Dissolution and residual solvent

A Two-Factor Response Surface Methodology Case Study 3—Dissolution and Residual Solvent Control in... 

A tablet-coating investigation was conducted to evaluate the effect of spray rate, inlet air temperature, and atomization air pressure on the six-hour dissolution and residual solvent levels of coated tablets. The goal was to find conditions which maximized the dissolution and minimized the residual solvents of the coated tablets. 

An overview is presented of plutonium process chemistry at Rocky Flats and of research in progress to improve plutonium processing operations or to develop new processes. Both pyrochemical and aqueous methods are used to process plutonium metal scrap, oxide, and other residues. The pyrochemical processes currently in production include electrorefining, fluorination, hydriding, molten salt extraction, calcination, and reduction operations. Aqueous processing and waste treatment methods involve nitric acid dissolution, ion exchange, solvent extraction, and precipitation techniques. 

Extraction of residues from soil samples is much more difficult than their extraction from plant or water samples. The pesticide residues in the soil exist often in several forms as bound residue , which may affect the extraction efficiency of pesticides from the soil. Then, various extraction methods such as organic solvent extraction, Soxhlet extraction, sonication extraction, microwave dissolution and supercritical fluid extraction (SEE) are used. Some extraction methods are described in the following. 

Extraction or dissolution almost invariably will cause low-MW material in a polymer to be present to some extent in the solution to be chromatographed. Solvent peaks interfere especially in trace analysis solvent impurities also may interfere. For identification or determination of residual solvents in polymers it is mandatory to use solventless methods of analysis so as not to confuse solvents in which the sample is dissolved for analysis with residual solvents in the sample. Gas chromatographic methods for the analysis of some low-boiling substances in the manufacture of polyester polymers have been reviewed [129]. The contents of residual solvents (CH2C12, CgHsCI) and monomers (bisphenol A, dichlorodiphenyl sulfone) in commercial polycarbonates and polysulfones were determined. Also residual monomers in PVAc latices were analysed by GC methods [130]. GC was also... 

Agut et al. (2011) assessed the different technology transfer options and reported that within Sanofi-Aventis that option 1 (comparative testing) is the approach of choice for critical methodologies, i.e. assay, degradation products, and in some cases water content and dissolution. Option 2 (co-validation) is reserved for less-critical methodologies, i.e. residual solvents by gas chromatography (GC), water content, dissolution and particle size methods whereas, option 4 (transfer waiver) is restricted to pharmacopoeial compendial methods, i.e. appearance, pH, particulate matter, etc. 

Figure 2 shows the extent of dissolution of red spruce in methylamine, the amount of precipitate collected in the first trap upon complete depressurization to 1 bar, and the Klason lignin content in the wood residue after extraction, as functions of extraction time. The total dissolution and precipitation are normalized with respect to oven dry weight of initial wood. The extraction conditions were 185°C, 275 bar, and 1 g/min solvent flow rate. As shown in the figure, dissolution initially increases with time and levels off at about 28% by weight. The precipitates which were collected as solids follow a similar trend. The Klason lignin content of the wood residue decreases with extraction time, from an initial value of 26.5% down to 10.1% after 5 h of extraction. 

The aim of validation of an analytical procedure is to demonstrate that the method employed in any product testing, such as the identification, control of impurities, assay, dissolution, particle size, water content, or residual solvents, is validated in the most important characteristics. Identification tests, quantitative tests for impurities content, limit tests for control of impurities, and quantitative tests of the active moiety in samples of pharmaceutical product are the most common types of analytical procedures that validation addresses [1]. 

The total content of residual solvent is determined by partially dissolving a weighed sample of the powder in a solvent (a mixture of alcohol and ether) and adding water so as to precipitate the nitrocellulose from the solution in llocculant form. The weight of this nitrocellulose is determined by evaporation to dryness, repeated dissolution and precipitation with water, and by final drying. The difference between the weight of the powder sample and that of the nitrocellulose is the weight of the residual solvent. 

Regarding production of bulk drug substances, specifications for contaminants should be established for all solvents used in the process. A comparison should be performed between the manufacturer s Certificate of Analysis and the submitted specifications, and any discrepancies should be justified. A full description for the route of synthesis should be given, as this is important for the testing and control of impurities and process solvent residues. The FDA expects that, at the time of submission, it will be determined if the drug substance exists in a multiple solid state form (racemic mixture stereoisomer) and whether this affects the dissolution and bioavailability of the drug product. 

Our screening concept is depicted in Fig. 19.2. For simplicity, operation of only one of the sensors from the sensor array is illustrated. An initially clean sensor crystal is exposed to a solvent containing a small amount of polymer followed by sensor withdrawal from the solution (Fig. 19.2a). Quantification of the residual dissolved polymer deposited onto the sensor is done by the measurements of the mass increase of the crystal, which is proportional to the amount of polymer film deposited onto the sensor from a polymer solution. Depending on the solvent-resistance of the polymers, the dissolution rate of polymers in solvents will be different as determined from multiple measurements of deposited polymers during the experiment (Fig. 19.2b). The measurements of frequency changes are done when the sensors are periodically withdrawn from the solvents and the solvents are evaporated. In this way, the measured signal change is indicative of the amount of the deposited material from the solution. 

Numerous methods are required to characterize drug substances and drug products (Chapter 10). Specifications may include description identification assay (of composite sample) tests for organic synthetic process impurities, inorganic impurities, degradation products, residual solvents, and container extractables tests of various physicochemical properties, chiral purity, water content, content uniformity, and antioxidant and antimicrobial preservative content microbial tests dissolution/disintegration tests hardness/friability tests and tests for particle size and polymorphic form. Some of these tests may be precluded, or additional tests may be added as dictated by the chemistry of the pharmaceutical or the dosage form. 

The phenomenon whereby solvent or water is incorporated in the crystal lattice or in interstitial voids, for example, has been termed pseudopolymorphism. When incorporated into a crystal lattice, the solvent usually has a space-filling role, especially where solvent molecules do not show strong interactions. If the crystal has large empty channels or holes, their nature will determine which solvent will be included and the structure of the resulting solvate. Although solvates can show higher solubilities and dissolution rates compared to non-solvated species (e.g., Stoltz et al. 1988 Suleiman and Najib 1989), solvates cannot normally be used in the pharmaceutical arena. Residual solvents have been classified the ICH into three classes ... 

One such chemical transformation is the catalytic hydrogenation of C=C bonds in the fatty acyl residues of unsaturated polar lipids [308,309], However, if we want to hydrogenate lipids within an intact membrane then the reaction has to be done in an aqueous environment, since on dissolution in organic solvents the membrane structure is lost. Certain lipids, including phosphatidyl cholines form vesicles (liposomes) in water upon dispersion by ultrasound, and such liposomes are often used in studies of the basic characteristics of membrane hydrogenations. 

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