Itraconazole Amorphous Solid Dispersion Tablets: Formulation and Compaction Process Optimization Using Quality by Design Principles and Tools
BCS Class II drugs, such as itraconazole (ITZ), exhibit poor solubility (1–4 ng/mL) and so require solubility enhancement. Therefore, ITZ and Kollidon<sup>®</sup> VA64 (KOL) amorphous solid dispersions (ASDs) were produced using hot-melt extrusion (HME) to improve ITZ’s poor solubility....
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-11-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/14/11/2398 |
| _version_ | 1827645688628903936 |
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| author | Hetvi Triboandas Kendal Pitt Mariana Bezerra Delphine Ach-Hubert Walkiria Schlindwein |
| author_facet | Hetvi Triboandas Kendal Pitt Mariana Bezerra Delphine Ach-Hubert Walkiria Schlindwein |
| author_sort | Hetvi Triboandas |
| collection | DOAJ |
| description | BCS Class II drugs, such as itraconazole (ITZ), exhibit poor solubility (1–4 ng/mL) and so require solubility enhancement. Therefore, ITZ and Kollidon<sup>®</sup> VA64 (KOL) amorphous solid dispersions (ASDs) were produced using hot-melt extrusion (HME) to improve ITZ’s poor solubility. A novel strategy for tablet formulations using five inorganic salts was investigated (KCl, NaCl, KBr, KHCO<sub>3</sub> and KH<sub>2</sub>PO<sub>4</sub>). These kosmotopric salts are thought to compete for water hydration near the polymer chain, hence, preventing polymer gelation and, therefore, facilitating disintegration and dissolution. Out of all the formulations, the KCl containing one demonstrated acceptable tensile strength (above 1.7 MPa), whilst providing a quick disintegration time (less than 15 min) and so was selected for further formulation development through a design of the experiment approach. Seven ITZ-KOL-ASD formulations with KCl were compacted using round and oblong punches. Round tablets were found to disintegrate under 20 min, whereas oblong tablets disintegrated within 10 min. The round tablets achieved over 80% ITZ release within 15 min, with six out of seven formulations achieving 100% ITZ release by 30 min. It was found that tablets comprising high levels of Avicel<sup>®</sup> pH 102 (30%) and low levels of KCl (5%) tend to fail the disintegration target due to the strong bonding capacity of Avicel<sup>®</sup> pH 102. The disintegration time and tensile strength responses were modeled to obtain design spaces (DSs) relevant to both round and oblong tablets. Within the DS, several formulations can be chosen, which meet the Quality Target Product Profile (QTPP) requirements for immediate-release round and oblong tablets and allow for flexibility to compact in different tablet shape to accommodate patients’ needs. It was concluded that the use of inorganic salts, such as KCl, is the key to producing tablets of ITZ ASDs with fast disintegration and enhanced dissolution. Overall, ITZ-KOL-ASD tablet formulations, which meet the QTPP, were achieved in this study with the aid of Quality by Design (QbD) principles for formulation and compaction process development and optimization. |
| first_indexed | 2024-03-09T18:44:42Z |
| format | Article |
| id | doaj.art-120039fd032a422bafdf075b8646bf81 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T18:44:42Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-120039fd032a422bafdf075b8646bf812023-11-24T06:21:37ZengMDPI AGPharmaceutics1999-49232022-11-011411239810.3390/pharmaceutics14112398Itraconazole Amorphous Solid Dispersion Tablets: Formulation and Compaction Process Optimization Using Quality by Design Principles and ToolsHetvi Triboandas0Kendal Pitt1Mariana Bezerra2Delphine Ach-Hubert3Walkiria Schlindwein4Leicester School of Pharmacy, De Montfort University, Leicester LE1 9BH, UKLeicester School of Pharmacy, De Montfort University, Leicester LE1 9BH, UKLeicester School of Pharmacy, De Montfort University, Leicester LE1 9BH, UKMedelpharm, 615 rue du Chat Botté, ZAC des Malettes, F-01700 Beynost, FranceLeicester School of Pharmacy, De