Mechanism of Supersaturation Suppression in Dissolution Process of Acidic Drug Salt
- 22 February 2019
- journal article
- research article
- Published by American Chemical Society (ACS) in Molecular Pharmaceutics
- Vol. 16 (4), 1669-1677
- https://doi.org/10.1021/acs.molpharmaceut.9b00006
Abstract
Supersaturable active pharmaceutical ingredients (sAPI), such as salts, cocrystals, and amorphous solids, can form supersaturated solutions after dissolving in the gastrointestinal fluids. However, there are cases in which supersaturation is not observed in an in vitro non-sink dissolution test. The purpose of the present study was to investigate the mechanisms of supersaturation suppression in the dissolution process of acidic drug salts. Diclofenac sodium (DCF Na, pKa = 4.0) was employed as a model drug. DCF Na APIs and tablets (25 mg, 0.08 mmol) showed little or no supersaturation at pH 1.2 (compendial paddle apparatus, 500 mL, 50 rpm). However, marked supersaturation was observed at pH 2.0 and pH 3.0. The liquid-liquid phase separation (LLPS) of DCF FA was observed in the surrounding of the DCF Na particles immediately after contact with acidic media. Particularly at pH 1.2, the surface of DCF Na was immediately covered with the liquid (oil) layer of DCF FA. The DCF FA liquid layer started to crystalize within several minutes. The LLPS concentration of DCF FA (0.30 mM) was twice as high as the theoretical maximum concentration after the complete dissolution of DCF Na in the dissolution test (0.16 mM). In addition, in the bulk phase precipitation test at 0.16 mM, rapid concentration reduction was not observed within 1 hour in the bulk media. Taken together, these results suggest that the LLPS (and subsequent crystallization) of DCF FA on the surface of DCF Na particles rather than in the bulk medium is more likely to have suppressed the supersaturation from DCF Na.Keywords
Funding Information
- Japan Agency for Medical Research and Development (JP17ak0101074)
This publication has 37 references indexed in Scilit:
- Improving Dissolution Rate of Carbamazepine-Glutaric Acid Cocrystal Through Solubilization by Excess CoformerPharmaceutical Research, 2018
- Harvesting Potential Dissolution Advantages of Soluble Cocrystals by Depressing Precipitation Using the Common Coformer EffectCrystal Growth & Design, 2016
- In situ monitoring of carbamazepine–nicotinamide cocrystal intrinsic dissolution behaviourEuropean Journal of Pharmaceutics and Biopharmaceutics, 2013
- Modifying the Diffusion Layer of Soluble Salts of Poorly Soluble Basic Drugs To Improve Dissolution PerformanceMolecular Pharmaceutics, 2010
- FINDING SOLUTIONSChemical & Engineering News, 2010
- Using Measured pKa, LogP and Solubility to Investigate Supersaturation and Predict BCS ClassCurrent Drug Metabolism, 2008
- Crystal engineering of active pharmaceutical ingredients to improve solubility and dissolution ratesAdvanced Drug Delivery Reviews, 2007
- Salt formation to improve drug solubilityAdvanced Drug Delivery Reviews, 2007
- Solubility and Dissolution Profile Assessment in Drug DiscoveryDrug Metabolism and Pharmacokinetics, 2007
- Effect of Diffusion Layer pH and Solubility on the Dissolution Rate of Pharmaceutical Bases and their Hydrochloride Salts I: PhenazopyridineJournal of Pharmaceutical Sciences, 1985