Solubilization dissolution rate

In order to achieve appropriate levels of solubilization, dissolution rate and potentially supersaturation, excipients are required (Rowe et al., 2006 International Pharmaceutical Excipients Council 2006). Excipients are components of dosage forms which are included for a variety of reasons and are usually not directly associated with the pharmacological activity of the selected drug substance. Historically, excipients have comprised ingredients e.g., to mask or... 

P Singh, S Desai, D Flanagan, A Simonelli, W Higuchi. Mechanistic study of the influence of micelle solubilization and hydrodynamic factors on the dissolution rate of solid drugs. J Pharm Sci 57 959, 1968. 

A method used to describe the enhanced dissolution rate following micelle-facilitated dissolution is to compare the dissolution of the drug in the surfactant solution to that of the dissolution rate in water this is often termed the reaction factor method. The reaction factor, ( vM, which is the total flux of the micelle-solubilized solute plus the free solute divided by the flux of the free solute, is given by... 

For highly permeable, poorly soluble drugs given in lower doses, the dissolution rate rather than the saturation solubility is the limiting factor. An increase in dissolution rate due to in vivo solubilization mediated by food intake could theoretically be obtained, but this situation is not always found in vivo. For example, food does not affect the rate and extent of bioavailability for candesartan cilexitil, a very poorly soluble compound [78], An in vitro dissolution and solubility study of this compound in simulated intestinal media provided a potential explanation it was revealed that the solubility was increased as a function of bile concentration as expected, whereas the dissolution rate was not increased by the higher bile concentrations being representative for the fed state (see Fig. 21.14). Thus, although... 

One approach to the study of solubility is to evaluate the time dependence of the solubilization process, such as is conducted in the dissolution testing of dosage forms [70], In this work, the amount of drug substance that becomes dissolved per unit time under standard conditions is followed. Within the accepted model for pharmaceutical dissolution, the rate-limiting step is the transport of solute away from the interfacial layer at the dissolving solid into the bulk solution. To measure the intrinsic dissolution rate of a drug, the compound is normally compressed into a special die to a condition of zero porosity. The system is immersed into the solvent reservoir, and the concentration monitored as a function of time. Use of this procedure yields a dissolution rate parameter that is intrinsic to the compound under study and that is considered an important parameter in the preformulation process. A critical evaluation of the intrinsic dissolution methodology and interpretation is available [71]. 

Complexation between the dissolving solute and an interactive ligand [116], or solubilization of the dissolving solute by a surface-active agent in solution [121]. Each of these phenomena tends to increase the dissolution rate. 

It is generally believed that the mechanism of bioavailability enhancement by CD complexation is through solubility and dissolution rate improvement. However, it should be also noted that CDs might also alter the lipid barrier of the absorption site, which may contribute to the enhanced drug absorption. This effect of CDs on the lipid barrier can be attributed to CDs ability to form complexes with membrane components such as cholesterol, phospholipids, and proteins (Nakanishi et al., 1992). Jambhekar et al. (2004) compared the solubilizing effeqte D, HP-ft-CD, and H -CD on IM. 

Devarakonda et al. (2005) compared the solubilization of niclosamide by complexing with polyamidoamine (PAMAM) dendrimers and CDs, and found the solubility of niclosamide was sig-niLcantly higher with PAMAM. However, the dissolution rate was lower with PAMAM compared to the CDs, which was owing to the strong interaction between niclosamide and PAMAM delayed the release of the drug from the complexes of dendrimers. 

For formulating poor water-soluble compounds, use of cosolvent(s) is one of the simplest and common approach. The approach is also widely used in the early development phase, as limited information is available for the molecule. The approach also allows overcoming dissolution rate limited drug absorption. In addition, solubilized formulations are greatly popular with pediatric, geriatric, and patients with swallowing difculties. 

Naylor et al. (1993) studied the ability of lecithin to modify the rate and mechanism of dissolution of hydrocortisone in the presence of sodium taurocholate (NaTC) solutions. They found that in the presence of lecithin, the CMC of NaTC dropped owing to the more effective solubilization capacity of the mixed micelle. Furthermore, the CMC value dropped more on saturation with hydrocortisone, implying some interaction between hydrocortisone and the NaTC/lecithin micelles. These results indicated that in the NaTC-only system, wetting effects predominated dissolution, whereas in the NaTC/lecithin system, the dissolution rate of hydrocortisone was enhanced mainly through solubilization. 

Another important factor that may inLuence solubility, dissolution rate, and therefore absorption of water-insoluble compounds is the contents ofthe Gl Luids. The Gl Luids contain various materials, such as bile salts, enzymes, and mucin. Bile salts are surface active and as such could potentially enhance the rate or extent of absorption of water-insoluble drugs. Thus, the increased absorption of a water-insoluble compound, griseofulvin (GF), after a fatty meal may be facilitated by bile salt secretion into the gut resulting in solubilization [1,2],... 

Many APIs are marketed in a salt form. Salt formation can confer a variety of physical, chemical, and biological properties on the API without changing its basic chemical structure. A few of the important properties are water solubilization, modified dissolution rates, improved stability, and beneficial pharmacological effects. 

An evaluation of the effect of pH on the aqueous solubility of a drug substance is an essential component of preformulation research, and such work is usually conducted along with determinations of ionization constants, solubilization mechanisms, and dissolution rates. ° Methods for the determination of the solubility... 

The combined effect of pH and surfactants on the dissolution of piroxicam has been reported. " In this system, the dissolution rate and solubility of the drug substance could be well estimated by a simple additive model for the effect of pH and surfactant, where the total dissolved concentration equaled the summation of the amoimt of dissolved non-ionized substance, the amount of dissolved ionized substance, and the amoimt of substance solubilized in the surfactant micelles. It was suggested that the model developed in this work could be useful in establishing an in vitro-in vivo correlation for piroxicam. 

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