Robust formulation

Overall, the development of a robust formulation with scale-up potential for Phase II studies involves integration of physicochemical, biopharmaceutical, and technical considerations. Whether a rudimentary formulated capsule or a more robust formulation closer to the commercial form will be used in Phase II studies will depend on the company policy, material cost, the complexity of clinical design, and the development strategy. 

ROBUST FORMULATIONS AND DOSAGE FORM DESIGN The Effect of Percolation Theory... 

Develop robust formulations by simulating production machines or running with dwell times similar to production tablet presses. 

Through the use of DOE, a robust formulation and process were developed, resulting in tablets that could be produced at production scale. The compaction profile shifted slightly on scale-up to production, but tablet... 

By identifying critical process parameters early on in the development process, a robust formulation was developed and successfully scaled-up... 

The purpose in the early phase of drug development is to deliver a known dose that is bioavailable for clinical studies. As product development continues, increasing emphasis is placed on identifying a stable, robust formulation from which multiple, bioequivalent lots can be manufactured and ultimately scaled up, transferred, and controlled for commercial manufacture. 

Finally, knowledge of excipient mechanical and physical properties is essential to creating a robust formulation that manufactures tablets that meet specifications in a time- and material-efficient manner. Excipient selection must also take into consideration API stability and biopharmaceutical performance of the dosage form. Uneducated selection of excipients will likely lead to numerous formulating iterations that require much time and material, which are luxuries that product development scientists do not have in the competitive pharmaceutical environment. 

Robust formulations are today an absolute prerequisite. Concerning the production of granules, the granule size distribution should not vary from batch to batch. The key factors are the correct amount and the type of granulating liquid. The interpretation of the power consumption method can be very important for an optimal selection of the type of granulating liquid. The possible variation of the initial particle size distribution of the active substance and/or excipients can be compen-... 

Development of a Robust Formulation of Low Wettability Drug during Early... 

The following studies from our research laboratories illustrate examples of critical issues and demonstrate the impact of percolation theory on the development of robust formulations involving poorly wettable drugs. 

As an ultimate goal, the use of DoE and ANN leads to the creation of expert systems including general rules as a valuable tool in the development of robust formulations (see Figure 20.7). 

The dissolution profiles for LBZ B110-l-2 and PPL B110-l-2 tablets were also compared using similarity factor f2. A value obtained for f2 that is below 50 (37.48) indicates the influence of drug solubility in the dissolution profile. Furthermore, other parameters, such as dextran-drug ratio, particle size of polymer and drug, and influence of pH, have to be studied to obtain an optimum and robust formulation. 

Knowledge of the percolation threshold of the components of the matrix formulations contributes to improve their design. First, in order to develop robust formulations, that is, to reduce variability problems when they are prepared at industrial scale, it is important to know the concentrations corresponding to the percolation thresholds. The percolation thresholds correspond to formulations showing a high variability in their properties as a function of the volume fraction of their components. Therefore, in order to design robust dosage forms, the nearby of the percolation thresholds should be avoided. 

HPLC method development has already been covered in Chapter 8. The focus of this chapter is to utilize HPLC and the data generated by this technique to help in developing a robust formulation for a drug product. However, the current section will discuss sample preparation solvent since it becomes an integral part of HPLC when we are discussing HPLC methods for a particular formulation. Any sample preparation solvent that is chosen for any HPLC method must be compatible with the HPLC solvents utilized for that particular test method. The current section will assume that a new molecular entity (NME) is utilized for a particular drug product. 

Consistency. All systems generate robust formulations with increased certainty and consistency. This is seen as a distinct benefit where regulatory issues are important. 

Hydrophilic matrices are the most commonly used oral extended-release systems because of their abihty to provide desired release profiles for a wide range of drugs, robust formulation, cost-effective manufacture, and broad regulatory acceptance of the polymers. Table 11.2 shows a fist of hydrophific polymers commonly used for fabrication of matrices [17, 18]. Hydrophobic materials are also used either alone (hydrophobic matrix systems) or in conjugation with hydrophilic matrix systems (hydrophilic-hydrophobic matrix systems) and are also fisted in Table 11.2. Cellulose ethers, in particular hypromeUose (hydroxypropyl methylcellulose, HPMC), have been the polymers of choice for the formulation of hydrophilic matrix systems. 

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