ADMET & DMPK

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

Konular:-

DOI:10.5599/admet.1.4.24

Anahtar Kelimeler:Sparingly-soluble drugs,PH-dependent solubility,Salt solubility products,Solubility equations,Aggregation,Shake-flask method

Özet: 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 oC, 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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