Itraconazole Nanosuspensions via Dual Centrifugation Media Milling: Impact of Formulation and Process Parameters on Particle Size and Solid-State Conversion as Well as Storage Stability
Nanocrystal suspensions proved to be a potent enabling principle for biopharmaceutics classification system class II drugs with dissolution limited bioavailability. In the example of itraconazole (ITZ) as a model drug combined with electrosteric stabilization using hydroxypropyl cellulose (HPC-SL),...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-07-01
|
| Series: | Pharmaceutics |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1999-4923/14/8/1528 |
| _version_ | 1797431809821114368 |
|---|---|
| author | Ann-Cathrin Willmann Kai Berkenfeld Thilo Faber Herbert Wachtel Georg Boeck Karl G. Wagner |
| author_facet | Ann-Cathrin Willmann Kai Berkenfeld Thilo Faber Herbert Wachtel Georg Boeck Karl G. Wagner |
| author_sort | Ann-Cathrin Willmann |
| collection | DOAJ |
| description | Nanocrystal suspensions proved to be a potent enabling principle for biopharmaceutics classification system class II drugs with dissolution limited bioavailability. In the example of itraconazole (ITZ) as a model drug combined with electrosteric stabilization using hydroxypropyl cellulose (HPC-SL), sodium dodecyl sulfate (SDS) and polysorbate 80 (PS80), the impacts of formulation and process parameters of a dual centrifugal mill on material attributes such as particle size, zeta potential, particle morphology, storage stability and especially solid-state characteristics were evaluated. A minimal concentration of 0.9% (<i>w</i>/<i>w</i>) HPC-SL, 0.14% (<i>w</i>/<i>w</i>) SDS and 0.07% (<i>w</i>/<i>w</i>) PS80 was necessary for sufficient nanoparticle stabilization. Despite the minor effect of PS80, its presence was beneficial for electrosteric stabilization. Choosing lower stabilizer concentrations resulted in a pronounced increase in particle size due to agglomeration, which was confirmed by SEM imaging and a decrease in zeta potential in combination with an amorphization of the particles. Milling temperature had no significant impact on the particle size, whereas milling speed and the size of the milling beads used were found to have a strong impact on the critical material attributes such as particle size and polydispersity index. The smallest particle sizes could be obtained by using the smallest milling bead size. However, the smallest obtainable particle size could only be achieved by using two-fold stabilizer concentrations, as smaller particles exhibit a larger specific surface area. |
| first_indexed | 2024-03-09T09:50:41Z |
| format | Article |
| id | doaj.art-289b207588534f169dfcc8136745e571 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T09:50:41Z |
| publishDate | 2022-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-289b207588534f169dfcc8136745e5712023-12-02T00:09:16ZengMDPI AGPharmaceutics1999-49232022-07-01148152810.3390/pharmaceutics14081528Itraconazole Nanosuspensions via Dual Centrifugation Media Milling: Impact of Formulation and Process Parameters on Particle Size and Solid-State Conversion as Well as Storage StabilityAnn-Cathrin Willmann0Kai Berkenfeld1Thilo Faber2Herbert Wachtel3Georg Boeck4Karl G. Wagner5Pharmaceutical Development, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, 88397 Biberach, GermanyDepartment of Pharmaceutical Technology, University of Bonn, Gerhard-Domagk-Straße 3, 53121 Bonn, GermanyDepartment of Pharmaceutical Technology, University of Bonn, Gerhard-Domagk-Straße 3, 53121 Bonn, GermanyDevice Development, Boehringer Ingelheim GmbH & Co. KG, Binger Straße 173, 55216 Ingelheim am Rhein, GermanyDepartment Discovery Research, Boehringer Ingelheim RCV GmbH & Co. KG, Dr.