Excipient application

Active substances Quality Excipients Application Raw material Labelling Pharmacopoeia FRC Solvents Surfactants Viscosity enhancers Preservatives Colouring agents Herbal... 

Fig. 23.3 Silica functionalities as they relate to excipient applications and interactions with active pharmaceutical ingredients...

The theory and application of this fluorescence method have been discussed in detail by LePecq and others (3,8). The assay requires that there is sufficient ionic strength to minimize ionic binding (e.g., O.IM sodium chloride), that the pH is 4-10, that no heavy metals are present, that the fluorescence is not enhanced on binding to other excipients (e.g., proteins) and that at least portions of the nucleic acids are not complexed. These requirements can usually he met when dealing with recombinant products in some cases the samples must he manipulated to create the appropriate conditions. In the intercalative method of dye binding, proteins rarely interfere with the assay, and procedures have been developed to remove the few interferences they may cause (e.g., the use of heparin or enzymatic digestion of the protein 9). 

For thousands of years, nature has provided humankind with a large variety of materials for the most diversified applications for its survival, such as food, energy, medicinal products, protection and defense tools, and others. The pharmaceutical industry has benefitted from such diversity of biomaterials and has exploited the use of natural products as sources of both drugs and excipients. One example of a promising biomaterial for pharmaceutical use is xylan, a hemicellulose largely found in nature, being considered the second most abundant polysaccharide after cellulose. 

The incompatibility of some macromolecules with lactide/glycolides has been observed. As with other polymeric excipients, lactide/glycolides will serve some but not all applications. 

Because of the nature of modern pharmaceutical systems, formulators have made more complete investigations of the materials they use. This interest has identified several materials that may have more than one use in tableted systems. The type of effect that an excipient will produce is often dependent upon the concentration in which it is used. For example, Table 5 lists some multiuse excipients and the corresponding concentration ranges required for their various applications. 

In summary, there are numerous variables to be adjusted and many choices of excipients required when tailoring a formulation of a particular therapeutic agent for ophthalmic application. But ultimately the choice rests on finding an economically viable formulation that clinically enhances the therapeutic index for that drug. 

Where an unusual excipient is chosen, or where an established excipient is chosen for a dosage form that results in its administration by a novel route of administration, then additional data will need to form part of the application. In effect, a novel excipient will need to be supported by data similar to those required for a new drug, with full supporting data including composition, function, and safety. Novel excipients include the components of the matrix in prolonged release products, new propellants, and new permeability enhancers. The exception to this need for extensive supporting data would be for a material already approved for food use and administered by the oral route or a material already approved for cosmetic use with a topical route of administration. In all cases the quality of the excipients has to be described adequately and shown to be satisfactory (which will depend on its role). 

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. 

Justifications for the use of nonstandard (i.e., nonpreferred or nonpharmacopeial) methods of sterilization may include the heat instability of the active ingredient or an essential excipient. The choice of a method based on filtration through a microbial retentive filter and/or aseptic assembly should be justified, and the appropriate in process controls (including bioburden controls on active ingredients, excipients, bulk solutions, process time constraints etc) discussed in detail in the application. Commercial considerations should not form part of the argument for the application of a nonstandard sterilization process. The highest possible sterility assurance level should be achieved. 

Where there are existing pharmacopeial specifications for active ingredients in the Ph Eur or the pharmacopeia of a member state, these will be expected to apply. Other pharmacopeial specifications or in-house specifications may be used in other cases. The same is true for excipients where harmonized specifications are mentioned. Particular quality requirements related to a particular application are discussed, e.g., particle size control requirements. 

AQ4a The use of ionising radiation in the manufacture of medicinal products (pages 23-30) 3AQ9a Excipients in the dossier for application for marketing authorisation of a medicinal product (pages 67-74)... 

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. 

Application of DSC and HPLC to determine the effects of mixture composition and preparation during the evaluation of niclosamide-excipients compatibility showed that although some reactions occurred, niclosamide was compatible with a majority of common tablet excipients tested [63],... 

The topics of polymorphism and pseudopolymorphism dominate the majority of publications that deal with utilizing infrared spectroscopy for the physical characterization of pharmaceutical solids. Typically, in each of the publications, IR spectroscopy is only one technique used to characterize the various physical forms. It is important to realize that a multidisciplinary approach must be taken for the complete physical characterization of a pharmaceutical solid. Besides polymorphism, mid- and near-IR have been utilized for identity testing at the bulk and formulated product level, contaminant analysis, and drug-excipient interactions. A number of these applications will be highlighted within the next few sections. 

The extent of homogeneous mixing of pharmaceutical components such as active drug and excipients has been studied by near-IR spectroscopy. In an application note from NIRSystems, Inc. [47], principal component analysis and spectral matching techniques were used to develop a near-IR technique/algorithm for determination of an optimal mixture based upon spectral comparison with a standard mixture. One advantage of this technique is the use of second-derivative spectroscopy techniques to remove any slight baseline differences due to particle size variations. 

The range of application of shear cell testing methodology is seen in Tables 2-6. Table 3 relates the flow properties of mixtures of spray-dried lactose and bolted lactose. These mixtures, in combination with the excipients tested, cover a broad range of flow. Tables 4 and 5, for example, show lot to lot variations in the flow properties of several materials, and Table 6 shows the variation in flow properties of bolted starch, sucrose, and phenacetin at different relative humidities (RH). Figure 8 presents the yield loci of sucrose at four different consolidation loads. Also shown in the figure are the shear indices determined at each consolidation load. 

Freeze-drying is a relatively gentle way of removing water from proteins in solution. However, this process can promote the inactivation of some protein types, and specific excipients (cryopro-tectants) are usually added to the product in order to minimize such inactivation. Commonly used cryoprotectants include carbohydrates (such as glucose and sucrose), proteins (such as HSA), and amino acids (such as lysine, arginine or glutamic acid). Alcohols/polyols have also found some application as cryoprotectants. 

The original applications of NIR were in the food and agricultural industries where the routine determination of the moisture content of foodstuffs, the protein content of grain and the fat content of edible oils and meats at the 1% level and above are typical examples. The range of industries now using the technique is much wider and includes pharmaceutical, polymer, adhesives and textile companies. The first in particular are employing NIR spectrometry for the quality control of raw materials and intermediates and to check on actives and excipients in formulated products. Figure 9.26(b) demonstrates that even subtle differences between the NIR spectra of enantiomers can be detected. 

The excipients present in pharmaceutical formulations can and often do interfere with quantitation of APIs, limiting the applications of direct UV-vis measurement for analyzing formulated products due to its lack of specificity. To minimize the interference of excipients, colorimetric methods based on chemical reactions have been used for rapid determination of drug substances in pharmaceutical formulations although their role in pharmacopoeias has been greatly reduced.117-122... 

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