Critical formulation variables

One example of the application of response surface analysis is a study of critical formulation variables for 20 mg piroxicam capsules [100]. Piroxicam is a BCS Class II drug (low solubility and high permeability). This... 

The initial approach should be to first identify which formulation properties are critical for its in vivo function. Thereafter, all potential physiological factors that may influence this function should be identified and the correlation between the animal and man regarding those factors should be considered. For example, in the case of a pH-dependent enteric-coat formulation, the dissolution of the coating layer will clearly be a critical formulation variable. The pH in the stomach and small intestine, as well as gastric emptying, will all be critical variables. If the correlation of such parameters with man is poor for all available animal models, there is no rationale for performing such studies if the deviations cannot be accounted for when interpreting the results. 

For MR formulations the in vitro dissolution conditions, which achieve an optimal IVTVC, will be those which possess the discriminatory power to detect the effect of critical manufacturing variables on drug release. An investigation of the dependence of the formulation on pH and surfactants is recommended in media of various compositions. A dependence on dissolution equipment, and range of equipment settings should also be considered in the investigations. 

Among the formulation variables that control extrudability of a product, several studies (25,26,33-35) point to the fluid or moisture content of the wet feed material being more critical than others. The force or torque of extrusion and power consumption are often inversely proportional to moisture content of the extrudate as seen from Figures 11 and 12 (26,36-38), while the particle size of pellets increases linearly with water content when extruded with gravity feed basket and roll extruders (33). Using instrumented gravity feed and radial screw extruders, a three- to fourfold decrease in the force has been noted, with a 10% increase in water content of feed material (37). 

Free Radical Cure UV Adhesives. As with any adhesive, formulation variables are critical to the processing and performance characteristics. Variables such as oligomer selection, modifiers and additives, monomer structure, molecular weight, and glass transition temperature directly affect application and performance properties. 

Identification and control of critical component and formulation variables early in development. 

A high-dose ( 75% drug loading) wet granulated tablet formulation was optimized using a DOE. The optimized critical formulation and process variables are shown in Table 10. 

In the critical variables analysis phase, a statistical experimental design is created (e.g., factorial, Box-Behnken) intended to assess critical formulation and process variables in relatively small-scale manufacture. In these studies, the ranges of composition variables are chosen to at least encompass those noted in the recommendations of the AAPS-FDA Workshop on Scale-up of Immediate Release Oral Solid Dosage Forms or SUP AC. This phase is usually preceded by a development phase during which variables and levels to be studied are determined and the exact method of manufacture is established. Experimental formulations are assessed at least in terms of dissolution performance, content uniformity, and weight variation. On the basis of these studies, the specific formulations to be manufactured for biostudy are selected. 

Rekhi G, Nellore RV, Hussain AS, Tillman LG, Malinowski HI, Augsburger LL. Identification of critical formulation and processing variables for metoprolol tartrate extended release (ER) matrix tablets. J Control Release 1999 59 327-42. 

The PIT is obviously linked with the so-called cloud point [24], at which the dehydration of the polyethoxylated chain reaches such a point that the surfactant is no longer soluble in water and a surfactant phase separates from the original aqueous solution (in the absence of oil phase). It is known that the presence of a small amount of dissolved hydrocarbon can change both the critical micelle concentration and cloud point, but the effect is not documented to a point that it can be quantified. On the contrary, the PIT measurement is quite reliable, and in its last version, it takes into account not only the surfactant type but also the aqueous- and oil-phase nature (i.e., all three formulation variables). 

The formulation dominates the properties of SOW systems when the surfactant concentration is not too low and when the water-to-oil ratio is close to unity. When this is not satisfied, then the composition, i.e., the relative proportions of different substances, has to be taken into account. Provided that the surfactant concentration is not high enough to produce a singlephase microemulsion, say less than 10 to 20%, the most critical composition variable is the water-to-oil ratio, which is often expressed as the oil or water fraction, because the surfactant amount is small. 

At each point on the critical locus Equations 40a and b are satisfied when the true values of the binary interaction parameters and the state variables, Tc, Pc and xc are used. As a result, following an implicit formulation, one may attempt to minimize the following residuals. 

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