Development and Characterization of Oral Raft Forming In Situ Gelling System of Neratinib Anticancer Drug Using 32 Factorial Design
Abstract
:1. Introduction
2. Resources and Methods
2.1. Materials
2.2. Methods
2.2.1. PEG—Neratinib Solid Dispersion Preparations
2.2.2. Determination of Saturation Solubility
2.2.3. Analytical Method Development
Determination of Absorption Maxima of NTB
2.2.4. Fourier Transform Infrared Spectroscopy (FT-IR) Studies
2.2.5. Scanning Electron Microscopy
2.2.6. NTB Floating In Situ Gel Preparation
2.2.7. Experimental Design
2.3. Evaluation
2.3.1. Physicochemical Properties
2.3.2. Drug Content Determination
2.3.3. pH Determination
2.3.4. In Vitro Gelling Capacity
2.3.5. In Vitro Floating Study
2.3.6. Water Uptake Study
2.3.7. In Vitro Drug Release Study
2.3.8. Kinetics of Drug Release Studies
3. Results and Discussion
3.1. Saturation Solubility Studies of NTB PEG Solid Dispersions
3.2. FT-IR Spectra
3.3. Scanning Electron Microscopy
3.4. Drug Content
3.5. Physicochemical Properties
3.6. pH Determination
3.7. In Vitro Gelling Capacity
3.8. In Vitro Floating Study
3.9. In Vitro Drug Release
3.10. Kinetics of Drug Release Studies
4. Data Analysis and Optimization
4.1. Impact of Independent Variables on Floating Lag Time Response
4.2. Impact of Independent Variables on Percentage Water Uptake Response
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
HER-2 | Pan-human epidermal growth factor (HER-2) |
HCL | Hydrochloric acid |
GIT | Gastrointestinal tract (GIT) |
KP | Korsemeyer Peppas |
PEG | Polyethylene glycol |
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Ingredients | F1 | F2 | F3 | F4 | F5 | F6 | F7 | F8 | F9 |
---|---|---|---|---|---|---|---|---|---|
Neratinib (mg) | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 |
Sodium alginate (g) | 1 | 2 | 3 | 1 | 2 | 3 | 1 | 2 | 3 |
HPMC K4M (g) | 1 | 1 | 1 | 1.5 | 1.5 | 1.5 | 2 | 2 | 2 |
Sodium bicarbonate (%) | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 |
Sodium citrate (%) | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 |
Methyl paraben (%) | 0.8 | 0.8 | 0.8 | 0.8 | 0.8 | 0.8 | 0.8 | 0.8 | 0.8 |
Variables | Actual Value (g) | Coded Value | ||||
---|---|---|---|---|---|---|
Low | Medium | High | Low | Medium | High | |
A: sodium alginate | 1 | 2 | 3 | −1 | 0 | +1 |
B: HPMC K4M | 1 | 1.5 | 2 | −1 | 0 | +1 |
Formulation | Drug: PEG Ratio | Percentage Drug Content NTB Solid Dispersion (%) * | Saturation Solubility of Solid Dispersion (μg/mL) * |
