Formulation drug stability issues

The physical properties of an API can significantly effect the physical and chemical stability of a formulation, its bioavailability and ultimately they can modify the pharmacokinetic profile of the drug. This issue will be discussed in more detail in section 3.4. For these reasons it is necessary to control the physical form of the API at the Pures crystallization step, and throughout the subsequent formulation steps, to ensure a consistent delivery profile to the patient. This control strategy must be documented in the New Drug Application... 

In the case where stability issues prevent the pursuit of the preferred formulation, then it becomes more important to optimize the dry granulation process to achieve an improved uniformity of drug as a function of particle size. For these cases, it is important to consider the impact of the optimized granulation on tableting performance. Although it is important to consider the commercial manufacturing efficiency, the process challenges that impact quality are of primary importance. 

If a compound is known to have chemical stability issues and is going to be administered in low dose, the best prevention is to ensure the highest degree of crystallinity of the bulk active ingredient delivered to the formulation and maintain it in the state with the highest ratio of drug to excipient possible. 

ICH guidelines ° describe and discuss stability issues and testing requirement for NCEs and macromolecules. These guidelines provide manufacturers and CSOs with acceptance specifications for accelerated and long-term stability studies. In addition to the drug substance and drug product, stability assessment is frequently conducted on raw materials, key intermediates, formulation excipients, and packaging materials. 

The importance of identifying the mode of delivery to the lung (i.e., nebulizer, MDI, DPI) as early as possible cannot be overemphasized. A drug salt form selected assuming development of a propellant-based MDI suspension formulation may be wholly unsuited for application in an aqueous-based nebulizer suspension on the basis of solubility and crystal growth potential. Physicochemical properties and stability issues considered to be of importance in the development of inhalation formulations are discussed later, as they relate to the individual dosage forms. 

The droplet size distribution of the emulsions may change as a consequence of photochemical reactions in TPN formulations. Physical stability of the emulsion is an important issue for patient safety because coalescence of the disperse phase and a subsequent increase in globule size could result in thrombosis in vivo (Ford, 1988). Thus, stability testing of TPN emulsions should also include size distribution analyses after exposure to irradiation, as described by Williams et al. (1990). Ideally, the emulsion should be formulated so that the disperse droplets have a size distribution corresponding to the chylomicra (500 to 1000 nm), which are the natural transport systems for fat through the blood stream (Ford, 1988). The size of the disperse droplets should not be affected by the storage temperature or exposure to optical irradiation. However, it is important to note that addition of any substance (e.g., a drug) to a photochemically stable TPN preparation may alter the photoreactivity and thus the photochemical stability of the formulation. 

Determining the shelf-life of a pharmaceutical product can sometimes be the slowest step in the effort to bring a new drug product to the market. This is especially important if stability issues arise requiring a change of formulation or process. Consequently, there is a desire in pharmaceutical corporations to determine the shelf-life... 

Reasons for chopping clinical candidates at any stage of the drug approval process included (1) stability, formulation, or other pharmaceutical development issues, (2) renal toxicity or neurotoxicity, and (3) insufficient advantage over current chugs. Since 1997, the NCI has also operated a screen for compounds active against the cytotoxic effects of HIV in CEM cells. Of 80,000 compounds tested, 4050 (or about 5%) were active. Of the compounds tested, 2291 have included metals. Of those, 136 (about 6%) were active, and two became clinical candidates. Both were chopped due to toxicity problems. One clinical candidate was a polyoxometallate, and therefore about 80 other similar molecules were tested. These were found to be strongly active in vitro, but too toxic in animal models in vivo. If a way around the toxicity problem can be found, interest in these... 

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