Formulation variables

The importance of using sphere-forming excipients was noted early on. Conine and Hadley dted the necessity of using microcrystalline cellulose (4). Reynolds went on to indicate the need for either adhesive or capillary type binders (5). He dted cellulose gums, natural gums, and synthetic polymers as adhesives and microcrystalline cellulose, talc, and kaolin as capillary type binders. Since then much work has been conducted in an attempt to understand the significance of material properties. Some of the studies are discussed in the following text. 

O Connor et al. studied the behavior of some common exdpients in extrusion/ spheronization. The materials were studied as single components using water as the granulating fluid in an attempt to understand their application in the process. Of the materials tested, only MCC or MCC with Na-CMC (Na-caboxymethyl cellulose) was capable of being processed. Others including dicaldum phosphate, lactose, starch, and modified starch did not process adequately (24). 

Kleinebudde and Jumaa concluded that during the extrusion process, water content in the extrudate and pellet porosity were increased as the degree of polymerization of MCC and powder cellulose in the matrix was increased (57). 

Millili and Schwartz demonstrated the effect of granulating with water and ethanol at various ratios. The physical properties of the spheres changed significantly as the ratio of the two fluids was varied. Spheres could not be formed with absolute ethanol but were possible with 5 95 waterlethanol. An increase in the water fraction resulted in a decrease in porosity, friability, dissolution, and compressibility and an increase in density. The porosity of spheres granulated with 95% ethanol was 54% 

In a later study, Millili et al. proposed a bonding mechanism, referred to as autohesion, to explain the differences in the properties of spheres granulated with water and ethanol. Autohesion is a term used to describe the strong bonds formed by the interdiffusion of free polymer chain ends across particle-particle interfaces (59). 

---

Whether any of the formulation variables change the mechanical properties significantly upon aging cannot be answered due to the lack of definition of chemical composition parameters as discussed previously... 

For the PS case, a three-variable Box-Behnken response surface methodology (RSM) design using formulation variables has been carried out. For the RF system, an eight-variable fractional-factorial screening study was done first to select significant factors, and this was followed by two RSM s which were similar in design to the one done for PS. The results have led directly to substantial improvements in both materials. 

The results for the RF screening study are shown in Table 3. The most striking result to come out of this experiment was that there appears to be a strong correlation between the low level of catalyst concentration and gel formation. The low level was outside the range of what had previously been tried. This has been confirmed in many subsequent experiments. Another important conclusion was that the chemistry appears to dominate the process, so it was reasonable to proceed with an RSM which dealt only with the formulation variables. Although the oven time was significant at the 90% confidence level, it was decided to optimize the chemistry first and deal with this as part of the processing conditions in later experiments. 

Rowe RC, Roberts RJ. The effect of some formulation variables on crack propagation in pigmented tablet film coatings using computer simulation. Int J Pharm 1992 86 49-58. 

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... 

All piroxicam batches were manufactured in compliance with Good Manufacturing Practices, and three formulations having fast, moderate, and slow dissolution were chosen for comparison to a lot of the innovator s product in a human bioavailability study [100]. The resulting pharmacokinetic data provided still another opportunity to examine the effects of formulation variables. To explore the relationship between the in vitro dissolution of piroxicam from these capsules and in vivo absorption, Polli [ 102] used the following previously described [145] deconvolution-based model ... 

Fig. 25 Response surfaces for the effect of formulation variables on percent of piroxicam dissolving from capsules in 10 minutes. (From Ref. 100.)...

It is interesting that the in vitro dissolution test (USP) was more sensitive to the piroxicam formulation variables than the biodata. The fast, moderate, and slow products were found bioequivalent to each other and to the lot of innovator product studied [100]. It is possible that either the formulation variables studied did not affect in vivo dissolution and/or the differences were not discernible because of the long biological half-life of piroxicam [146]. 

Another formulation variable that must be considered is that of the solution pH and bulfer capacity. Since the anterior chamber fluid (aqueous humor) contains essentially the same buffering systems as the blood, products with a pH outside the physiological range of 7.0-7.4 are converted to this range by the buffering capacity of the aqueous humor if a relatively small volume of the solution is introduced. Often,... 

