Formulation of Pharmaceutical Tablets Containing β-Cyclodextrin-4-Methyl-Umbelliferone (Hymecromone) Inclusion Complexes and Study of the Dissolution Kinetics
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
Synthesis of 4-Methyl-Umbelliferone (4-MU)
2.2. Preparation of β-CD—4-Methyl-Umbelliferone Inclusion Complexes (β-CD-4-MU ICs)
2.3. Characterization of the β-CD—4-Methyl-Umbelliferone ICs
2.3.1. Inclusion Efficiency of the β-CD—4-Methyl-Umbelliferone ICs
2.3.2. Dynamic Light Scattering (DLS)
2.3.3. Nuclear Magnetic Resonance Spectroscopy (NMR Spectroscopy)
2.3.4. FT-IR Spectroscopy
2.3.5. Thermogravimetric Analysis (TGA)
2.3.6. Scanning Electron Microscopy (SEM)
2.4. Biological Activity Evaluation of the β-CD—4-Methyl-Umbelliferone ICs
2.4.1. Determination of Reducing Activity Using the Stable Radical 1,1-Diphenyl-Picrylhydrazyl (DPPH)
2.4.2. Inhibition of Linoleic Acid Peroxidation
2.4.3. Soybean Lipoxygenase Inhibition Study
2.5. In Vitro Release Studies of the β-CD—4-Methyl-Umbelliferone ICs
2.6. Preliminary Tests
2.7. Preparation of Pharmaceutical Tablets
2.8. Dissolution Testing
3. Results and Discussion
3.1. Characterization of the β-CD-4-MU ICs
3.1.1. Inclusion Efficiency, Process Yield, Size, Size Distribution, and Zeta-Potential
3.1.2. Nuclear Magnetic Resonance Spectroscopy (NMR Spectroscopy)
3.1.3. FT-IR Spectroscopy
3.1.4. Thermogravimetric Analysis (TGA)
3.1.5. Scanning Electron Microscopy (SEM)
3.2. Biological Activity Evaluation
3.3. In Vitro Release Studies of the 4-MU from β-CD—4-Methyl-Umbelliferone ICs
3.4. Dissolution Testing
3.5. Formulation Optimization by Means of Extreme Vertices Mixture Design
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Tablet | β-CD-4-MU IC (mg) | β-CD (mg) | 4-MU (mg) | Lactose (mg) | Microcrystalline Cellulose (MCC) (mg) | Calcium Phosphate (CaP) (mg) | Magnesium Stearate (Mg-St) (mg) | Starch (St) (mg) | Total Tablet Mass (mg) | Hardness (N) |
---|---|---|---|---|---|---|---|---|---|---|
TT1 | - | 150 | - | 30 | 40 | 26 | 2 | 2 | 250 | 19 |
TT2 | - | 150 | - | 30 | 40 | 26 | 2 | 2 | 250 | 69 |
TT3 | - | 150 | - | 30 | 40 | 26 | 2 | 2 | 250 | 73 |
TT4 | - | 150 | - | 24 | 60 | 12 | 2 | 2 | 250 | 77 |
TT5 | - | 150 | - | - | 84 | 12 | 2 | 2 | 250 | 110 |
TT6 | - | 150 | - | - | 84 | 12 | 2 | 2 | 250 | 83 |
TT7 | - | 150 | - | - | 84 | 12 | 2 | 2 | 250 | 110 |
TT8 | 150 | - | - | - | 84 | 12 | 2 | 2 | 250 | 156 |
TT9 | - | 135 | 15 | - | 84 | 12 | 2 | 2 | 250 | 108 |
TT10 | 150 | - | - | - | 84 | 12 | 2 | 2 | 250 | 149 |
Ingredient | Factor | Low | High |
---|---|---|---|
β-CD | x1 | 0.55 | 0.65 |
MCC | x2 | 0.30 | 0.35 |
CaP | x3 | 0.04 | 0.05 |
Tablet | β-CD-4-MU Inclusion Complex X1 (mg) | Microcrystalline Cellulose (MCC) X2 (mg) | Calcium Phosphate (CaP) X3 (mg) | Starch (St) X4 (mg) | Magnesium Stearate (Mg-St) X5 (mg) |