---|---|---|---|
Neratinib | - | - | 58.3 ± 1.82 |
A1 | 1:1 | 96.22 ± 1.67 | 96.37 ± 1.67 |
A2 | 1:2 | 97.70 ± 1.89 | 92.81 ± 1.53 |
A3 | 1:3 | 96.90 ± 2.14 | 132.11 ± 2.14 |
Formulations | pH | Drug Content * (%) | In Vitro Gelation | Floating Lag Time * (min) | Total Floating Time (h) | % Drug Release * (6 h) | % Drug Release * (12 h) |
---|---|---|---|---|---|---|---|
F1 | 7.2 ± 0.44 | 98.7 ± 0.52 | +++ | 2.47 ± 0.4 | >24 | 73.1 ± 0.42 | 99.89 ± 0.27 |
F2 | 7.8 ± 0.24 | 99.3 ± 0.32 | +++ | 3.12 ± 0.2 | >12 | 65.2 ± 0.53 | 87.54 ± 0.65 |
F3 | 7.8 ± 0.32 | 97.8 ± 0.41 | +++ | 6.27 ± 0.2 | >12 | 58.3 ± 0.21 | 84.32 ± 0.14 |
F4 | 7.1 ± 0.21 | 97.4 ± 0.22 | +++ | 30 ± 0.8 | 1.0 | 70.2 ± 0.02 | 84.33 ± 0.17 |
F5 | 7.4 ± 0.52 | 98.8 ± 0.16 | +++ | 42 ± 0.5 | >12 | 45.6 ± 0.62 | 74.31 ± 0.02 |
F6 | 7.3 ± 0.12 | 99.2 ± 0.51 | +++ | 49 ± 0.4 | >12 | 30.2 ± 0.76 | 55.44 ± 0.87 |
F7 | 7.1 ± 0.52 | 97.8 ± 0.46 | +++ | 74 ± 0.6 | <3 | 42.3 ± 0.29 | 69.91 ± 0.54 |
F8 | 7.2 ± 0.52 | 98.4 ± 0.31 | +++ | 86 ± 0.2 | <3 | 34.2 ± 0.71 | 59.16 ± 0.22 |
F9 | 7.2 ± 0.52 | 97.7 ± 0.61 | +++ | 89 ± 0.7 | <3 | 29.4 ± 0.63 | 50.73 ± 0.87 |
Formulation | Zero Order | Hix Crow | Higuchi Matrix | 1st Order | Korsmeyer–Peppas | Mechanism of Drug Release | Release Kinetic | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
R2 | K | R2 | K | R2 | K | R2 | K | R2 | K | n | |||
F1 | 0.994 | 10.845 | 0.968 | 25.480 | 0.979 | 13.179 | 0.971 | 11.194 | 0.982 | 10.052 | 0.385 | fickian | Zero order |
F2 | 0.918 | 10.539 | 0.973 | 15.678 | 0.871 | 12.802 | 0.945 | 11.986 | 0.996 | 12.983 | 0.417 | fickian | Peppas release |
F3 | 0.974 | 6.132 | 0.835 | 10.605 | 0.997 | 19.769 | 0.994 | 16.897 | 0.987 | 18.529 | 0.564 | Nonfickian | Higuchi matrix |
F4 | 0.942 | 12.195 | 0.899 | 11.481 | 0.934 | 11.983 | 0.992 | 10.631 | 0.995 | 14.777 | 0.399 | fickian | Peppas release |
F5 | 0.891 | 10.523 | 0.971 | 10.771 | 0.909 | 16.911 | 0.919 | 12.752 | 0.979 | 11.650 | 0.672 | Nonfickian | Peppas release |
F6 | 0.917 | 15.225 | 0.993 | 17.232 | 0.781 | 17.668 | 0.984 | 11.981 | 0.843 | 21.811 | 0.685 | Nonfickian | Hix Crow |
F7 | 0.932 | 13.809 | 0.789 | 10.765 | 0.927 | 21.286 | 0.912 | 10.098 | 0.998 | 16.659 | 0.391 | fickian | Peppas release |
F8 | 0.874 | 17.220 | 0.985 | 13.723 | 0.801 | 10.096 | 0.951 | 13.231 | 0.992 | 10.526 | 0.772 | Nonfickian | Peppas release |
