Excipients solid drug stability

Chemical stability under a variety of macro- and microenvironmental conditions is a highly critical property determining the expected shelf life of products. The stability of the bulk solid and in solution must be studied, whereby the influence of environmental factors (pH, temperature, humidity, oxygen, light) and including the presence of various excipients on drug stability must be established. 

Oguchi and coworkers examined the decarboxylation behavior of -aminosalicylic acid (PAS) as a freeze-dried solid under thermal stress conditions (80°C) in the presence of the excipients pullulan (a linear polysaccharide which can not form inclusion complexes with PAS) and a-cyclodextrin (39). The solid-state stability was shown to correlate with the fraction of amorphous PAS. Increasing relative amounts of pullulan resulted in higher fractions of amorphous PAS. Rapid freezing (liquid nitrogen) was shown to result in a greater relative amount of amorphous drug, as expected. 

Selzer T, Radau M, Kreuter J. Use of isothermal heat conduction microcalorimetry to evaluate stability and excipient compatibility of a solid drug. Int J Pharm 1998 171 227-241. 

Lundgren P.a.A., C, Methods for the evaluation of solid state stability and compatibility between drug and excipient. Acta Pharm Suecica 1985 22(6) 305-314. 

Konno H, Taylor LS (2006) Influence of different polymers on the crystallization tendency of molecularly dispersed amorphous felodipine. J Pharm Sci 95 2692-2705 Konno H, Handa T, Alonzo DE, Taylor LS (2008) Effect of polymer type on the dissolution profile of amorphous solid dispersions containing felodipine. Eur J Pharm Biopharm 70 493 99 Lauer ME, Grassmann O, Siam M, Tardio J, Jacob L, Page S et al (2011) Atomic force microscopy-based screening of drug-excipient miscibility and stability of solid dispersions. Pharm Res 28 572-584... 

Lauer ME, Grassmann O, Siam M, Tardio J, Jacob L, Page S, Kindt JH, Engel A, Alsenz J (2011) Atomic force microscopy-based screening of drug-excipient miscibility and stability of solid dispersions. Pharm Res 28 572-584... 

This process will require a significant amount of labor to construct all of the samples, and then conduct extensive LC-MS and solid-state analysis to determine compatibility with a given excipient. Automation can be used to speed and reduce the amount of labor required for this process. One such robotic technique utilizes a robotic platform to construct the excipient and drug mixtures. There are a number of automated platforms that can dispense and mix powders in an accurate and reproducible manner. The platform can then utilize a fluid handling system to extract and inject the samples into an HPLC system for chemical analysis, or the samples can be removed and tested by a solid-state analysis system (XRPD or SSNMR). The samples can then be stored under accelerated conditions, and returned to the automation platform and tested to determine the stability when in the presence of the excipient. Most robotic platforms are able to track the samples using barcodes, to ensure that the sample identity and storage condition are linked properly to the data generated by the analytical systems. 

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