Reproducibility dissolution

The nature of the disturbed layer on the surface of crushed quartz was described at the beginning of the section on solubility, and its abnormal solubility is discussed in Chapter 7 in relation to a theory of silicosis. When crushed powders are to be used for solubility measurements it is essential that the highly soluble outer layers and fine fractions be eliminated. The problems involved in obtaining quartz with a reproducible dissolution behavior have been described by Baumann (223b), who found that subsequent adsorption of silicic acid from solution or heating the cleaned powder above 800 C can reestablish a layer which is abnormally soluble. 

A typical drug as administered to a patient may be in the form of a tablet, a capsule, or a solution for injection and it contains not only the active ingredient, but also additional substances that serve to promote the stability of the drug and aid in its reproducible dissolution and/or distribution. This section addresses the manufacture of the active ingredients. 

Kinetic measurements were performed employii UV-vis spectroscopy (Perkin Elmer "K2, X5 or 12 spectrophotometer) using quartz cuvettes of 1 cm pathlength at 25 0.1 C. Second-order rate constants of the reaction of methyl vinyl ketone (4.8) with cyclopentadiene (4.6) were determined from the pseudo-first-order rate constants obtained by followirg the absorption of 4.6 at 253-260 nm in the presence of an excess of 4.8. Typical concentrations were [4.8] = 18 mM and [4.6] = 0.1 mM. In order to ensure rapid dissolution of 4.6, this compound was added from a stock solution of 5.0 )j1 in 2.00 g of 1-propanol. In order to prevent evaporation of the extremely volatile 4.6, the cuvettes were filled almost completely and sealed carefully. The water used for the experiments with MeReOj was degassed by purging with argon for 0.5 hours prior to the measurements. All rate constants were reproducible to within 3%. 

Figure 6. Bipolar precipitates consisting of an inner anion-selective layer and an outer cation-selective layer.19 When the electrode is polarized to the more noble side, protons and chloride ions are kept from permeating through the film, so that anodic dissolution of the substrate metal is blocked. (Reproduced from N. Sato, Corrosion, 45 354, 1989, Fig. 24 with permission of NACE International.)...

Figure 20. Pit-dissolution current density pit radius and ion concentration buildup AC in the pit electrolyte corresponding to the critical condition for growing pits on 18Cr-8Ni stainless steel to passivate at different repassivation potentials, EK, in 0.5 kmol m 3 H2S04 + 0.5 kmol m-3 NaCl during cathodic potential sweep at different sweep rates.7 (From N. Sato, J. Electrochem. Soc. 129,261,1982, Fig. 1. Reproduced by permission of The Electrochemical Society, Inc.)...

Sublimation without prior dissolution is likely to cause thermal annealing eflFects. Even dissolution of the samples at room temperature may cause thermal reactions to occur, although these, at least, are usually reproducible. 

Figure 48-12. Schematic illustration of some aspects of the role of the osteoclast in bone resorption. Lysosomal enzymes and hydrogen ions are released into the confined microenvironment created by the attachment between bone matrix and the peripheral clear zone of the osteoclast. The acidification of this confined space facilitates the dissolution of calcium phosphate from bone and is the optimal pH for the activity of lysosomal hydrolases. Bone matrix is thus removed, and the products of bone resorption are taken up into the cytoplasm of the osteoclast, probably digested further, and transferred into capillaries. The chemical equation shown in the figure refers to the action of carbonic anhydrase II, described in the text. (Reproduced, with permission, from Jun-queira LC, Carneiro J BasicHistology. Text Atlas, 10th ed. McGraw-Hill, 2003.)...

Figure 9.24 Amounts of dissolved platinum, normalized to 1 cm and 1 mL of solution, plotted against the dissolution potentials for all the investigated surfaces. (Reproduced with permission from Komanicky et al. [2006].)...

HPLC methods of determining the amounts of different additives in polymeric materials are preceded by an extraction process or dissolution of the polymer matrix. Although extraction-HPLC is often observed to be superior to the traditional spectroscopic techniques (UV and IR) in analysing additives, it is frequently difficult to obtain reproducible results in view of the variability of the extraction yield. On the other hand, it is equally difficult to obtain quantitative data in the dissolution/reprecipitation-HPLC method because of entrapment of analytes in the polymer precipitate and the potential for high absorption of the additives on the polymer surface. 

