Excipient concentration

There are some useful methods to improve the physical stability of a suspension, such as decreasing the salt concentration, addition of additives to regulate the osmolarity, as well as changes in excipient concentrations, unit operations in the process, origin and synthesis of the drug substance, polymorphic behavior of the drug substance crystals, and other particle characteristics. However, methods based on changes of the particle properties and the surfactants used are the most successful [43],... 

FIGURE 2.37 The relationship between the tablet hardness and excipient concentration. 

As with all pharmaceutical products, the most important rule to bear in mind when formulating parenterals is the keep it simple principle. Wherever possible, formulations should be developed using excipients which have an established use in parenteral products administered by the same route as the product under development. Both the excipient concentration, rate... 

Excipients Concentration ( hglmL) Change in fluorescence intensity (%)... 

Compounding Local pH hotspots and high excipient concentrations pH adjnstments and addition of excipients create transient regions of destabilizing conditions... 

Bioavailability, Bioequivalence, and Pharmacokinetics. Bioavailabihty can be defined as the amount and rate of absorption of a dmg into the body from an adrninistered dmg product. It is affected by the excipient ingredients in the product, the manufacturing technologies employed, and physical and chemical properties of the dmg itself, eg, particle size and polymorphic form. Two dmg products of the same type, eg, compressed tablets, that contain the same amount of the same dmg are pharmaceutical equivalents, but may have different degrees of bioavailabihty. These are chemical equivalents but are not necessarily bioequivalents. For two pharmaceutically equivalent dmg products to be bioequivalent, they must achieve the same plasma concentration in the same amount of time, ie, have equivalent bioavadabihties. 

The second example is the SE-HPLC analysis of recombinant hGH. In this example, SE-HPLC is used for both a purity and a protein concentration method for bulk and formulated finished products. This method selectively separates both low molecular weight excipient materials and high molecular weight dimer and aggregate forms of hGH from monomeric hGH, as shown... 

By choosing the excipient type and concentration, and by varying the spray-drying parameters, control was achieved over the physical properties of the dry chitosan powders. The in vitro release of betamethasone showed a dose-dependent burst followed by a slower release phase that was proportional to the drug concentration in the range 14-44% w/w [200]. 

Co-administration of ofloxacin and chitosan in eyedrops increased the bioavailabUity of the antibiotic [290]. Trimethyl chitosan was more effective because of its solubility (plain chitosan precipitates at the pH of the tear fluid). On the other hand, N-carboxymethyl chitosan did not enhance the corneal permeability nevertheless it mediated zero-order ofloxacin absorption, leading to a time-constant effective antibiotic concentration [291]. Also W,0-carboxymethyl chitosan is suitable as an excipient in ophthalmic formulations to improve the retention and the bioavailability of drugs such as pilocarpine, timolol maleate, neomycin sulfate, and ephedrine. Most of the drugs are sensitive to pH, and the composition should have an acidic pH, to enhance stability of the drug. The delivery should be made through an anion exchange resin that adjusts the pH at around 7 [292]. Chitosan solutions do not lend themselves to thermal sterilization. A chitosan suspension, however. 

Because of the nature of modern pharmaceutical systems, formulators have made more complete investigations of the materials they use. This interest has identified several materials that may have more than one use in tableted systems. The type of effect that an excipient will produce is often dependent upon the concentration in which it is used. For example, Table 5 lists some multiuse excipients and the corresponding concentration ranges required for their various applications. 

This aromatic alcohol has been an effective preservative and still is used in several ophthalmic products. Over the years it has proved to be a relatively safe preservative for ophthalmic products [138] and has produced minimal effects in various tests [99,136,139]. In addition to its relatively slower rate of activity, it imposes a number of limitations on the formulation and packaging. It possesses adequate stability when stored at room temperature in an acidic solution, usually about pH 5 or below. If autoclaved for 20-30 minutes at a pH of 5, it will decompose about 30%. The hydrolytic decomposition of chlorobutanol produces hydrochloric acid (HC1), resulting in a decreasing pH as a function of time. As a result, the hydrolysis rate also decreases. Chlorobutanol is generally used at a concentration of 0.5%. Its maximum water solubility is only about 0.7% at room temperature, which may be lowered by active or excipients, and is slow to dissolve. Heat can be used to increase dissolution rate but will also cause some decomposition and loss from sublimation. Concentrations as low as 0.125% have shown antimicrobial activity under the proper conditions. 

The choice of the excipients and their concentration, including their function (e.g., antimicrobial preservatives, antioxidants. ..). In the case of antimicrobial preservatives, data are expected on the preservative efficacy in products on storage, including after reconstitution or dilution and during the period of use. 

The choice of the excipients, their intended function, and their concentration will need to be considered in relation to those characteristics that may affect product performance. 

Antioxidants should be used only when it can be shown that their incorporation cannot be avoided by appropriate manufacturing methods or packaging. Their intended performance in the product should be clearly stated—e.g., whether for the benefit of the active ingredient or an excipient. Their efficacy can depend on their nature, their concentration (subject to safety considerations), when they are incorporated in the manufacture of the finished product, the container, and the formulation (particularly their compatibility with other constituents). All of these issues should be addressed. Their activity should also be determined in the finished product under conditions simulating the use of the product. The extent of degradation should be determined with and without the antioxidant. 

The problem is that we want to separate these from one another, and from excipients in a commercial tablet. To get an idea of the conditions needed for the separation, you have to concentrate on the differences between them. 

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