---|---|---|---|---|---|
Τ1 | 161.00 | 75.00 | 10.00 | 2.00 | 2.00 |
Τ2 | 156.000 | 78.13 | 11.87 | 2.00 | 2.00 |
Τ3 | 151.000 | 84.37 | 10.63 | 2.00 | 2.00 |
Τ4 | 149.75 | 84.38 | 11.87 | 2.00 | 2.00 |
Τ5 (i, ii) * | 153.50 | 81.25 | 11.25 | 2.00 | 2.00 |
Τ6 | 158.50 | 75.00 | 12.50 | 2.00 | 2.00 |
Τ7 | 146.00 | 87.50 | 12.50 | 2.00 | 2.00 |
Τ8 | 157.25 | 78.12 | 10.63 | 2.00 | 2.00 |
Τ9 | 148.50 | 87.50 | 10.00 | 2.00 | 2.00 |
Molar ratio β-CD:4-MU (mol) | β-CD (gr) | Size (nm) | Polydispersity Index (PdI) | Zeta-Potential (mV) | Process Yield % | Inclusion Efficiency (IE) % |
---|---|---|---|---|---|---|
2:1 | 0.5 | 917.9 ± 127.5 | 0.709 ± 0.087 | −16.8 ± 2.6 | 69 | 57 |
1:1 | 0.5 | 145.6 ± 52.0 | 0.370 ± 0.025 | −29.5 ± 1.4 | 78 | 75 |
1:1 | 4 | 271.0 ± 20.5 | 0.367 ± 0.065 | −29.1 ± 0.9 | 82 | 77 |
Proton | Chemical Shifts (δ1) of β-CD Protons (ppm) | Chemical Shifts (δ2) of β-CD Protons in β-CD—ICs (ppm) | Δδ = δ2 − δ1 (ppm) |
---|---|---|---|
H-1′ | 5.085 | 5.076 | −0.009 |
H-2′ | 3.664 | 3.652 | −0.012 |
H-3′ | 3.980 | 3.965 | −0.015 |
H-4′ | 3.599 | 3.595 | −0.004 |
H-5′ | 3.893 | 3.845 | −0.048 |
H-6′ | 3.893 | 3.884 | −0.009 |
Sample | O–H Stretching Vibration | C–H Stretching Vibration (Aromatic Ring) | C–H Stretching Vibration | C=O Stretching Vibration | Asymmetric C–H Stretching (-CH2) | C=C Stretching Vibration (Aromatic Ring) | O–H Bending Vibration | C–H in Plane Bending Vibration (Aromatic Ring) | C-O Stretching Vibration of the Secondary Alcohol | C–O Stretching Vibration of Phenols |
---|---|---|---|---|---|---|---|---|---|---|
4-MU | - | 3155 | - | 1680 | - | 1601 | 1390 | 1274 | - | 1067 |
β-CD | 3377 | - | 2925 | - | 1643 | - | 1415 | - | 1029 | - |
β-CD-4-MU | 3389 | - | 2927 | 1708 | 1630 | - | 1417 | - | 1030 | 1079 |
%DPPH Scavenging Ability ± SD # (100 μM) 20/60 min | % Lipid Peroxidation Inhibition (AAPH) ± SD # (100 μM) | Inhibition of Soybean Lipoxygenase Enzyme (LOX) IC50 (μΜ) ± SD # | |
---|---|---|---|
4-MU | No/No | 93 ± 1.5 | No |
β-CD | No/No | 18 ± 0.6 | 51.5 ± 1.7 |
β-CD-4-MU | 63 (±2.2)/78 (±3.1) | 100 ± 2.6 | 10.0 ± 0.2 |
Trolox | - | 88 ± 0.8 | - |
NDGA | 84 (±1.6)/83 (±1.8) | - | 0.45 ± 0.1 |
pH | Zero-Order | First-Order | Higuchi | Korsmeyer–Peppas | Higuchi | |
---|---|---|---|---|---|---|
R2 | R2 | R2 | R2 | R2 | n | Equation |
1.2 | 0.808 | 0.341 | 0.941 | 0.872 | 0.9151 | y = 2.003x + 78.58 |
7.4 | 0.539 | 0.365 | 0.823 | 0.893 | 0.8787 | y = 6.142x + 16.95 |
6.8 | 0.663 | 0.427 | 0.899 | 0.917 | 0.9144 | y = 7.369x + 12.73 |
Tablet | Zero-Order | First-Order | Higuchi | Korsmeyer–Peppas | Higuchi | |
---|---|---|---|---|---|---|
R2 | R2 | R2 | R2 | n | Equation | |
1 | 0.775 | 0.536 | 0.925 | 0.968 | 0.8865 | y = 6.377x + 0.6819 |
