Excipient process

The objective of the excipient compatibility screening is to quickly find those excipients/processes that should be avoided for the particular API. In order to obtain a result as rapidly as possible we carry out these studies at elevated temperature as discussed above. The question arises as to how long and at what temperature We need to be able to extrapolate the results to a convenient time frame at 25°C/ 60% RH for ICH Climatic Zones I and II (or 30°C/65% RH for ICH Climatic Zones III and IV). Based on the approximation from the Arrhenius equation (see above) that the reaction rate doubles for a 10°C rise in temperature, we have standard multipliers that have been widely accepted within the pharmaceutical industry. For example, a study carried out at 40° C for one month would equate to three... 

While drinking water is used for many excipient processes, purified water is also widely used in the manufacture of excipients. Because of the well recognized potential for microbial growth in... 

Similar principles to those discussed above for purified water apply to Water For Injection (WFI) utilized in sterile and pyrogen-free excipient processing. The WFI system must be monitored for microorganisms and the validation data and reports of monitoring should be reviewed as is required for finished dosage forms. 

Locally administered medicines may exert a systemic effect as well, due to drug absorption. The design of the dosage form (active substance and excipients processed into a specific structure) is important to reduce the systemic effect when only a local effect is aimed for. 

Material Processing. There are many types of dmg deHvery systems and the manufactuting of each system consists of fabricating a device as weU as loading the dmg and other excipients iato this device. The dmg can be iatroduced iato various components of the system by physical and chemical means, and at various stages of system fabrication (150). 

Comprehensive physicochemical characterization of any raw material is a crucial and multi-phased requirement for the selection and validation of that matter as a constituent of a product or part of the product development process (Morris et al., 1998). Such demand is especially important in the pharmaceutical industry because of the presence of several compounds assembled in a formulation, such as active substances and excipients, which highlights the importance of compatibility among them. Besides, variations in raw materials due to different sources, periods of extraction and various environmental factors may lead to failures in production and/or in the dosage form performance (Morris et al., 1998). Additionally, economic issues are also related to the need for investigating the physicochemical characteristics of raw materials since those features may determine the most adequate and low-cost material for specific procedures and dosage forms. 

Phase separation microencapsulation procedures are suitable for entrapping water-soluble agents in lactide/glycolide excipients. Generally, the phase separation process involves coacervation of the polymer from an organic solvent by addition of a nonsolvent such as silicone oil. This process has proven useful for microencapsulation of water-soluble peptides and macromolecules (48). 

When a hydrophobic polymer with a physically dispersed acidic excipient is placed into an aqueous environment, water will diffuse into the polymer, dissolving the acidic excipient, and consequently the lowered pH will accelerate hydrolysis of the ortho ester bonds. The process is shown schematically in Fig. 6 (18). It is clear that the erosional behavior of the device will be determined by the relative movements of the hydration front Vj and that of the erosion front V2- If Vj > V2, the thickness of the reaction zone will gradually increase and at some point the matrix will be completely permeated with water, thus leading to an eventual bulk erosion process. On the other hand, if V2 = Vj, a surface erosion process wiU take place, and the rate of polymer erosion will be completely determined by the rate at which water intrudes into the matrix. 

Convincing evidence for a surface erosion process is shown in Fig. 8, which shows the concomitant release of the incorporated marker, methylene blue, release of the anhydride excipient hydrolysis product, succinic acid, and total weight loss of the device. According to these data, the release of an incorporated drug from an anhydride-catalyzed erosion of poly (ortho esters) can be unambiguously described by a polymer surface erosion mechanism. 

When acidic or latent acidic excipients (anhydrides) are incorporated into the polymer to control erosion rate, the polymers become quite sensitive to moisture and heat and must be processed in a dry environment. A rigorous exclusion of moisture is particularly important with materials that are designed to erode in less than 24 hr. Such materials may contain up to 5 wt% of an acidic catalyst and are analogous to a "loaded gun" in that even the slightest amount of moisture will initiate hydrolysis at the elevated processing temperatures. ... 

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. 

Medicinal products and bulk pharmaceutical chemicals are produced mainly in batch processes. Controlling these products and chemicals at the end of their manufacturing processes is not in line with the general principle of quality assurance, which is that quality should be built into the product. It is then necessary to ensure that appropriate good manufacturing practices are adhered to throughout the manufacture of both bulk pharmaceutical chemicals (active ingredients as well as excipients) and medicinal products. 

Most formulations are composed of one or more medicaments plus a variety of excipients. Irrespective of the type of tablet, general criteria for these raw materials are necessary. In order to produce accurate, reproducible dosage forms, it is essential that each component be uniformly dispersed within the mixture and that any tendency for component segregation be minimized. In addition, the processing operations demand that the mixture be both free-flowing and cohesive when compressed. 

A relatively new class of co-processed excipients now exists. These excipients are essentially a preblend of two or more excipients that are commonly used in conjunction with each other. 

The influence of the actual manufacturing process can also affect the contribution of the diluent to the final characteristics of the product. For instance, Shah et al. [45] demonstrated that the release of drug from tablets formulated with soluble excipients may be more... 

For most tablets, it is necessary to overcome the cohesive strength introduced into the mass by compression. It is therefore common practice to incorporate an excipient, called a disintegrant, which induces this process. Several types, acting by different mechanisms, may be distinguished (a) those that enhance the action of capillary forces in producing a rapid uptake of aqueous liquids, (b) those that swell on contact with water, (c) those that release gases to disrupt the tablet... 

Normally, the lubricants present in the tableting mass also act as antiadherents, but in the worst cases it may be necessary to add more starch or even talc to overcome the defect. So by judicious choice of a combination of excipients, all of these undesirable effects of the tableting process can be minimized. 

Often these design criteria involve competitive requirements. What is best for meeting one criterion may be counterproductive in meeting another. For example, certain excipients such as the hydrophobic stearate lubricants are important for efficient manufacture, yet they have the potential to retard the release of drug from an immediate-release formulation. The design of a dosage form thus frequently requires the optimization of formulation and process variables in a way that best meets all design criteria. 

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