Drug stability profiles

The process of formulation for any of the above is generically the same, beginning with some form of product specification and ending with one or more formulations that meet the requirements. Correct choice of additives or excipients is paramount in the provision of efficacy, stability, and safety. For instance, the excipients may be chemically or physically incompatible with the drug or they may exhibit batchwise variability to such an extent that at the extremes of their specification they may cause failure in achieving the desired drug release profile. In addition, some excipients, especially those that are hydroscopic, may be contraindicated if the formulation is to be manufactured in tropical countries. Flence formulators must work in a design space that is multidimensional in nature and virtually impossible to conceptualize. 

An elastomeric closure is a packaging component that is, or may be, in direct contact with a drug product. Elastomer selection for parenteral packaging principally involves consideration of chemical, physical, and biological properties, with emphasis on the stability profile of the drug/container system. Typical elastomeric closure compositions are listed in Tables 1 1. Although certain packaging applications frequently call to mind certain elastomer types, it is not feasible to prescribe specific... 

The past two decades have produced a revival of interest in the synthesis of polyanhydrides for biomedical applications. These materials offer a unique combination of properties that includes hydrolytically labile backbone, hydrophobic bulk, and very flexible chemistry that can be combined with other functional groups to develop polymers with novel physical and chemical properties. This combination of properties leads to erosion kinetics that is primarily surface eroding and offers the potential to stabilize macromolecular drugs and extend release profiles from days to years. The microstructural characteristics and inhomogeneities of multi-component systems offer an additional dimension of drug release kinetics that can be exploited to tailor drug release profiles. 

In this section, discussion of physicochemical profiling is limited to solubility, permeability, drug stability, and limited solid-state characterization (as we will see in Section 3.4, there are other physical-mechanical properties that must also be considered). For convenience, methods available for physicochemical profiling are discussed under the following categories computational tools (sometimes referred to as in silico tools), HTS methods, and in-depth physicochemical profiling.16... 

It must be ensured that a drug product within a produced batch contains the same amount of the active ingredient, the same stability profile, and the same bioavailability. Furthermore all batches produced should be comparable in their properties as mentioned before. 

Studies on drug stability have a central role in physicochemical profiling [1-6]. It is important to know (i) how long the substrate maintains its chemical identity in various environments carrying out its therapeutic action and (ii) the pathway followed when it degrades. Both sets of information are vitally important issues in the pharmaceutical industry. The first is necessary to decide whether to continue to investigate the molecule of interest or not An unstable drug can reduce its efficiency... 

Carstensen, J. T. (2000), Solution Kinetics Kinetic pH profiles Oxidation in solution Catalysis, Complexation, and Photolysis, in Carstensen, J.T. and Rhodes, C.T., Eds., Drug Stability, Principle and Practice, 3rd ed., Marcel Dekker, New York, Chapters 2-5, pp. 19-143. 

For long-term studies, frequency of testing should be sufficient to establish the stability profile of the drug product. For products with a proposed shelf life of at least 12 months, the frequency of testing at the long-term storage condition should normally be every 3 months over the first year, every 6 months over the second year, and annually thereafter through the proposed shelf life. 

A quick means to identify whether or not a drug may be more suitable for solution or suspension is to overlap the pH-stability profile with the pH-solubility profile. This overlap creates a window, which may suggest which dosage form might be most desirable and subsequently the type of excipients needed. The overlapped figures below demonstrate for aspirin (which is a weak acid) that the pH of greatest stability is also the pH at which there is low solubility (Fig. 1). 

Stamper GF, Lambert WJ. Accelerated stability testing of proteins and peptides pH-stability profile of insulinoptropin using traditional Arrhenius and non-linear fitting analysis. Drug Dev Ind Pharm 1995 21 1503-1511. 

Drug discovery Lead candidate Screening Protein identification natural products identification metabolic stability profiles molecular weight determination for combinatorial/ medicinal chemistry support. 

Fink, S. W. Rourick, R. A. Whitney, J. L. Volk, K. J. Klohr, S. E. DiDo-nato, G. C. Kerns, E. H. Lee, M. S. 1997. Accelerating drug development using automated predictive stability profiling methodologies. Annual Meeting of the American Association of Pharmaceutical Scientists (Boston, Massachusetts), 590. 

The pH stability profile for pantoprazole was studied at 25°C, and the percentage of original drug left after 24 hours of elapsed time was determined. The data are plotted in Figure 13, where it is evident that the stability of pantoprazole sodium was strongly dependent on the solution pH, and the compound was least stable at low pH. The highest stability of pantoprazole sodium can be achieved at pH higher than 5.5. 

The focus of the FDA continues to be guaranteeing that the drug products in the public domain have the reproducible purity and stability profile which they originally approved. Detail of the regulations continues to be debated and the FDA remains open to ideas for reducing the Regulatory burden carried by the pharmaceutical... 

The pH-stability profile is a plot of reaction rate constant for drug degradation versus pH and may help to predict if some of the drug will decompose in the GI tract. The stability of erythromycin is pH-dependent. In acidic medium, erythromycin decomposition occurs rapidly, whereas at neutral or alkaline pH the drug is relatively stable. Consequently, erythromycin tablets are enteric coated to protect against acid degradation in the stomach. In addition, less soluble erythromycin salts that are more stable in the stomach have been prepared. 

The selection of a buffer system for use in a pharmaceutical dosage form is relatively straightforward. It is evident from the preceding discussion that the most important prerequisite for a buffer is the approximate equality of the pA A value of the buffer with the intended optimal pH value for the formulation. Knowledge of the pH stability profile of a drug substance enables one to deduce the pH range for which formulation is desirable, and the basis for the most appropriate buffer system would be the weak acid or base whose p A or pKe value was numerically equal to the midpoint of the pH range of stability. 

In addition, preformulation scientists routinely use buffer systems to set the pH of a medium in which they intend to perform experimentation. For instance, the pH stability profile of a drug substance is routinely obtained through the use of buffers, and the pH dependence of solubility is frequently measured using buffered systems. However, the possibility that the buffer system itself may influence or alter the results must be considered in these studies. 

Use of Buffers to Study the pH Stability Profile of Drug Substances... 

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