2 | 0.799 | 0.594 | 0.915 | 0.971 | 0.8454 | y = 4.9163x − 0.9497 |
3 | 0.870 | 0.589 | 0.957 | 0.982 | 0.9047 | y = 6.8621x − 1.4428 |
4 | 0.699 | 0.54 | 0.859 | 0.961 | 0.9003 | y = 6.358x + 1.6102 |
5 i | 0.799 | 0.523 | 0.953 | 0.965 | 0.8442 | y = 5.2721x + 2.1428 |
5 ii * | 0.917 | 0.648 | 0.932 | 0.990 | 0.845 | y = 5.3008x + 2.0575 |
6 | 0.814 | 0.577 | 0.932 | 0.975 | 0.8644 | y = 5.6027x − 0.6935 |
7 | 0.694 | 0.493 | 0.890 | 0.951 | 0.8393 | y = 5.004x + 4.4583 |
8 | 0.795 | 0.536 | 0.946 | 0.967 | 0.814 | y = 4.3748x + 2.4986 |
9 | 0.678 | 0.515 | 0.857 | 0.958 | 0.8556 | y = 5.4429x + 0.7738 |
Run | x1 | x2 | x3 | f80 | f120 |
---|---|---|---|---|---|
1 | 0.6440 | 0.3000 | 0.0400 | 0.5772 | 0.7054 |
2 | 0.6240 | 0.3125 | 0.0475 | 0.4347 | 0.5355 |
3 | 0.6040 | 0.3375 | 0.0425 | 0.6023 | 0.7421 |
4 | 0.5990 | 0.3375 | 0.0475 | 0.5932 | 0.7251 |
5 i | 0.6140 | 0.3250 | 0.0450 | 0.4929 | 0.5989 |
5 ii | 0.6140 | 0.3250 | 0.0450 | 0.49462 | 0.60116 |
6 | 0.6340 | 0.3000 | 0.0500 | 0.4941 | 0.6067 |
7 | 0.5840 | 0.3500 | 0.0500 | 0.4907 | 0.5908 |
8 | 0.6290 | 0.3125 | 0.0425 | 0.4178 | 0.5066 |
9 | 0.5940 | 0.3500 | 0.0400 | 0.4953 | 0.6055 |
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Kavetsou, E.; Pitterou, I.; Dimitrioglou, N.G.; Kikionis, S.; Kritsi, E.; Zoumpoulakis, P.; Pontiki, E.; Hadjipavlou-Litina, D.; Hatziavramidis, D.T.; Detsi, A. Formulation of Pharmaceutical Tablets Containing β-Cyclodextrin-4-Methyl-Umbelliferone (Hymecromone) Inclusion Complexes and Study of the Dissolution Kinetics. Micro 2023, 3, 892-911. https://doi.org/10.3390/micro3040061
Kavetsou E, Pitterou I, Dimitrioglou NG, Kikionis S, Kritsi E, Zoumpoulakis P, Pontiki E, Hadjipavlou-Litina D, Hatziavramidis DT, Detsi A. Formulation of Pharmaceutical Tablets Containing β-Cyclodextrin-4-Methyl-Umbelliferone (Hymecromone) Inclusion Complexes and Study of the Dissolution Kinetics. Micro. 2023; 3(4):892-911. https://doi.org/10.3390/micro3040061
Chicago/Turabian StyleKavetsou, Eleni, Ioanna Pitterou, Nikos G. Dimitrioglou, Stefanos Kikionis, Eftichia Kritsi, Panagiotis Zoumpoulakis, Eleni Pontiki, Dimitra Hadjipavlou-Litina, Dimitris T. Hatziavramidis, and Anastasia Detsi. 2023. "Formulation of Pharmaceutical Tablets Containing β-Cyclodextrin-4-Methyl-Umbelliferone (Hymecromone) Inclusion Complexes and Study of the Dissolution Kinetics" Micro 3, no. 4: 892-911. https://doi.org/10.3390/micro3040061
APA StyleKavetsou, E., Pitterou, I., Dimitrioglou, N. G., Kikionis, S., Kritsi, E., Zoumpoulakis, P., Pontiki, E., Hadjipavlou-Litina, D., Hatziavramidis, D. T., & Detsi, A. (2023). Formulation of Pharmaceutical Tablets Containing β-Cyclodextrin-4-Methyl-Umbelliferone (Hymecromone) Inclusion Complexes and Study of the Dissolution Kinetics. Micro, 3(4), 892-911. https://doi.org/10.3390/micro3040061