Salt solubility products of diprenorphine hydrochloride, codeine and lidocaine hydrochlorides and phosphates - novel method of data analysis not dependent on explicit solubility equations

Gergely Völgyi, Attila Marosi, Krisztina Takács-Novák, Alex Avdeef

Research output: Contribution to journalArticle

21 Citations (Scopus)


A novel general approach was described to address many of the challenges of salt solubility determination of drug substances, with data processing and refinement of equilibrium constants encoded in the computer program pDISOL-XTM. The new approach was illustrated by the determinations of the solubility products of diprenorphine hydrochloride, codeine hydrochloride and phosphate, lidocaine hydrochloride and phosphate at 25 °C, using a recently-optimized saturation shake-flask protocol. The effects of different buffers (Britton-Robinson universal and Sörensen phosphate) were compared. Lidocaine precipitates were characterized by X-ray powder diffraction (XRPD) and polarization light microscopy. The ionic strength in the studied systems ranged from 0.25 to 4.3 M. Codeine (and possibly diprenorphine) chloride were less soluble than the phosphates for pH > 2. The reverse trend was evident with lidocaine. Diprenorphine saturated solutions showed departure from the predictions of the Henderson-Hasselbalch equation in alkaline (pH > 9) solutions, consistent with the formation of a mixed-charge anionic dimer.

Original languageEnglish
Pages (from-to)48-62
Number of pages15
JournalADMET and DMPK
Issue number4
Publication statusPublished - Dec 1 2013



  • Aggregation
  • Salt solubility products, solubility equations
  • Shake-flask method
  • Sparingly-soluble drugs
  • pH-dependent solubility

ASJC Scopus subject areas

  • Chemistry (miscellaneous)
  • Medicine (miscellaneous)
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Pharmacology (medical)

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