F9 | 0.909 | 10.448 | 0.987 | 11.791 | 0.923 | 11.776 | 0.926 | 11.875 | 0.975 | 15.433 | 0.566 | Nonfickian | Hix Crow |
Formulations | Variables | Responses | ||||
---|---|---|---|---|---|---|
A (Sodium Alginate) g | B (HPMC K4M) g | Floating Lag Time * (min) | Water Uptake at 2 h *(%) | % Drug Release * (6 h) | % Drug Release * (12 h) | |
F1 | 1 | 1 | 2.47 ± 0.4 | 44 ± 0.76 | 73.1 ± 0.42 | 99.89 ± 0.27 |
F2 | 2 | 1 | 3.12 ± 0.2 | 6.8 ± 0.42 | 65.2 ± 0.53 | 87.54 ± 0.65 |
F3 | 3 | 1 | 6.27 ± 0.2 | 42 ± 0.71 | 58.3 ± 0.21 | 84.32 ± 0.14 |
F4 | 1 | 1.5 | 30 ± 0.8 | 13 ± 0.18 | 70.2 ± 0.02 | 84.33 ± 0.17 |
F5 | 2 | 1.5 | 42 ± 0.5 | 17.3 ± 0.22 | 45.6 ± 0.62 | 74.31 ± 0.02 |
F6 | 3 | 1.5 | 49 ± 0.4 | 15.7 ± 0.32 | 30.2 ± 0.76 | 55.44 ± 0.87 |
F7 | 1 | 2 | 74 ± 0.6 | 10.82 ± 0.43 | 42.3 ± 0.29 | 69.91 ± 0.54 |
F8 | 2 | 2 | 86 ± 0.2 | 30.87 ± 0.21 | 34.2 ± 0.71 | 59.16 ± 0.22 |
F9 | 3 | 2 | 89 ± 0.7 | 7.2 ± 0.11 | 29.4 ± 0.63 | 50.73 ± 0.87 |
Intercept | A[1] | A[2] | B[1] | B[2] | R2 | |
---|---|---|---|---|---|---|
Floating lag time | +42.4289 | −6.93889 | 1.27778 | −38.4756 | −2.09556 | 0.9924 |
p−value | 0.0530 | 0.0530 | <0.0001 | <00001 | ||
% Water uptake at 2 h | +20.8444 | 1.75556 | −2.5444 | 10.0889 | −5.511 | 0.9111 |
p−value | 0.059 | 0.059 | 0.0517 | 0.0517 | ||
% Drug release at 6 h | +49.82 | −3.09 | +12.01 | +3.78 | +6.68 | 0.8977 |
p−value | 0.0748 | 0.0748 | 0.0197 | 0.0197 | ||
% Drug release at 12 h | +73.96 | −3.10 | +10.75 | +4.35 | +3.05 | 0.9312 |
p−value | 0.0523 | 0.0523 | 0.0528 | 0.0528 |
Source | b-Coefficient | Sum of Sqaure | d.f. | Mean Square | F-Value | p-Value |
---|---|---|---|---|---|---|
Floating Lag Time (min) | ||||||
Model | +42.43 | 9637.8 | 4 | 2409.45 | 131.23 | 0.0002 |
A[1] | −6.94 | 245.49 | 2 | 122.74 | 6.69 | 0.0530 |
B[1] | −38.48 | 9392.32 | 2 | 4696.16 | 255.78 | <0.0001 |
Residual | 73.44 | 4 | 18.36 | |||
9711.25 | 8 | |||||
% Water Uptake | ||||||
Model | +20.84 | 489.88 | 4 | 122.47 | 41.59 | 0.059 |
A[1] | +1.76 | 30.54 | 2 | 15.27 | 5.18 | 0.095 |
B[1] | +10.09 | 459.34 | 2 | 229.67 | 7.8 | 0.051 |
Residual | 1177.84 | 4 | 294.46 | |||
1667.72 | 8 | |||||
% Drug Release at 6 h | ||||||
Model | +49.82 | 2058.12 | 4 | 514.53 | 8.78 | 0.0292 |
A[1] | −3.09 | 622.67 | 2 | 311.33 | 5.31 | 0.748 |
B[1] | +3.78 | 1435.45 | 2 | 717.72 | 12.25 | 0.0197 |
Residual | 234.41 | 4 | 58.6 | |||
2292.53 | 8 | |||||
% Drug Release at 12 h | ||||||
Model | +73.96 | 800.58 | 4 | 200.53 | 8.78 | 0.0571 |
