Multi-Compartmental Dissolution Method, an Efficient Tool for the Development of Enhanced Bioavailability Formulations Containing Poorly Soluble Acidic Drugs
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
2.2. Equilibrium Solubility Measurements
2.3. Dissolution Testing
2.3.1. USP Dissolution Method
2.3.2. GIS Dissolution Method
2.4. Determination of Dissolved Drug Content by High-Performance Liquid Chromatography (HPLC)
2.5. In Vitro In Vivo Correlation (IVIVC)
3. Results and Discussion
3.1. Thermodynamic Equilibrium Solubility Measurements
3.1.1. pH-Dependent Solubility
3.1.2. Solubility in Biorelevant Media
3.2. Dissolution Results Obtained by the USP Method
3.3. Dissolution Results Obtained by GIS Method
3.4. Establishment of the IVIVC Model
3.4.1. Analysis of In Vivo Data
3.4.2. Fitting of In Vitro Dissolution Data
3.4.3. Correlation
3.4.4. Simulation of Plasma Concentration Profiles
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
API | Active pharmaceutical ingredient |
ASD | Artificial stomach duodenal model |
BCS | Biopharmaceutics Classification System |
BR | Britton–Robinson |
DGM | Dynamic Gastric Model |
GIS | Gastrointestinal Simulator |
HPLC | High-Performance Liquid Chromatography |
HGM | Human Gastric Simulator |
IVIVC | In vitro–In vivo correlation |
NSAID | Non-Steroidal Anti-Inflammatory Drug |
SpH | PH-dependent solubility |
TIM | TNO gastro-Intestinal Model |
UIR | Unit impulse response |
USP | United States Pharmacopoeia |
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Product | Manufacturer | API Form | Abbreviation |
---|---|---|---|
Advil 200 mg coated tablets | Pfizer Consumer Healthcare, Madison, NJ, USA | ibuprofen free acid | IBU |
Advil 256 mg film-coated tablets | Pfizer Consumer Healthcare, Madison, NJ, USA | ibuprofen sodium | IBU-Na |
Dolowill RAPID 342 mg film-coated tablets | Goodwill Pharma, Szeged, Hungary | ibuprofen lysinate | IBU-Lys |
Advil ULTRA 200 mg soft-gelatin capsules | Pfizer Consumer Healthcare, Madison, NJ, USA | Ibuprofen in solution | IBU-lq |
Blank Biorelevant Media | Biorelevant Media | |||||
---|---|---|---|---|---|---|
Blank FaSSGF | Blank FaSSIF | Blank FaSSIF conc. | Full FaSSGF | Full FaSSIF | Full FaSSIF conc. | |
NaCl | 2.00 g | 6.19 g | 40.24 g | 2.00 g | 6.19 g | 40.24 g |
NaOH | - | 0.40 g | 2.60 g | - | 0.40 g | 2.60 g |
NaH2PO4. H2O | - | 3.96 g | 25.74 g | - | 3.96 g | 25.74 g |
SIF powder | - | - | - | 0.06 g | 2.25 g | 14.63 g |
Pepsin | - | - | - | 0.10 g | - | - |
pH adjustment | cc. HCl:purified water = 1:1 | 1M NaOH | - | cc. HCl:purified water = 1:1 | 1M NaOH | - |
pH | SpH ± SD (µg/mL) 1 | logSpH (mol/L) |
---|---|---|
1.92 | 70.8 ± 3.0 | −3.46 |
3.96 | 124 ± 13 | −3.22 |
5.95 | 1910 ± 70 | −2.03 |
7.17 | 32,033 ± 4135 | −0.81 |
8.02 | 300,000 ± 6500 | 0.16 |
14 | 734,000 ± 30,500 | 0.55 |
Solvent | SpH ± SD (µg/mL) 1 |
---|---|
FaSSGF blank, pH 1.6 | 56.3 ± 0.6 |
FaSSGF, pH 1.6 | 56.0 ± 0.5 |
FeSSGF-acetate, pH 4.5 | 194 ± 2 |
FeSSIF blank, pH 5.0 | 416 ± 12 |
FeSSIF, pH 5.0 | 2103 ± 56 |
FaSSIF blank, pH 6.5 | 2513 ± 15 |
FaSSIF, pH 6.5 | 3160 ± 31 |
Formulation | B | MDT (min) |
---|---|---|
IBU | 1.759 | 71.55 |
IBU-Na | 1.786 | 48.23 |
IBU-Lys | 2.087 | 44.55 |
IBU-lq | 2.274 | 52.18 |
Clinical Data Statistical Analysis of Individual Profiles | Clinical Data Mean Plasma conc. Profiles | IVIVC Prediction from GIS Dissolution | ||||||
---|---|---|---|---|---|---|---|---|
Formulation | Cmax | Ratio | tmax | Cmax | Ratio | Cmax | Ratio | tmax |
IBU | 37.70 | N/A | 82.1 | 28.25 | N/A | 37.80 | N/A | 81.7 |
IBU-Na | 47.00 | 1.25 | 35.2 | 44.00 | 1.56 | 41.00 | 1.09 | 60.5 |
IBU-Lys | 49.90 | 1.32 | 35.1 | 42.75 | 1.51 | 42.40 | 1.12 | 61.4 |
IBU-lq | 46.80 | 1.24 | 40.0 | 39.00 | 1.38 | 42.20 | 1.12 | 60.5 |
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Katona, M.T.; Nagy-Katona, L.; Szabó, R.; Borbás, E.; Tonka-Nagy, P.; Takács-Novák, K. Multi-Compartmental Dissolution Method, an Efficient Tool for the Development of Enhanced Bioavailability Formulations Containing Poorly Soluble Acidic Drugs. Pharmaceutics 2023, 15, 753. https://doi.org/10.3390/pharmaceutics15030753
Katona MT, Nagy-Katona L, Szabó R, Borbás E, Tonka-Nagy P, Takács-Novák K. Multi-Compartmental Dissolution Method, an Efficient Tool for the Development of Enhanced Bioavailability Formulations Containing Poorly Soluble Acidic Drugs. Pharmaceutics. 2023; 15(3):753. https://doi.org/10.3390/pharmaceutics15030753
Chicago/Turabian StyleKatona, Miklós Tamás, Lili Nagy-Katona, Réka Szabó, Enikő Borbás, Péter Tonka-Nagy, and Krisztina Takács-Novák. 2023. "Multi-Compartmental Dissolution Method, an Efficient Tool for the Development of Enhanced Bioavailability Formulations Containing Poorly Soluble Acidic Drugs" Pharmaceutics 15, no. 3: 753. https://doi.org/10.3390/pharmaceutics15030753