Effect of Extent of Supersaturation on the Evolution of Kinetic Solubility Profiles
Bibliographic record
Abstract
Solubility limited compounds require enabling formulations such as amorphous solid dispersions (ASDs) to increase the apparent solubility by dissolving to a concentration higher than the equilibrium solubility of the drug. This may lead to subsequent precipitation and thus the loss of the solubility advantage. Although higher supersaturation is known to result in faster precipitation, the overall effect of this faster precipitation on the bioavailability is not well understood. The objective of this study is to gain a better understanding of the impact of extent of supersaturation (i.e., dose) on the resulting kinetic solubility profiles of supersaturating dosage forms. Experimental concentration-time curves of two model compounds with different recrystallization tendencies, indomethacin (IND) and naproxen (NAP), were explored under varying sink indices (SIs) by infusing varying volumes of dissolved drug (e.g., in ethanol) into the dissolution medium. The experimental results were simulated with a mechanistic model considering classical nucleation theory and interface controlled growth on the nucleus surface. In the absence of dissolved polymer to inhibit precipitation, experimental and predicted results show that there exists a critical supersaturation below which no precipitation is observed, and due to this supersaturation maintenance, there exists an optimal dose which maximizes the area under the curve (AUC) of the kinetic solubility concentration-time profile. In the presence of dissolved polymer from ASD dissolution, similar trends were observed except the critical supersaturation was increased due to crystallization inhibition by the dissolved polymer. The importance of measuring the experimental "kinetic solubility" is emphasized. However, we show that the true solubility advantage of amorphous solids depends not on the "kinetic solubility" of amorphous dosage forms, typically arising from the balance between the rate of supersaturation generation and the precipitation kinetics, but rather on the critical supersaturation below which precipitation is not observed for a sufficiently long period.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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 source (direct Gemma or distilled Codex), 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".