For PMMA/additive dissolutions, it was not possible to identify any additive characteristic mass peaks, either by direct laser desorption or with matrix-assistance (dithranol, DHBA or sinapinic acid, 4-hydroxy-3,5-dimethoxy-cinnamic acid). This has again been ascribed to very strong interaction between PMMA and additives, which suppresses desorption of additive molecules. Also, partial depolymerisation of pho-tolytically labile PMMA by laser irradiation may play a role, which leads to saturation of the detector by PMMA fragment-ions and disappearance of additive mass peaks below noise level. Meyer-Dulheuer [55] has also reported MALDI-TOFMS analysis of a coating/2-ethylhexyldiphenylphosphate sample. Quantitative determination of the additives by means of MALDI-ToFMS proved impossible. Possibly the development of reproducible (automated) sample handling procedures or thin films might overcome this problem. 

The test apparatus chosen for disintegration testing and dissolution testing should be one of those described in the Ph Eur unless another pharmacopoeial or a noncompendia method can be justified. The test conditions and the proposed release rates should be justified in terms of batch reproducibility. 

Figure 15 Dissolution of theophylline in water at 25°C. (Reproduced with permission from Ref. 50.)...

Figure 5.17 STM image of H-terminated n-Si(l 1 1) in 0.1 M HCI04 + 1 mM Pb(CI04)2, onto which two Pb clusters have been deposited by a burst-like dissolution of Pb from the STM tip. (Reproduced with permission from Ref. [77].)...

Figure 5.4 LbL assembly of polyelectrolyte capsule. Alternately charged molecules are added to the template several times, giving species (d).This is followed by dissolution ofthe template (e) leaving the polyelectrolyte capsule. Reproduced with permission from [36],...

FIGURE 14.5 Multiprotein electrical detection protocol based on different inorganic colloid nanocrystal tracers, (a) Introduction of antibody-modified magnetic beads (b) binding of the antigens to the antibodies on the magnetic beads (c) capture of the nanocrystal-labeled secondary antibodies (d) dissolution of nanocrystals and electrochemical stripping detection (reproduced from [29] with permission). 

The surface area of a solid material is important in that it provides information on the available void spaces on the surfaces of a powdered solid [48]. In addition, the dissolution rate of a solid is partially determined by its surface area. The most reproducible measurements of the surface area of a solid are obtained by adsorbing a monolayer of inert gas onto the solid surface at reduced temperature and subsequently desorbing this gas at room temperature. The sorption isotherms obtained in this technique are interpreted using the equations developed by Brunauer, Emmett, and Teller, and therefore the technique is referred to as the B.E.T. method [49]. The surface area is obtained in units of square meters of surface per gram of material. 

While batch dissolution methods are simple to set up and to operate, are widely used, and may be carefully and reproducibly standardized, they suffer from the following disadvantages (1) the hydrodynamics are usually poorly characterized, with the notable exception of the rotating disc method, (2) a small change in dissolution rate will often create an undetectable and therefore an immeasurable perturbation in the dissolution time curve, and (3) the solute concentration cb may not be uniform throughout the solution volume V. 

Fig. 14 Dissolution-time profiles for a batch-type dissolution apparatus (A), and a continuous-flow dissolution apparatus (B). (Reproduced with permission of the copyright owner, John Wiley and Sons, Inc., from Ref. 1, p. 476.)...

Fig. 15 Two of the simplest theories for the dissolution of solids (A) the interfacial barrier model, and (B) the diffusion layer model, in the simple form of Nemst [105] and Brunner [106] (dashed trace) and in the more exact form of Levich [104] (solid trace). c is the concentration of the dissolving solid, cs is the solubility, cb is the concentration in the bulk solution, and x is the distance from the solid-liquid interface of thickness h or 8, depending on how it is defined. (Reproduced with permission of the copyright owner, John Wiley and Sons, Inc., from Ref. 1, p. 478.)...

Fig. 16 Lines of flow of liquid in the Levich rotating disc method of determining dissolution rates. There is a transition from (A) flow essentially normal to the surface to (B) flow parallel with the surface, pointing to the existence of a viscous boundary layer. (Reproduced with permission of the copyright owner, the Royal Society of Chemistry, from Ref. 101.)...

Properly simulating a dissolution process of solid particles in a stirred vessel operated in the turbulent-flow regime urges for a very detailed simulation of the turbulent-flow field itself. Just reproducing the overall flow pattern by means of... 

One really may need an inherently transient LES to capture all these details. The finer the grid for such a LES, the more reliably the local transient conditions may be taken into account in reproducing this turbulent mass transfer process (while ignoring the issue of supplying the heat for the dissolution which may also depend on a proper representation of the turbulent-flow field). An additional important issue is how many particles have to be tracked for a proper representation of the transient spatial distribution of the particles over the vessel. 

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