Excipients moisture

In essence, the test battery should include XRPD to characterize crystallinity of excipients, moisture analysis to confirm crystallinity and hydration state of excipients, bulk density to ensure reproducibility in the blending process, and particle size distribution to ensure consistent mixing and compaction of powder blends. Often three-point PSD limits are needed for excipients. Also, morphic forms of excipients should be clearly specified and controlled as changes may impact powder flow and compactibility of blends. XRPD, DSC, SEM, and FTIR spectroscopy techniques may often be applied to characterize and control polymorphic and hydrate composition critical to the function of the excipients. Additionally, moisture sorption studies, Raman mapping, surface area analysis, particle size analysis, and KF analysis may show whether excipients possess the desired polymorphic state and whether significant amounts of amorphous components are present. Together, these studies will ensure lotto-lot consistency in the physical properties that assure flow, compaction, minimal segregation, and compunction ability of excipients used in low-dose formulations. 

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. ... 

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... 

In many products it seems highly probable that there exists a narrow range of optimum moisture contents that should be maintained. More specifically, the effect of moisture on MCC-containing tablets has been the subject of an investigation that demonstrates the sensitivity of this important excipient to moisture content [10]. These researchers found that differences exist in both the cohesive nature and the moisture content to two commercial brands of MCC. A very useful report on the equilibrium moisture content of some 30 excipients has been compiled by a collaborative group of workers from several pharmaceutical companies and appears in the Handbook of Pharmaceutical Excipients [11,12],... 

S. T. Tzannis and S. J. Prestrelski, Moisture effects on protein-excipient interactions in spray dried powders. Nature of destabilizing effects of sucrose, J. Pharm. Sci, 88(3), 360 (1999). 

The moisture uptake models we have discussed have been concerned with pure components. The deliquescing material could be a drug substance or an excipient material. In pharmaceuticals, however, mixtures of materials are also important. One possible situation involves mixing nondeliquescing and deliquescing materials that are formed into a porous tablet or powder blend. The obvious question is, Do the models for pure components apply to porous heterogeneous materials For pure components we have assumed that the mass and heat limiting transport... 

Surface area and moisture uptake have been related to the disintegration properties of excipients such as crosspovidone, starch, and alginic acid [17]. The surface areas of the three materials were measured, and a linear correlation was found between the maximum moisture sorption and specific surface area for the three disintegrants. The greater the surface area of the material, the more numerous were the sites for capillary attraction of water to its surface. It was postulated that the capillary action appears to be responsible for the disintegration properties of the materials. 

Table 5 Wm Values for Various Pharmaceutical Excipients Obtained from BET Analysis of Moisture Uptake Isotherms...

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 stability of moisture-sensitive drugs has been studied by Vromans and Schalks [1.143] using amorphous vecuronium bromide. Its decomposition in a formulation depends more on the water activity aw (see Chapter 4, point 2) than on the water content. Glass-forming excipients may not only be cryoprotective but also stabilizing. 

A linearization of the steady-state concentration gradient could be demonstrated by relating the depth to the weight of the tissue, removed per piece of adhesive tape. However, large errors, especially, within the first tapes, cast doubt over these findings [127, 128], The procedure is time-consuming and artifacts, due to absorption and desorption of moisture, formulation excipients, or sebaceous lipids, are likely. 

We now turn briefly to the problem of peptide stability in the solid state [8] [88], First, we note that most - if not all - reactions discussed in the previous and subsequent sections can also occur in the solid state, although the kinetics and mechanisms of the reactions can be quite different from those observed in solution. Moisture content, the presence of excipients that act as catalysts, and surface phenomena are all factors whose roles are all-but-im-possible to predict. As a result, each formulation poses a new challenge to pharmaceutical scientists. As a rule, solution data cannot be used to predict the shelf-life of solid formulations, and extrapolating from one solid formulation to another can be misleading. 

Crowley and Martini [48] reported on several studies evaluating the impact of unit process operations on hydrates. AU showed some level of dehydration liberating freed crystalline water to participate in moisture-mediated reactions. The authors speculated that such energetic processing conditions are likely to have a similar affect on hydrated excipients with a potential deleterious effect on moismre-sensitive APIs. They commented that classical excipient compatibility studies were ill-equipped to predict such moismre-mediated interactions and that compression, attrition and other energy-intensive unit operations were rarely mentioned as requiring investigations. 

The three hygroscopic excipients used were citric acid anhydrous, sorbitol, and maltodextrin. It was found that hygroscopic materials do not markedly increase the adsorption of atmospheric moisture by a tablet until high relative humidities were attained. 

S.A. Sangekar, M. Sarli and P.R. Sheth, Effect of moisture on physical characteristics of tablets prepared from direct compression excipients. J. Pharm. Sci., 61 (1972) 939. 

Given that extruders of various designs, types and geometries are available in the marketplace, let us examine some aspects that drive selection of the appropriate extruder for a product. The key factors relevant in selecting the extruders are formulation factors (selection of excipients, thermal stability, plasticity, aqueous solubility, and moisture holding capacity) and equipment factors (batch versus continuous operation and scalability of the extruder). 

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