A[1] | −3.10 | 551.24 | 2 | 275.33 | 5.31 | 0.852 |
B[1] | +4.35 | 249.45 | 2 | 124.72 | 12.25 | 0.0432 |
Residual | 1389.41 | 4 | 347 | |||
2189.53 | 8 |
Formulations | % Water Uptake * | ||
---|---|---|---|
At 30 min | At 60 min | At 120 min | |
F1 | 7.5 ± 0.61 | 33 ± 0.49 | 44 ± 0.76 |
F2 | 15.6 ± 0.31 | 23.5 ± 0.28 | 6.8 ± 0.42 |
F3 | 16 ± 0.22 | 16 ± 0.12 | 42 ± 0.71 |
F4 | 7.4 ± 0.34 | 7.5 ± 0.18 | 13 ± 0.18 |
F5 | 0 ± 0.76 | 15.3 ± 0.08 | 17.3 ± 0.22 |
F6 | 4.5 ± 0.28 | 14.79 ± 0.32 | 15.7 ± 0.32 |
F7 | 0.57 ± 0.11 | 2.2 ± 0.63 | 10.82 ± 0.43 |
F8 | 5.26 ± 0.37 | 12.5 ± 0.42 | 30.87 ± 0.21 |
F9 | 13 ± 0.28 | 5.6 ± 0.28 | 7.2 ± 0.11 |
Factor A | Factor B | Optimized Formulation Independent Variables | Predicted Value | Observed Value | Desirability |
---|---|---|---|---|---|
3 g | 1 g | Floating lag time (min) | 9.61 | 8.91 | 0.822 |
% Water uptake at 2 h | 31.72 | 30.96 | |||
% Drug release at 6 h | 44.67 | 43.21 | |||
% Drug release at 12 h | 84.32 | 86.12 |
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Hani, U.; Rahamathulla, M.; Osmani, R.A.M.; Begum, M.Y.; Wahab, S.; Ghazwani, M.; Fatease, A.A.; Alamri, A.H.; Gowda, D.V.; Alqahtani, A. Development and Characterization of Oral Raft Forming In Situ Gelling System of Neratinib Anticancer Drug Using 32 Factorial Design. Polymers 2022, 14, 2520. https://doi.org/10.3390/polym14132520
Hani U, Rahamathulla M, Osmani RAM, Begum MY, Wahab S, Ghazwani M, Fatease AA, Alamri AH, Gowda DV, Alqahtani A. Development and Characterization of Oral Raft Forming In Situ Gelling System of Neratinib Anticancer Drug Using 32 Factorial Design. Polymers. 2022; 14(13):2520. https://doi.org/10.3390/polym14132520
Chicago/Turabian StyleHani, Umme, Mohamed Rahamathulla, Riyaz Ali M. Osmani, M.Yasmin Begum, Shadma Wahab, Mohammed Ghazwani, Adel Al Fatease, Ali H. Alamri, Devegowda V. Gowda, and Ali Alqahtani. 2022. "Development and Characterization of Oral Raft Forming In Situ Gelling System of Neratinib Anticancer Drug Using 32 Factorial Design" Polymers 14, no. 13: 2520. https://doi.org/10.3390/polym14132520
APA StyleHani, U., Rahamathulla, M., Osmani, R. A. M., Begum, M. Y., Wahab, S., Ghazwani, M., Fatease, A. A., Alamri, A. H., Gowda, D. V., & Alqahtani, A. (2022). Development and Characterization of Oral Raft Forming In Situ Gelling System of Neratinib Anticancer Drug Using 32 Factorial Design. Polymers, 14(13), 2520. https://doi.org/10.3390/polym14132520