Abdul-Fattah Ahmad M, Dellerman Karen M, Bogner Robin H, Pikal Michael J
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut 06269, USA.
J Pharm Sci. 2007 May;96(5):1237-50. doi: 10.1002/jps.20947.
The objective of this study was to investigate the effect of annealing on the chemical stability and calorimetric structural relaxation times of freeze-dried moxalactam. Moxalactam disodium was freeze dried with 12% mannitol and split into several batches after freeze drying. One batch was held as a control while others were subjected to a further heating (annealing) treatment at 60 degrees C, 70 degrees C, and 80 degrees C for different periods of time. Isothermal microcalorimetry studies using thermal activity monitor (TAM) were performed on the freeze-dried samples to measure relaxation times (tau) and stretched exponential values (beta). Modulated DSC experiments were carried out to determine T(g) and DeltaC(P) for moxalactam-12% w/w mannitol systems at various moisture contents to allow extrapolation of these quantities to zero residual moisture. Storage stability studies were performed at 25 degrees C, 40 degrees C and 50 degrees C. Decarboxylated moxalactam and parent contents after various storage times were measured by reverse phase HPLC. Annealing moxalactam-12% mannitol amorphous systems improved chemical stability of moxalactam and reduced molecular mobility, as measured by TAM. Moxalactam-12% w/w mannitol systems annealed at higher temperatures and for longer times had higher tau(beta) values than the "control" sample, with tau(beta) values increasing as annealing temperature increased. Additionally, tau(beta) value increased as annealing time at the same temperature increased. These observations indicated that higher temperature annealing decreased molecular mobility in the glass, as expected. Further, chemical stability improved as annealing temperatures and annealing times increased. For example, the rate of decarboxylation of the sample annealed at 70 degrees C for 8 h was roughly 1.7 times lower than the "control." Note that in spite of degradation during the annealing process, the level of degradation at the end of storage is actually less in the annealed sample than in the control sample; thus, annealing can result in samples having less degradation at the end of a storage period. Chemical stability and relaxation times are correlated, thus indicating that molecular mobility and structural relaxation time are coupled.
本研究的目的是考察退火对冻干头孢氧哌唑化学稳定性及量热结构弛豫时间的影响。头孢氧哌唑钠与12%的甘露醇一起冻干，冻干后分成几批。一批作为对照，其他批次在60℃、70℃和80℃下进行不同时间的进一步加热（退火）处理。使用热活性监测仪（TAM）对冻干样品进行等温微量热法研究，以测量弛豫时间（τ）和伸展指数值（β）。进行调制DSC实验，以确定不同水分含量下头孢氧哌唑-12% w/w甘露醇体系的玻璃化转变温度（Tg）和热容变化（ΔCP），以便将这些量外推至零残留水分。在25℃、40℃和50℃下进行储存稳定性研究。通过反相HPLC测定不同储存时间后的脱羧头孢氧哌唑和母体含量。对头孢氧哌唑-12%甘露醇无定形体系进行退火处理，可提高头孢氧哌唑的化学稳定性并降低分子流动性，这通过TAM测定。在较高温度下退火较长时间的头孢氧哌唑-12% w/w甘露醇体系的τ（β）值高于“对照”样品，且τ（β）值随退火温度升高而增加。此外，在相同温度下，τ（β）值随退火时间增加而增加。这些观察结果表明，如预期的那样，较高温度的退火降低了玻璃态中的分子流动性。此外，化学稳定性随着退火温度和退火时间的增加而提高。例如，在70℃下退火8小时的样品的脱羧速率比“对照”样品低约1.7倍。请注意，尽管在退火过程中会发生降解，但退火样品在储存结束时的降解水平实际上低于对照样品；因此，退火可使样品在储存期结束时降解更少。化学稳定性和弛豫时间相关，因此表明分子流动性和结构弛豫时间是相互关联的。
