Differential effect of buffering agents on the crystallization of gemcitabine hydrochloride in frozen solutions.
The purpose of this study was to evaluate the differential effect of buffering agents on the crystallization of gemcitabine hydrochloride (GHCl) in frozen solutions. Four buffering agents, viz. citric acid (CA), malic acid (MA), succinic acid (SA) and tartaric acid (TA) were selected and their effect on GHCl crystallization was monitored using standard DSC and low temperature XRD. Onset of GHCl crystallization during heating run in DSC was measured to compare the differential effect of buffering agents. Glass transition temperature (Tg'), unfrozen water content in the freeze concentrate and crystallization propensity of the buffering agents was also determined for mechanistic understanding of the underlying effects. CA and MA inhibited while SA facilitated crystallization of GHCl even at 25 mM concentration. Increasing the concentration enhanced their effect. However, TA inhibited GHCl crystallization at concentrations <100mM and facilitated it at concentrations ≥100 mM. Lyophilization of GHCl with either SA or TA yielded elegant cakes, while CA and MA caused collapse. Tg' failed to explain the inhibitory effects of CA, MA and TA as all buffering agents lowered the Tg' of the system. Differential effect of buffering agents on GHCl crystallization could be explained by consideration of two opposing factors: (i) their own crystallization tendency and (ii) unfrozen water content in the freeze concentrate. In conclusion, it was established that API crystallization in frozen solution is affected by the type and concentration of the buffering agents.
Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, SAS Nagar, Mohali, Punjab 160062, India.
Mehulkumar
M
Patel
Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, SAS Nagar, Mohali, Punjab 160062, India.
Bhushan
B
Munjal
Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, SAS Nagar, Mohali, Punjab 160062, India. Electronic address: akbansal@niper.ac.in.
Arvind K
AK
Bansal
D002021:Buffers; D002152:Calorimetry, Differential Scanning; D019343:Citric Acid / Q000737:chemistry*; D003460:Crystallization; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry; D005079:Excipients / Q000737:chemistry*; D005612:Freeze Drying; D005615:Freezing; D008293:Malates / Q000737:chemistry*; D012996:Solutions; D019802:Succinic Acid / Q000737:chemistry*; D013644:Tartrates / Q000737:chemistry*; D044366:Transition Temperature; D014961:X-Ray Diffraction; D000093542:Gemcitabine
D002021:Buffers; D005079:Excipients; D008293:Malates; D012996:Solutions; D013644:Tartrates; D003841:Deoxycytidine; D019343:Citric Acid; C030298:malic acid; D019802:Succinic Acid; C029768:tartaric acid; D000093542:Gemcitabine
Calorimetry (DSC); Citric acid (PubChem CID: 311); Crystallization tendency; Gemcitabine hydrochloride (PubChem CID: 60749); Low temperature XRD; Lyophilization; Malic acid (PubChem CID: 525); Succinic acid (PubChem CID: 1110); Supersaturation; Tartaric acid (PubChem CID: 875); Unfrozen water