Excipients characteristics

To assess unknown incompatibilities it is customary to make a small mix of drug substance with an excipient [54,55], place it in a vial, place a rubber stopper in the vial, and dip the stopper in molten carnauba wax (to render it hermetically sealed). The wax will harden and form a moisture barrier up to 70°C. A list of common excipients characteristic of this type of test is shown in Table 1. At times it is possible to obtain quantitative relationships of... 

Characterisation Typical data that may be provided to describe the physical and chemical characteristics of the drug substance are shown in Figure 6.3. The description of the drug product should include the recipe detailing all the other ingredients (excipients) that are used to formulate the final product. It is vital to provide adequate data on the dissolution behaviour of the drug product, as the reviewer may wish to tie this in with pharmacokinetic or bioavailability data submitted in the other modules. 

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. 

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... 

It may sometimes by necessary to supplement the properties of the drug so that it compresses more easily, and these needs have been realized by several manufacturers of excipients. Materials described as compression aids are now commercially available. Ideally, such adjuvants should develop mechanical strength while improving, or at least not adversely affecting, release characteristics. Among the most successful at meeting both these needs have been the microcrystalline celluloses (partially acid-hydrolyzed forms of cellulose). A number of grades are available based upon particle size and distribution. 

The choice of the excipients, their intended function, and their concentration will need to be considered in relation to those characteristics that may affect product performance. 

For nonpharmacopeial materials a full specification should be included in the application. This should include appropriate tests and requirements for physical characteristics, identification, relevant purity tests, and performance-related tests. Characteristics likely to influence bioavailability of the finished product should be controlled. Routine tests and specifications should be described. Methods should be validated. The material should be fully characterized, with full data on the chemistry concerned and including consideration of the safety of the excipient. Any relevant European Directive requirements or other international specifications should be met, but additional requirements might apply depending on the intended use of the product—e.g., for materials to be used in sterile products. 

Factors affecting the mix of active ingredients and excipients should be discussed. These should include particle size and shape, rugosity, charge, flow properties, and water content. Since the dose delivery for these products is dependent on air flow characteristics, an attempt should be made to establish an in vivo-in vitro correlation. 

Before the start of any formal laboratory work, the characteristics of the drug and excipients to be used must be considered. When performing this evaluation, it is necessary to keep in mind all of the pharmacokinetic and physical changes experienced by the elderly and pediatric population. 

The comprehensive profiling of drug substances and pharmaceutical excipients as to their physical and analytical characteristics remains at the core of pharmaceutical development. As a result, the compilation and publication of comprehensive summaries of physical and chemical data, analytical methods, routes of compound preparation, degradation pathways, uses and applications, etc., has always been a vital function to both academia and industry. 

It may be envisioned that a protocol for the complete physical characterization of a solid material could easily be developed. At the early stages in drug development, each lot of active drug, excipients, and formulated blends would be characterized as fully as possible. A feedback loop would be established after each formulation run, in which the physical characteristics of the input materials were correlated with the quality of formulated product. Out of these studies would come an understanding of what particular properties were essential to the production of an acceptable formulation. 

The sorption of water by excipients derived from cellulose and starch has been considered by numerous workers, with at least three thermodynamic states having been identified [82]. Water may be directly and tightly bound at a 1 1 stoichiometry per anhydroglucose unit, unrestricted water having properties almost equivalent to bulk water, or water having properties intermediate between these two extremes. The water sorption characteristics of potato starch and microcrystalline cellulose have been determined, and comparison of these is found in Fig. 11. While starch freely adsorbs water at essentially all relative humidity values, microcrystalline cellulose only does so at elevated humidity values. These trends have been interpreted in terms of the degree of available cellulosic hydroxy groups on the surfaces, and as a function of the amount of amorphous material present [83]. 

The surface characteristics of excipients have also been studied and related to the dispersion and dissolution of poorly soluble drugs [58]. It was found that excipients with rough surfaces (such as Emcompress, with a porous surface) trap the drug particles in the indentations, which can then be blocked by fine excipient particles and decrease dissolution. Smooth surfaces (such as spherical sugar beads), however, produced high dissolution efficiency of the poorly soluble drugs. 

Thermal methods can be extremely useful during the course of preformulation studies, since carefully planned work can be used to indicate the existence of possible drug-excipient interactions in a prototype formulation [2]. During the course of this aspect of drug development, thermal methods can be used to evaluate compound purity, polymorphism, solvation, degradation, drug-excipient compatibility, and a wide variety of other desirable characteristics. Several recent reviews have been written on such investigations [2-6]. 

In addition to the studies listed in Figure 4.5, stability characteristics of the protein with regard to e.g. temperature, pH and incubation with various potential excipients are studied. Such information is required in order to identify a suitable final product formulation, and to give an early indication of the likely useful shelf-life of the product (Chapter 6). 

Addition of various excipients (substances other than the active ingredient(s) which, for example, stabilize the final product or enhance the characteristics of the final product in some other way). 

Only the first three are discussed in any detail here. Most of these routes of administration place a drug directly or indirectly into systemic circulation. There are a number of these routes, however, by which the drug exerts a local effect, in which case most of the drug does not enter systemic circulation (e.g., intrathecal, intraventricular, intraocular, intraracistemal). Certain routes of administration may exert both local and systemic effects depending on the characteristics of the drug and excipients (e.g., subcutaneous). 

Available and commonly used vehicles and formulating agents are reviewed along with basic information on their characteristics and usages, in Section 13.8 at the end of this chapter. There is a general presumption that those excipients and... 

Nagel, K. M., Peck, G. E. Investigating the effects of excipients on the powder flow characteristics of theophyline anhydrous powder formulations. Drug Dev. Ind. Pharm., 29, 2003, 277-287. 

In some cases, sample preparation for CZE requires only the dilution of the sample, mostly to accommodate detection (for signal and linearity of response). However, as was previously mentioned, sample characteristics such as viscosity, buffer composition (pH and excipients), and salt content can especially affect electrophoretic injection and performance. 

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