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, K. Takács-Novák, Alex Avdeef

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

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
Volume1
Issue number4
DOIs
Publication statusPublished - Dec 1 2013

Fingerprint

Diprenorphine
Codeine
data processing program
Lidocaine
polarization
Solubility
data analysis
Salts
Phosphates
drug
trend
Polarization Microscopy
Powder Diffraction
X-Ray Diffraction
Osmolar Concentration
Chlorides
Equilibrium constants
Buffers
Software
Ionic strength

Keywords

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

ASJC Scopus subject areas

  • Health(social science)
  • Pharmacology (medical)

Cite this

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abstract = "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 S{\"o}rensen 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.",
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AU - Takács-Novák, K.

AU - Avdeef, Alex

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N2 - 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.

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