Formulation stage

The collection of problems at the formulation stage, which identifies the compound or activity of concern, the persons or species to be protected, and the effect and end-point evaluation. 

The primary method for demonstration of the existence of drug polymorphs, or solvate species, is that of powder x-ray diffraction (XRD). Such measurements represent a specification of the internal structure within a crystal, and an evaluation of its lattice type. Since dissolution and subsequent drying can sometimes yield an undesired structure, it is also important to confirm crystal structures at each formulation stage during the beginning of the development process. 

The Texas Transportation Institute has just completed a very extensive two year FHWA sponsored program to look into other aspects of safety and environmental impact of sulfur-asphalt construction [53]. A number of typical sulfur-asphalt and sulfur-concrete paving systems were evaluated to assess their potential environmental impact and establish safety considerations relative to their formulation, construction and maintenance. The environmental impact was investigated from the formulation stages, through weathering, and included considerations of simulated fires and chemical spills. 

There are a number of crystal aspects of the API that should be briefly examined. Knowledge of crystal habit, particle size distribution, surface area, and optical properties are important because these characteristics will affect the stability of all solid dosage forms in excipient compatibility testing (9,10). Although single crystal data may not be available at early formulation stages, predicted data may be available, based on powder x-ray diffraction (PXRD) studies, and should be considered (11). 

To aid in dispersing, mixing, and wetting of components in the resin system at the formulation stage... 

Developing the specification is a critical part of the standard-setting process. It follows logically from the problem formulation stage. The specification makes the following clear ... 

After the formulation stage, we have all the equations of the model, but they are not useful yet, because parameters in the equations do not have a particular value. Consequently, the model cannot be used to reproduce the behavior of a physical entity. The parameter estimation procedure consists of obtaining a set of parameters that allows simulation with the model. In many cases, parameters can be found in literature, but in other cases it is required to fit the model to the experimental behavior by using mathematical procedures. The easier and more used types of procedures are those based on the use of optimization algorithms to make minimum the differences between the experimental observations and the model outputs. The more frequently used criterion to optimize the values of the parameters is the least square regression coefficient. In this procedure, a set of values is proposed for all model parameters (one for every parameter) and the model is run. After that, the error criterion is calculated as the sum of the squares of the residues (differences between the values of every experimental and modeled value). Then, an optimization procedure is used to change the values of the model parameters in order to get the minimum value of this criterion. 

Besides the description of the position dependence, there is other important description level which has to be defined to formulate a model the model species. From this perspective, there are two main types of models those that consider all the significant compounds presented in the reactor as model species (multivariable models) and those that summarize different species into a small number of model species (in the more strict case only one variable and they are called as single-variable models). It is clear that the higher the number of species, the higher the complexity of the simulation. Hence, in the formulation stage it is important to study in detail what it is desired to model and to make a compromise as a function of our modeling goal between the optimum situation for the analysis of the process (many model species) and the optimum situation for the mathematical simulation (few model species). 

Understanding the degradation chemistry of drug with excipients is essential to select proper excipients in the formulation stages [16, pp 101-151]. Drug-excipient compatibility studies are crucial to decide optimal tablet formulation and to understand the possible mechanism in many cases [10,12,14], Drug instability occurs by three types of reactions hydrolysis, oxidation, and aldehyde-amine addition. Table 11 gives reaction types of chemical and physical instability. 

Another common property of multireaction networks is stiffness, that is, the presence of kinetic steps with widely different rate coefficients. This property was pointed out by Curtiss and Hirschfelder (1952), and has had a major impact on the development of numerical solvers such as BASSE (Petzold 1983) and DDAPLUS of Appendix B. Since stiff equations take added computational effort, there is some incentive to reduce the stiffness of a model at the formulation stage this can be done by substituting Eq. (2.5-2b) or (2.5-3) for some of the reaction or production rate expressions. This strategy replaces some differential equations in the reactor model by algebraic ones to expedite numerical computations. 

Step 4 Manufacturing scale-up Inoculum stage Fermentation or cell culture stage Protein purification stage Formulation stage... 

These cells are also helpful at the formulation stages. Very little is known about the effect of excipients on intestinal permeability therefore, it is advantageous to measure the permeation of the active ingredients in the presence of excipients,20 as revealed in recent studies.21... 

During the preformulation and formulation stages of a parenteral dosage form, the physicochemical properties and excipient compatibility of the pharmaceutical active ingredient (API) should be thoroughly evaluated. The test method requirements are similar to those for oral dosage forms. 

Validation can be considered to start with the conception of the formulation. Thus the presence of each component may be justified as a result of the experimental designs, carried out at the preformulation and formulation stages of the project, such as the screening and compatibility testing described in chapter 2. The quantitative composition is supported by the response surface and optimization studies carried out according to the methods of this and the previous chapter and, more specifically, for mixtures in chapters 9 and 10. 

The objective of the problem formulation stage is to formulate the inventive problem in the form appropriate for using TRIZ. Specifically, the results of the problem definition stage must be translated into the TRIZ language or formulated in TRIZ terms. 

The development of an API into a viable dosage form requires a vast amount of information to be gathered at the pre-formulation stage. Gathering knowledge of the crystal form diversity exhibited and evaluation of physicochemical profiles of thermodynamically stable forms are activities that facilitate form selection for development of a product. Crystal form diversity of the API is often thought of as its propensity to exhibit polymorphism, but it can also be described further by multi-component phases such as salt forms, solvates, hydrates and co-crystals, all of which may, too, be polymorphic (see Figure 3.1) [3-5]. 

These natural or spontaneous mechanisms of emulsion breakdown, as well as others, must be addressed in the formulation stage in order to understand and control a particular multiple emulsion system of interest. In all cases, the final stability of the system will depend on the nature of the oil phase of interest, the characteristics of the primary and secondary emulsifier systems, and the relationship between the internal and continuous phases. 

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