Volume Available for Dissolution

Influence of Osmolality on Intestinal Transit and on Chyme Volume Available for Dissolution... 

Hydrodynamics in the upper GI tract contribute to in vivo dissolution. Our ability to forecast dissolution of poorly soluble drugs in vitro depends on our knowledge of and ability to control hydrodynamics as well as other factors influencing dissolution. Provided suitable conditions (apparatus, hydrodynamics, media) are chosen for the dissolution test, it seems possible to predict dissolution limitations to the oral absorption of drugs and to reflect variations in hydrodynamic conditions in the upper GI tract. The fluid volume available for dissolution in the gut lumen, the contact time of the dissolved compound with the absorptive sites, and particle size have been identified as the main hydrodynamic determinants for the absorption of poorly soluble drugs in vivo. The influence of these factors is usually more pronounced than that of the motility pattern or the GI flow rates per se. 

The solubility of an active substance in the different body fluids and the efficacy of the absorption process, together with the dose determine the bioavailability of a medicine. The dose number (DN) is a dimensionless parameter that finks solubility (Cs) to dose (D) and volume available for dissolution (V) during the absorption process. The dose number can be calculated from (16.4) ... 

The transport of the dissolved active substance over the membranes to the blood circulatiOTi is called absorption. The extent and rate of absorption are determined by several factors, including the size and charge of the active substance molecule, its lipophilicity, the volume available for active substance dissolution, the surface and permeability of the absorbing membrane, the presence of metabolising enzymes and, in the case of active transport, the presence of transporters. As a consequence, poor bioavailability may be caused by incomplete dissolutimi of the active substance, by poor permeation over the absorbing membrane, or by metabolism during absorption. 

A typical example is ibuprofen. The BCS-relevant characteristics of the drug are given in Table 5. Obviously, there will be little or no dissolution of ibuprofen under typical gastric conditions in the fasted state. However, the D S falls almost within the BCS limit of < 250 mL at pH 6.8, so it can be assumed that dissolution into a standard volume of medium (e.g., 500 mL, as recommended in Table 3) can be completed. This assumption is borne out by the results for dissolution of the pure drug and several IR oral drug products available on the European market as shown in Figure 4. 

Consequently, absorption enhancers were used in dry powder and liquid formulations to enhance the pulmonary absorption of SCT. Without absorption enhancers, SCT absorption from dry powder or solution was similar to that observed after intratracheal administration. However, the absorption was more improved from dry powder than from solution when absorption enhancers (oleic acid, lecithin, citric acid, taurocholic acid, dimethyl-[5-cyclodextrin, octyl-P-D-glu-coside) were co-administered intratracheally. Such improved absorption could be due to the fact that enhancers added to the dry powder dissolved at high concentration because only a trace volume of fluid lining the alveolar epithelium was available for their dissolution. However, the potential implications of such a mechanism on lung toxicity, especially in lung edema, is yet to be investigated in detail [68]. 

A typical HTS campaign may require hundreds of thousands of samples delivered daily. Thus it is necessary to have all neat (solid) samples in liquid form in order to prepare and deliver them quickly. The first process in compound management to support HTS is dissolution of all solid samples into solutions—a process known as solubilization that makes samples readily available for biological testing. Another advantage to centralized compound solubilization, even for post-HTS activities, is to preserve the samples and reduce waste of the crown jewels. Compound solubilization usually requires (1) selection of solvent, (2) determining concentration and volume, (3) weighing of solids, and (4) solubilization. 

Figure I plots the surface to volume ratio in Equation (3) versus the particle diameter this graph shows that as the panicle size decreases, the surface to volume ratio tends towards infinity. In other words, the total. surface area of a set of panicles is greatly affected by the panicle size. Thus, phenomena that occur at a panicle s surface, such as dissolution, will occur at a faster rate for panicles with a higher surface to volume ratio, because there is more surface area available for interaction with the surroundings conversely slower reactions will occur for panicles with a lower surface to volume ratio. As shown in Figure 1, the effect of panicle size can be very significant as panicle size decreases. For example, panicles with diameter of 1 pm will yield a surface to volume...

M is the time-dependent undissolved (solid) drug amount present in the donor compartment S is the area available for permeation K, is the drug dissolution constant Cj is the drug solubility Vr is the receiver compartment volume Ai, A3, and A2 are, respectively, the thicknesses of the first and the second stagnant layers and the membrane Cjo and Mg are, respectively, the initial drug concentration and undissolved drug amount in donor compartment, while K2X, K22, and K r are partition coefficients defined as follows ... 

Satisfactory dissolution of the starch at atmospheric pressure is difficult to achieve and a thermostable a-amylase is often included. Pressure cooking with an autoclave at 130°C is better, but such equipment is uncommon in laboratories. Dimethyl sulfoxide, with 10% water included, is an excellent solvent for starch, but this water content is critical, and the organic solvent is present during the subsequent enzyme hydrolysis. However, commercial kits are available that employ dimethyl sulfoxide as solvent. Acid may also be used for dissolution but, if a large amount is used, care must be taken that the starch does not salt-out on neutrafization. A most convenient solvent has proved to be cold dilute sodium hydroxide solution. The starch, 250 mg, is slurried in 25 ml of water, an equal volume of 1 moll sodium hydroxide is added and stirring is continued for 5 min. Before addition of enzymes the solution is adjusted to pH 4.5-5.0 with acetic acid. 

As the reactions proceed, the dissolved oxygen in the small volume of stagnated solution inside the crevice is consumed. However, this does not prevent the dissolution reaction inside the crevice because the electrons reach outside the crevice through the metal, where plenty of oxygen is available for reduction. A concentration cell (differential aeration) is set up between the crevice area and the area outside the crevice. 

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