Instead of using the oral bioavailability of a drug, one can attempt to correlate PM values with permeability coefficients generated from in situ perfused intestinal preparations. Here, one eliminates the complexities of liver metabolism, clearance, and formulation variables. Recently, this type of in vitro-in situ correlation has been conducted using the model peptides (described previously in Section V.B.2). The permeabilities of these model peptides were determined using a perfused rat intestinal preparation which involved cannulation of the mesenteric vein (Kim et al., 1993). With this preparation, it was possible to measure both the disappearance of the peptides from the intestinal perfusate and the appearance of the peptides in the mesenteric vein. Thus, clearance values (CLapp) could be calculated for each peptide. Knowing the effective surface area of the perfused rat ileum, the CLapp values could be converted to permeability coefficients (P). When the permeability coefficients of the model peptides were plotted as a function of the lipophilicity of the peptides, as measured by partition coefficients in octanol-water, a poor correlation (r2 = 0.02) was observed. A better correlation was observed between the permeabilities of these peptides and the number of potential hydrogen bonds the peptide can make with water (r2 = 0.56,... 

Similar overlaying of other response surface plots led to conclusions regarding the formulation variables and their effects on the properties of the copolymers. In addition, another (proprietary) computer program was used, which allowed the combination of several regression equations (for the various responses) and the calculation of variable values needed to achieve any desired combination of response values (if the models permit). 

Formulation Properties which Enhance Wetting Effect of Operating and Formulation Variables... 

Properties which Minimize Attrition Effects of Operating and Formulating Variables... 

Setting of specifications for IVIVC on Level B is more of a challenge. A procedure has been described requiring homomorphic dissolution profiles on the in vitro side and BA data for at least three formulation variables on the in vivo side using interpolation (24). Extrapolation of Level B IVIVC is considered to be very questionable, so one is limited to interpolation within the established limits of the IVIVC. For Level B or C correlations, additional BA/BE will be needed if the IVIVC is to be extended to different types of formulations and/or different brands. 

In this chapter, we will review studies on formulation variables affecting monocyte and macrophage targeting (e.g., size and number of vesicles), in vitro characterization in cell cultures, and in vivo immunomodulation and anti-inflammatory responses. 

For the majority of analyses of drugs in formulations, variable wavelength UV or diode array UV detectors are used. A typical UV dector has a narrow cell about 1 mm in diameter with a length of 10 mm, giving it an internal volume of about 8. ... 

When HLD = 0 three-phase behavior takes place because of the exact compensation of the effect of the different formulation variables expressed in Eqs. 4 and 5. hi practice, an unidimensional formulation scan is carried out to detect the occurrence of three-phase behavior. In such a scan, only one of the formulation variables (appearing in Eqs. 4 and 5) is changed, while all the others are held constant, as well as composition variables, i.e., surfactant concentration and water/oil ratio (WOR). 

Marquez N, Graciaa A, Lachaise J, Salager JL (2002) Partitioning of ethoxylated alkylphenol surfactants in microemulsion-oil-water systems Influence of physicochemical formulation variables. Langmuir 18 6021-6024... 

Chowhan [9] defined different pathways of physical instability of tablet formulations. These physical paths may involve one or more complex physical processes, e.g. change in polymorphism, crystallization, vaporization and adsorption. These pathways and thus the physical tablet parameters, are influenced by different types of variables formulation variables (e.g. solubility and hygroscopicity), in-process variables (e.g. moisture content) and aging variables (e.g. temperature and relative humidity). 

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). 

Among formulation variables, the moisture content particularly on surface of the material needs to be optimized. While excess surface moisture could lead to uncontrolled agglomeration, a dry extrudate can break up into fine powder. Upon spheronization for prolonged periods at high speeds, moisture gradients develop within pellets by migration from core to the surface. This is also a function of the concentration of dissolved solids and spheronizing time. The surface moisture could be lost over time, due to... 

A 20 run 2 fractional factorial design with four replicate center points was carried out to assess whether it was possible to optimize the current formulation for scale-up or if major reformation would be necessary. Table 3 lists the formulation variables that were evaluated. 

Table 3 2 Experimental Design, Formulation Variables and Their Ranges...

Much of the data developed during product and process development is often empirically derived and, as such, reflects the relative experience and preferences of those responsible for that development process. While application of such experience can be of tremendous value, it is not unusual to find that each new product that is being developed, or process refinement being employed, has inherent idiosyncrasies that reduce the relevance of prior experience. In order to create a robust product and process, personal bias has to be removed, and, instead, decisions must be made based on scientific validity. All too often, the phrase we have fully optimized the product and process is used to describe a situation where decisions have been made on the basis of an iterative process where process (and formulation) variables have been studied in a trial and error manner, changing one parameter at a time. This process, often called one of successive approximation, is followed until an acceptable process has been achieved. The problems associated with employing such techniques include ... 

Smyth HDC. The influence of formulation variables on the performance of alternative propellant-driven metered dose inhalers. Adv Drug Delivery Rev 2003 55(7) 807-828. 

---