Maximizing the Solubility Advantage of Controlled Release Amorphous Solid Dispersions by Rational Formulation of a Membrane-reservoir Coated Bead Design
Bibliographic record
Abstract
Biopharmaceutic Classification System Class II drugs pervasively overwhelm product pipelines since they suffer from dissolution-rate limited bioavailability. Although amorphization can impart a significant ‘solubility advantage’ to these compounds, solution-mediated phase transformation (SMPT) (i.e., recrystallization to the poorly soluble form) has limited its commercial application. Recently, controlled release amorphous solid dispersions (CRASD) have been introduced to circumvent excessive precipitation, while boasting precise, predictable sustained release. Hence, expanded research in this field may ultimately lead to greater industrial success rates and a wider breadth of available therapies. In this thesis, CRASD membrane-reservoir coated beads prepared by fluid-bed coating were investigated as a potential solid oral delivery system for poorly soluble model drug, celecoxib (CEL). By analyzing dissolution and recrystallization behaviors, the effects of: (1) pore-former (polyvinylpyrrolidone (PVP)) content and coating level, (2) novel terpolymer nanoparticle (TPN) versus conventional pore former (PVP), and (3) dose configuration by ASD reservoir loading level and bead quantity were evaluated. In the first study, the combination of high pore former content (PVP) and high coating level of a polyvinyl acetate-based CR membrane provided a moderately fast initial CEL release rate followed by sustained release, yielding the highest overall extent of release. The thicker, porous coating structure was proposed to serve as a transient drug reservoir, relieving supersaturation at both the interior and exterior sides of the membrane. In the second part, incorporation of TPN as an advanced pore former in ethylcellulose-based CR membranes produced smoother coatings resistant to surface precipitation and higher extent of release compared to those of PVP. The non-leachability and swelling mechanism of TPN advantageously enhanced molecular separation and steric hindrance of CEL crystal formation within the membrane. In the final study, excess ASD reservoir loading in CRASD with ethylcellulose-TPN membranes was disadvantageous, as release profiles were significantly supressed compared to lower reservoir loadings with lower doses, which was attributed to a higher propensity for internal SMPT. To conclude, truly maximizing the benefit of solubility enhancement requires the CRASD strategy to focus on all system features capable of enhancing and balancing the preservation of amorphous drug both within and external to the dosage form.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.005 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.002 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.008 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".