Dissolution/particle size-limited

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]. 

Reduction of particle size increases the total specific surface area exposed to the solvent, allowing a greater number of particles to dissolve more rapidly. Furthermore, smaller particles have a small diffusion boundary layer, allowing faster transport of dissolved material from the particle surface [58]. These effects become extremely important when dealing with poorly water-soluble drugs, where dissolution is the rate-limiting step in absorption. There are numerous examples where reduction of particle size in such drugs leads to a faster dissolution rate [59-61], In some cases, these in vitro results have been shown to correlate with improved absorption in vivo [62-64]. 

Particle size of chemical in solid dosage form smaller particle sizes will increase the rate and/or degree of absorption if dissolution of the chemical is the rate-limiting factor in absorption. Chemicals that have a low dissolution rate may be made in a micronized form to increase their rate of 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. 

Important specifications for the manufacture of all solutions include assay and microbial limits. Additional important specifications for suspensions include particle size of the suspended drug, viscosity, pH, and in some cases, dissolution. Viscosity can be important, from a processing aspect, to minimize segregation. In addition, viscosity has also been shown to be associated with bioequivalency. pH may also have some meaning regarding effectiveness of preservative systems and may even have an effect on the amount of drug in solution. With regard to dissolution, there are at least three products that have dissolution specifications. These products include pheny-toin suspension, carbamazepine suspension, and sulfamethoxazole and trimethoprim suspension. Particle size is also important, and at this point it would seem that any... 

In many cases in drug development, the solubility of some leads is extremely low. Fast dissolution rate of many drug delivery systems, for example, particle size reduction, may not be translated into good Gl absorption. The oral absorption of these molecules is usually limited by solubility (VWIImann et al., 2004). In the case of solubility limited absorption, creating supersaturation in the Gl Luids for this type of insoluble drugs is very critical as supersaturation may provide great improvement of oral absorption (Tanno et al., 2004 Shanker, 2005). The techniques to create the so-called supersaturation in the Gl Luids may include microemulsions, emulsions, liposomes, complexations, polymeric micelles, and conventional micelles, which can be found in some chapters in the book. 

There are a number of physicochemical properties of an API that are impacted upon size reduction, which need to be considered while resolving pharmaceutical problems related to solubility limitations. Clearly, dissolution rate and its dependence upon particle size reduction is one of those critical properties (Ross and Morrison, 1988 Rabinow, 2004 Kocbek et al., 2006). For example, in the case of oral administration of a poorly water-soluble API, the increase in dissolution rate attendant with size reduction provides for more drug in solution, and available for absorption, during its gastrointestinal transit (Chaumeil, 1998 Merisko-Liversidge et al., 2003 Patravale et al., 2004 Pouton, 2006). 

This equation again demonstrates that particle size and solubility are the main parameters affecting dissolution kinetics of drug powders, which, in turn, could affect the release profile of dosage forms if dissolution is the rate-limiting step of in vivo absorption. Table 5.1 demonstrates several examples of dissolution times of spherical particles (assuming monodispersed systems) as a function of solubility and particle size. 

Chandrasekaran and Paul19 have found that for such systems where dissolution is the rate-limiting step [small AJVin Eq. (5.14), where drug loading is low and particle size is large], the release is linear with time, and the release rate is a zero order, as shown by... 

In the case of compounds that exhibit low solubility in gastric fluids, the rate of dissolution may limit the availability of the compound in vivo. The dissolution rate can be improved by increasing the surface area of the compound. In this case, the API physical property (either surface area or particle size distribution) will likely be a critical quality attribute, as it could directly impact the safety, identity, strength, purity and quality (SISPQ) of the drug product.1 2... 

Principal product specifications are microbial limits and testing methods, particle size, viscosity, pH, and dissolution of components. Process validation requires control of critical parameters observed during compounding and scale-up. Product stability examination is based on chemical degradation of the active components and interac-... 

Product Specifications The most important specifications or established limits for liquid dosage forms are microbial limits and test methods, medium pH, dissolution of components, viscosity, as well as particle size uniformity of suspended components and emulsified droplets. Effectiveness of the preservative system depends on the dissolution of preservative components and may be affected by the medium pH and viscosity. In addition, dissolved oxygen levels are important for components sensitive to oxygen and/or light [6],... 

The bioavailability of a poorly water-soluble drug is often limited by its dissolution rate, which in turn is controlled by the surface area available for dissolution. The effect of the particle size of a drug on its dissolution rate and its biological activity is well known. For example, Atkinson et al. reported that micro-nization of griseofulvin resulted in reduction of the therapeutic dose by half. 

Furthermore, pharmacokinetic administration, distribution, metabolism and excretion (ADME) factors affect drug bioavailability, efficacy and safety, and, thus, are a vital consideration in the selection process of oral drug candidates in development pipelines. Since solubility, permeability, and the fraction of dose absorbed are fundamental BCS parameters that affect ADME, these BCS parameters should prove useful in drug discovery and development. In particular, the classification can used to make the development process more efficient.For example, in the case of a drug placed in BCS Class II where dissolution is the rate-limiting step to absorption, formulation principles such as polymorph selection, salt selection, complex formation, and particle size reduction (i.e., nanoparticles) could be applied earlier in development to improve bioavailability. 

Particle size reduction is typically used to enhance dissolution rate and/or bioavailability of APIs with limited in vivo solubility. Because the rate of dissolution of a particle is not only directly proportional to solubility, but also directly proportional to particle surface area (Pick s first law, Noyes-Whitney equation), increasing the surface area by reducing the average particle size increases dissolution rate. 

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