Influence of Microenvironment pH, Humidity, and Temperature on the Stability of Polymorphic and Amorphous Forms of Clopidogrel Bisulfate

Abstract

Abstract. The effect of microenvironment pH, humidity, and temperature was evaluated on the stability of polymorphic and amorphous forms of clopidogrel bisulfate, when present alone or in combinations. Oxalic acid and sodium carbonate were used as solid stressors to create acidic and alkaline pH, respectively. The samples without and with stressors were subjected for 3 months to (1) 0% RH, 25% RH, 75% RH, and 85% RH at 40°C and also to (2) 60°C, 80°C, and 100°C at 0% RH. In case of solid samples without stressors, the mixture of polymorphic and amorphous forms showed more degradation than the individual forms above critical relative humidity (85% RH). Similar higher degradation was observed between 75% RH and 85% RH in case of acid-stressed samples. In alkaline microenvironment, all the samples showed identical decomposition attributed to conversion of bisulfate salt to free base. Thermal studies indicated that polymorphic forms of clopidogrel bisulfate and also its glassy amorphous form were highly resistant to temperature, whereas the rubbery state of the drug degraded significantly at temperatures of ≥80°C.

Solid-State Transformations of Sulfathiazole Polymorphs: The Effects of Milling and Humidity

“…It is well known that storage conditions, such as temperature, humidity or pharmaceutical excipients may affect the stability of amorphous and metastable crystalline forms [8]. In particular, hygroscopicity can have a significant impact on the physical and chemical stability of active pharmaceutical ingredients (APIs) [9].…”

One-phase crystal disorder in pharmaceutical solids and its implication for solid-state stability

“…The form 1 XRPD pattern shows sharp diffraction peaks typical of a crystalline phase, whereas the amorphous pattern is broad and featureless, characteristic of an amorphous phase. Surprisingly, the 13 C SSNMR resonances are broad in both forms, which typically suggest a noncrystalline material. Residual EtOAc from the crystallization process is trapped in the solid of both forms and is observed at 171.7, 60.3, and 22.0 ppm in the 13 C SSNMR spectra.…”

“…13 C SSNMR experiments were performed on an Avance 400 NMR spectrometer (Bruker BioSpin, Billerica, MA) operating at a 1 H frequency of 399.87 MHz and a 13 C frequency of 100.55 MHz. 13 C crosspolarization (CP) spectra were obtained with a Bruker 4-mm triple resonance magic-angle spinning (MAS) probe tuned to 1 H, 19 F, and 13 C with a MAS spinning rate (ν r ) of 8 kHz. A Bruker MAS-2 rate controller was used to control ν r within ±2 Hz of the set point.…”

“…[7][8][9] Different versions and forms are known to exhibit distinct reactivity and degradants because of their differences in solid-state structure. [10][11][12][13][14] Molecules undergoing a solid-state reaction may need to reorient before a reaction can occur or a reaction gas may need to diffuse into the crystal. Both of these events require free volume within the crystal and/ or molecular mobility.…”

X-ray diffraction characterization of different polymorphyc forms of clopidogrel bisulphate in substance and pharmaceutical dosage form

“…Because clopidogrel bisulphate polymorphs comprise an enantiotropic system, and Form II is the thermodynamically more stable at room temperature [1,9], there is potential for the transformation of Form I into Form II, both in the production stage and during storage [10,11]. This fact requires a suitable analytical technique for the detection and quantification of the stable form within the metastable form.…”