent release at 30 min (%) | 85.0 | 86.21 ± 1.61 | –1.42 |
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Jabbar, A.A.; Al-Ani, I.; Al-Shdefat, R.I.; Ghazal, N.; Jaffal, A.; Fayed, M.H. Design of Experiment Approach for Enhancing the Dissolution Profile and Robustness of Loratadine Tablet Using D-α-Tocopheryl Polyethylene Glycol 1000 Succinate. Pharmaceutics 2025, 17, 380. https://doi.org/10.3390/pharmaceutics17030380
Jabbar AA, Al-Ani I, Al-Shdefat RI, Ghazal N, Jaffal A, Fayed MH. Design of Experiment Approach for Enhancing the Dissolution Profile and Robustness of Loratadine Tablet Using D-α-Tocopheryl Polyethylene Glycol 1000 Succinate. Pharmaceutics. 2025; 17(3):380. https://doi.org/10.3390/pharmaceutics17030380
Chicago/Turabian StyleJabbar, Alhasan A., Israa Al-Ani, Ramadan I. Al-Shdefat, Nadia Ghazal, Anwar Jaffal, and Mohamed H. Fayed. 2025. "Design of Experiment Approach for Enhancing the Dissolution Profile and Robustness of Loratadine Tablet Using D-α-Tocopheryl Polyethylene Glycol 1000 Succinate" Pharmaceutics 17, no. 3: 380. https://doi.org/10.3390/pharmaceutics17030380
APA StyleJabbar, A. A., Al-Ani, I., Al-Shdefat, R. I., Ghazal, N., Jaffal, A., & Fayed, M. H. (2025). Design of Experiment Approach for Enhancing the Dissolution Profile and Robustness of Loratadine Tablet Using D-α-Tocopheryl Polyethylene Glycol 1000 Succinate. Pharmaceutics, 17(3), 380. https://doi.org/10.3390/pharmaceutics17030380