-Boehringer-Gasse 5-11, 1121 Vienna, AustriaDepartment of Pharmaceutical Technology, University of Bonn, Gerhard-Domagk-Straße 3, 53121 Bonn, GermanyNanocrystal suspensions proved to be a potent enabling principle for biopharmaceutics classification system class II drugs with dissolution limited bioavailability. In the example of itraconazole (ITZ) as a model drug combined with electrosteric stabilization using hydroxypropyl cellulose (HPC-SL), sodium dodecyl sulfate (SDS) and polysorbate 80 (PS80), the impacts of formulation and process parameters of a dual centrifugal mill on material attributes such as particle size, zeta potential, particle morphology, storage stability and especially solid-state characteristics were evaluated. A minimal concentration of 0.9% (<i>w</i>/<i>w</i>) HPC-SL, 0.14% (<i>w</i>/<i>w</i>) SDS and 0.07% (<i>w</i>/<i>w</i>) PS80 was necessary for sufficient nanoparticle stabilization. Despite the minor effect of PS80, its presence was beneficial for electrosteric stabilization. Choosing lower stabilizer concentrations resulted in a pronounced increase in particle size due to agglomeration, which was confirmed by SEM imaging and a decrease in zeta potential in combination with an amorphization of the particles. Milling temperature had no significant impact on the particle size, whereas milling speed and the size of the milling beads used were found to have a strong impact on the critical material attributes such as particle size and polydispersity index. The smallest particle sizes could be obtained by using the smallest milling bead size. However, the smallest obtainable particle size could only be achieved by using two-fold stabilizer concentrations, as smaller particles exhibit a larger specific surface area.https://www.mdpi.com/1999-4923/14/8/1528dual centrifugationitraconazolemedia millingnanocrystalsnanosuspensionagglomeration |
| spellingShingle | Ann-Cathrin Willmann Kai Berkenfeld Thilo Faber Herbert Wachtel Georg Boeck Karl G. Wagner Itraconazole Nanosuspensions via Dual Centrifugation Media Milling: Impact of Formulation and Process Parameters on Particle Size and Solid-State Conversion as Well as Storage Stability Pharmaceutics dual centrifugation itraconazole media milling nanocrystals nanosuspension agglomeration |
| title | Itraconazole Nanosuspensions via Dual Centrifugation Media Milling: Impact of Formulation and Process Parameters on Particle Size and Solid-State Conversion as Well as Storage Stability |
| title_full | Itraconazole Nanosuspensions via Dual Centrifugation Media Milling: Impact of Formulation and Process Parameters on Particle Size and Solid-State Conversion as Well as Storage Stability |
| title_fullStr | Itraconazole Nanosuspensions via Dual Centrifugation Media Milling: Impact of Formulation and Process Parameters on Particle Size and Solid-State Conversion as Well as Storage Stability |
| title_full_unstemmed | Itraconazole Nanosuspensions via Dual Centrifugation Media Milling: Impact of Formulation and Process Parameters on Particle Size and Solid-State Conversion as Well as Storage Stability |
| title_short | Itraconazole Nanosuspensions via Dual Centrifugation Media Milling: Impact of Formulation and Process Parameters on Particle Size and Solid-State Conversion as Well as Storage Stability |
| title_sort | itraconazole nanosuspensions via dual centrifugation media milling impact of formulation and process parameters on particle size and solid state conversion as well as storage stability |
| topic | dual centrifugation itraconazole media milling nanocrystals nanosuspension agglomeration |
| url | https://www.mdpi.com/1999-4923/14/8/1528 |
| work_keys_str_mv | AT anncathrinwillmann itraconazolenanosuspensionsviadualcentrifugationmediamillingimpactofformulationandprocessparametersonparticlesizeandsolidstateconversionaswellasstoragestability AT kaiberkenfeld itraconazolenanosuspensionsviadualcentrifugationmediamillingimpactofformulationandprocessparametersonparticlesizeandsolidstateconversionaswellasstoragestability AT thilofaber itraconazolenanosuspensionsviadualcentrifugationmediamillingimpactofformulationandprocessparametersonparticlesizeandsolidstateconversionaswellasstoragestability AT herbertwachtel itraconazolenanosuspensionsviadualcentrifugationmediamillingimpactofformulationandprocessparametersonparticlesizeandsolidstateconversionaswellasstoragestability AT georgboeck itraconazolenanosuspensionsviadualcentrifugationmediamillingimpactofformulationandprocessparametersonparticlesizeandsolidstateconversionaswellasstoragestability AT karlgwagner itraconazolenanosuspensionsviadualcentrifugationmediamillingimpactofformulationandprocessparametersonparticlesizeandsolidstateconversionaswellasstoragestability |