Montfort University, Leicester LE1 9BH, UKBCS Class II drugs, such as itraconazole (ITZ), exhibit poor solubility (1–4 ng/mL) and so require solubility enhancement. Therefore, ITZ and Kollidon<sup>®</sup> VA64 (KOL) amorphous solid dispersions (ASDs) were produced using hot-melt extrusion (HME) to improve ITZ’s poor solubility. A novel strategy for tablet formulations using five inorganic salts was investigated (KCl, NaCl, KBr, KHCO<sub>3</sub> and KH<sub>2</sub>PO<sub>4</sub>). These kosmotopric salts are thought to compete for water hydration near the polymer chain, hence, preventing polymer gelation and, therefore, facilitating disintegration and dissolution. Out of all the formulations, the KCl containing one demonstrated acceptable tensile strength (above 1.7 MPa), whilst providing a quick disintegration time (less than 15 min) and so was selected for further formulation development through a design of the experiment approach. Seven ITZ-KOL-ASD formulations with KCl were compacted using round and oblong punches. Round tablets were found to disintegrate under 20 min, whereas oblong tablets disintegrated within 10 min. The round tablets achieved over 80% ITZ release within 15 min, with six out of seven formulations achieving 100% ITZ release by 30 min. It was found that tablets comprising high levels of Avicel<sup>®</sup> pH 102 (30%) and low levels of KCl (5%) tend to fail the disintegration target due to the strong bonding capacity of Avicel<sup>®</sup> pH 102. The disintegration time and tensile strength responses were modeled to obtain design spaces (DSs) relevant to both round and oblong tablets. Within the DS, several formulations can be chosen, which meet the Quality Target Product Profile (QTPP) requirements for immediate-release round and oblong tablets and allow for flexibility to compact in different tablet shape to accommodate patients’ needs. It was concluded that the use of inorganic salts, such as KCl, is the key to producing tablets of ITZ ASDs with fast disintegration and enhanced dissolution. Overall, ITZ-KOL-ASD tablet formulations, which meet the QTPP, were achieved in this study with the aid of Quality by Design (QbD) principles for formulation and compaction process development and optimization.https://www.mdpi.com/1999-4923/14/11/2398solubility enhancementamorphous solid dispersion (ASD)hot-melt extrusion (HME)itraconazole (ITZ)tablet compactionquality by design (QbD) |
| spellingShingle | Hetvi Triboandas Kendal Pitt Mariana Bezerra Delphine Ach-Hubert Walkiria Schlindwein Itraconazole Amorphous Solid Dispersion Tablets: Formulation and Compaction Process Optimization Using Quality by Design Principles and Tools Pharmaceutics solubility enhancement amorphous solid dispersion (ASD) hot-melt extrusion (HME) itraconazole (ITZ) tablet compaction quality by design (QbD) |
| title | Itraconazole Amorphous Solid Dispersion Tablets: Formulation and Compaction Process Optimization Using Quality by Design Principles and Tools |
| title_full | Itraconazole Amorphous Solid Dispersion Tablets: Formulation and Compaction Process Optimization Using Quality by Design Principles and Tools |
| title_fullStr | Itraconazole Amorphous Solid Dispersion Tablets: Formulation and Compaction Process Optimization Using Quality by Design Principles and Tools |
| title_full_unstemmed | Itraconazole Amorphous Solid Dispersion Tablets: Formulation and Compaction Process Optimization Using Quality by Design Principles and Tools |
| title_short | Itraconazole Amorphous Solid Dispersion Tablets: Formulation and Compaction Process Optimization Using Quality by Design Principles and Tools |
| title_sort | itraconazole amorphous solid dispersion tablets formulation and compaction process optimization using quality by design principles and tools |
| topic | solubility enhancement amorphous solid dispersion (ASD) hot-melt extrusion (HME) itraconazole (ITZ) tablet compaction quality by design (QbD) |
| url | https://www.mdpi.com/1999-4923/14/11/2398 |
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