Pharmaceuticals long-term stability

Content uniformity and long-term stability of a pharmaceutical product are required for a consistent and accurate dosing. Aggregation of dispersed particles and resulting instabilities such as flocculation, sedimentation (in suspensions), or creaming and coalescence (in emulsions) often represent major problems in formulating pharmaceutical disperse systems. 

For the application of membrane reactors it can be concluded that these are accepted as proven technology for many biotechnological apphcations. The membranes used in this area can operate under relatively mild conditions (low temperature and aqueous systems). However, there is a tremendous potential for membrane reactors in the chemical industry, which often requires apphcation in nonaqueous systems. Long term stability of the membrane materials in these systems will require an ongoing development from the side of materials scientists. As reaction selectivity is of major importance in the production of fine chemicals and pharmaceutical products, it seems plausible to expect that membrane reactors will find their way in the production of chemicals through applications in these areas. 

The application of HPLC in routine environments, like pharmaceutical, food, or environmental analysis and particularly quality assurance, makes not only great demands on the robnstness of HPLC hardware, comprising pumps, column thermostats, and detection units, bnt in addition to the column reproducibility. Column reproducibility can be investigated at different levels of complexity Run-to-run reproducibility compares consecutive chromatographic runs, whereas long-term stability describes the column variance over several hundreds of injections. Column-to-column (batch-to-batch) reproducibility finally explores the match of independently fabricated chromatographic columns. Column characteristics that are routinely consulted for the determination of the robustness are retention, selectivity, column efficiency, and peak symmetry. 

Beezer AE, Gaisford S, Hills AK, Willson RJ, Mitchell JC. Pharmaceutical microcalorimetry applications to long term stability studies. Int J Pharm 1999 179(2) 39-45. 

The trails left by cells are unavoidable and they can influence the long-term stability of micro-systems, especially sensors. But they can also be used to advantage. Since a trail is characteristic of the cell which made it, trails can be used to identify cells, if necessary on an occasional monitoring basis. Also the rate at which trails appear in a unit area can give information about cell vitality or the effect of pharmaceuticals. 

The need for a multidose formulation may also dictate the use of a solid-state formulation. As the name implies, multidose products are intended to provide the patient with a product that contains several doses of the therapeutic within one container. Multidose formulations contain preservatives to kill any bacteria and prevent mold growth that may result from repeated entry into the drug product. Phenol and benzyl alcohol are two widely used preservatives in protein-based parenteral pharmaceuticals. Frequently, the addition of a preservative to the formulation compromises the long-term stability of the drug product, typically because the protein becomes physically unstable and/or exhibits oxidation. If the formulation scientist can obtain sufficient short-term stability (e.g., 2 weeks) for a formulation containing a preservative, then the use of a solid-state product may enable production of a multiuse formulation. In this case, the preservative is NOT added to the liquid bulk used to prepare the solid state. Instead, when the solid-state formulation is reconstituted prior to use, a preservative is included in the water for reconstitution. Thus the final product to be used is a multidose formulation that will experience only short-term exposure to the preservative. 

This overview has attempted to show that calorimetry has found applications in all areas of the pharmaceutical industry from discovery through receptor site binding to characterisation, on through compatibility to formulation and stability. The nanocalorimeters should find their real application in HTS whilst the more macro (but still micro ) calorimeters will still be needed, because of their better long-term stability to define the physicochemical properties of the selected pharmaceutical systems. 

Long-term stability testing for countries in Climatic Zones II is recommended to be conducted at 25°C/60% RH, whereas storage temperatures of pharmaceutical products in pharmacies according to the USP may fluctuate between 15 and 30°C. 

For pharmaceutical products in semi-permeable packaging material, the standard long-term stability testing condition has now been moved to 30°C/75% RH. 

Microemlusion system applications span many areas including EOR, soil and aquifer decontamination and remediation, wood treatment, foods, pharmaceuticals (drug delivery systems), cosmetics and pesticides [6,107,144-148]. Some of these are listed in Table 3.6. The widespread interest in microemulsions and use in these different industrial applications are based mainly on their high solubilization capacity for both hydrophilic and lipophilic compounds, their large interfacial areas, the ultra-low interfacial tensions achieved when they coexist with excess aqueous and oil phases and their long-term stability. 

Sane, S.U. Wong, R. Hsu, C.C. Raman spectroscopic characterization of drying-induced structural changes in a therapeutic antibody Correlating structural changes with long-term stability. Journal of Pharmaceutical Sciences, 2004,93, 1005—1018. 

Modifications of the GMO Matrix As a fatty acid ester of glycerol GMO is principally vulnerable to hydrolysis. Although the presence of PX407 in the dispersions seems to protect the monoglyceride in comparison to the PX407-free GMO/water system this possibility remains a concern, especially with regard to the long term stability required for pharmaceutical applications. 

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