The Risk of Recrystallization: Changes to the Toxicity and Morphology of Pyrimethamine
Bibliographic record
Abstract
PURPOSE: Pyrimethamine, an anti-malarial agent known to exhibit solid state polymorphism, may be purified by means of recrystallization. Recrystallization may alter the solid state chemistry of pharmaceuticals, which may impact the toxicity and/or manufacturability thereof. We evaluated the risks associated with the recrystallization of pyrimethamine. METHODS: Pyrimethamine was recrystallized using several organic solvents. X-ray diffraction, thermal analysis, infra-red spectroscopy, microscopy, flowability -, solubility and dissolution testing as well as computational work were employed to evaluate the recrystallized products. RESULTS: A toxic solvatomorph of pyrimethamine (Pyr-MeOH) was found to be the product from methanol recrystallization. The elucidation of - and the elaboration on the unique characteristics of Pyr-MeOH provides the pharmaceutical industry with several means to identify Pyr-MeOH and to distinguish it from the pharmaceutically preferred anhydrous form (Pyr). Thermal methods of analysis found that the toxicity of Pyr-MeOH may be reversed by overcoming a desolvation activation energy of 148 kJ/mol. In addition it was found that recrystallization altered the morphology of Pyr. Angle of repose and tapped density determinations identified that the different morphologies of Pyr displayed differences in powder flow and compressibility behaviour and In Silico calculations were successful in rendering morphologies resembling that found experimentally. CONCLUSION: We present a solvatomorph of pyrimethamine and provide several characteristic means to identify this unwanted toxic form and quantified the energy required to overcome its toxicity. In addition we describe that Pyr may present in different morphologies and show how it may impact the manufacturability thereof.
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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 | 0.000 |
| 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 | 0.000 |
| 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".