Excipient construction

Figure 4.50. Cumulative dissolution results. Two experimental tablet formulations were tested against each other in a dissolution test in which tablets are immersed in a stirred aqueous medium (number of tablets, constructional details and operation of apparatus, and amount of medium are givens). Eighty or more percent of the drug in either formulation is set free within 10 minutes. The slow terminal release displayed by formulation B could point towards an unwanted drug/excipient interaction. The vertical bars indicate ymean - with Sy 3%. A simple linear/exponential model was used to approximate the data for the strength 2 formulation. Strengths I and 3 are not depicted but look very similar.

Phase diagrams are often constructed to provide a visual picture of the existence and extent of the presence of solid and liquid phases in binary, ternary and other mixtures of substances. Phase diagrams are normally two-component (binary) representations but multicomponent phase diagrams can also be constructed. Interactions between active substances and excipients can often be evaluated using phase diagrams. 

Tablets account for more than 80% of all pharmaceutical formulations therefore, the development and implementation of NIR methods for determining APIs in intact tablets is of a high interest with a view to assuring content uniformity and quality in the end product. Blanco et al developed an innovative strategy to prepare calibration samples for NIR analysis by using laboratory-made samples obtained by mixing the API and excipients in appropriate proportions and compacting the mixture at a pressure similar to that used industrially. This way of matching laboratory and production samples affords more simple and robust NIR methods which require the use of neither HPLC nor UV-vis spectroscopy as reference rather, reference values are obtained by weighing during preparation of the samples. The PLS calibration models thus constructed exhibited a good predictive ability with various production batches.

A replication-deficient adenovirus has been used to deliver a gene construct, which contains within its promoter region a radiation-responsive element. Upon irradiation with conventional doses of X rays, this construct initiates transcription of the gene coding for the toxic cytokine, tumor necrosis factor-a (35). The above is an exquisite example of how emerging delivery and gene therapies are fast blurring the distinction between an active and an excipient (Fig. 3D). 

Whether chelation (as opposed to covalent bonding) of an active moiety to an excipient qualifies the entire construct as a new chemical entity (NCE) is a moot point. A case in point is polymer platinate. This compound consists of a polymer backbone, hydroxypropylmethacrylamide, linked to a polypeptide spacer. The peptide is in turn linked with an aminomalonate chelating group, which chelates the platinum compound (Fig. 2). 

The second way in which equipment can lead to excipient contamination is from equipment construction. Production equipment should not be reactive under the conditions used for producing the excipient. Also the materials used for the operation of the equipment such as lubricants, grease, coolants, etc. should not be... 

Experimental procedures for running excipient compatibility studies using isothermal microcalorimetry include the collection of power-time curves for each component of the mixture alone, as well as in combinations (Fig. 8). The separate drug and excipient curves can then be used to construct a theoretical non-interaction curve for the blend, which then is subtracted from the actual blend curves in order to define the interaction between the components. 

This begs the question of what effect the transition comprising has in this example. We have already seen that we cannot read the claim to allow addition to structural formula I itself. However, the preamble to the claim clearly explains that a pharmaceutical composition is being claimed and not merely a compound. We do not need to get into the exact nature of any claim construction limitations that this preamble might introduce to appreciate that this claim is not limited in scope to the compound of formula I and at least one pharmaceutically acceptable excipient, but would also cover the addition of materials that might be understood to go into a pharmaceutical composition. If the preamble is understood to be a limitation of the claim, then the claim can be read to be broad enough to capture the compound in a pharmaceutical composition but not so broad as to capture the compound in any possible setting, to ensure this interpretation, the patent drafter has carefully added an additional required element, the pharmaceutically acceptable excipient.19... 

Independent use patents offer the weakest patent protection. They almost invite others to seek possibilities to circumvent them and they do not cover the products that result from the invented new use. Wherever the necessary requirements are fulfilled, product patents should be applied for. In the first example given above, it seems hardly justified to construct product claims for (all) products made by the modified fermentation process. The excipient with adjuvant effects could probably be patented as a product patent, claiming "vaccines containing substance X as a novel adjuvant" with the non-obvious advantage of a better tolerability or efficacy over existing adjuvants. As for the third example, any advantageous characteristic of the resulting product may be used to justify a product patent. 

Few excipients are manufactured specifically for pharmaceutical use. Many are manufactured for other purposes (e.g., food, cosmetics, paint thickeners, construction, etc.). For their use in pharmaceuticals, additional quality, functionality, and safety requirements must be met. 

In this era of automatic titrators, microprocessor-controlled thermal analysis, and definitive spectral techniques, one of the most powerful techniques, that is, optical microscopy, is frequently overlooked. The value of direct sample observation, preferably while it is exposed to different relative humidities, cannot be overstated. In the author s laboratory, a plexiglass chamber was constructed that can be placed on the stage of the microscope, through which air of known humidity can be circulated. This simple technique has been very useful in examining the swelling (or lack) of disintegrants and the influence of very hydrophilic excipients in combination with a moisture sensitive drug. ... 

Sondermann and Kovar described a study using NIRS for the identification of ecstasy street samples. Ecstasy tablets may contain either A-methyl-3,4-methylendioxyamphetamine (MDMA) or A-ethyl-3,4-methylendioxyamphetamine (MDE) as well as other amphetamine derivatives. In addition, various excipients were present, and non-standardized production procedures contributed to inhomogeneous tablets. The authors researchers included a broad range of excipients in their calibration work and succeeded in constructing three PLS models for identification. 

Relevant data and constructive criticism are welcome and may be used to assist in the preparation of any future editions or electronic versions of the Handbook. The reader is asked to send any comments to the Editor, Handbook of Pharmaceutical Excipients, Royal Pharmaceutical Society of Great Britain, 1 Lambeth High Street, London SEl 7JN, UK, or Editor, Handbook of Pharmaceutical Excipients, American Pharmacists Association, 2215 Constitution Avenue, NW, Washington, DC 20037-2985, USA. 

Selectivity is one of the essential characteristics of the membrane electrodes. Accordingly, it is important that by-products, degradation products, metabolites, and compressing components (excipients) do not interfere, and thus the ISMEs can be successfully used for raw material assays as well as for raw material determinations in pharmaceutical formulations. To improve the selectivity, it is necessary to choose another counter ion for membrane construction, because the selectivity of membrane electrodes can be explained through the stability constants of the ion pair complexes between the counter ion and the ions from the solution. To be selective over one ion from the solution it is necessary for the stability constant of the ion pair complex to be less than the stability constant of the ion pair complex obtained between the main ion and counter ion. 

Any building or buildings used in the manufacture, processing, packaging, or holding of an excipient should be of suitable size, construction and location to facilitate cleaning, maintenance, and proper operations. 

Process equipment should be constructed so that their contact surfaces will not be reactive, additive, or absorptive so as to alter the quality attributes of the excipient... 

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