Preformulation studies characterization

The sample temperature is increased in a linear fashion, while the property in question is evaluated on a continuous basis. These methods are used to characterize compound purity, polymorphism, solvation, degradation, and excipient compatibility [41], Thermal analysis methods are normally used to monitor endothermic processes (melting, boiling, sublimation, vaporization, desolvation, solid-solid phase transitions, and chemical degradation) as well as exothermic processes (crystallization and oxidative decomposition). Thermal methods can be extremely useful in preformulation studies, since the carefully planned studies can be used to indicate the existence of possible drug-excipient interactions in a prototype formulation [7]. 

In a more traditional pharmaceutical setting, this characterization would be done during preformulation studies. With the availability of automation and the ability to conduct most of these experiments with small quantities of material, more preformulation activities are being shifted earlier into drug discovery. Recently, Balbach and Korn37 reported a "100 mg approach" to pharmaceutical evaluation of early development compounds. Additional absorption, metabolism, distribution, elimination, and toxicity38 screens may also be conducted at this stage. 

Finally, an anti-inflammatory peptide. Spantide 11, blocks the inflammation associated with Substance P (Eikwai et al., 2004). The peptide was characterized in a topical formulation for the treatment of dermal inflammatory disorders (Kikwai et al., 2004). Preformulation studies indicated that Spantide 11 undergoes Lys-Pro diketopiperazine degradation. Formulation of Spantide 11 in PG, ethanol, N-methyl-2-pyrrolidone, ethanol/water and ethanol/ethyl oleate resulted in increased stability, where the Log K at 40°C were —0.93, —1.70, — 1.81, —1.94 and —2.30, respectively. 

Preformulation studies inevitably extend beyond the basic characterization of the lead compound, because what is considered as an acceptable characteristic of a lead compotmd will largely depend on the intended or anticipated dosage form. For example, the solubility issues will largely determine the route of administration conversely, if a particular route of administration is the only desired route, then preformulation studies should attempt to find out the structural changes necessary for the candidate molecule. 

The scope of preformulation studies to be carried out will depend not only on the expertise, equipment and drug substance available but also on any organizational preferences or restrictions. Some companies like to conduct detailed characterization studies, whilst others... 

Preformulation is usually defined as the science of the physicochemical characterization of candidate drugs. However, any studies carried out to define the conditions under which the candidate drug should be formulated can also be termed preformulation. This is a broader definition than was used in Chapter 3, and, as such, it can include studies on preliminary formulations under a variety of conditions. These studies may influence the Product Design and should be conducted at the earliest opportunity at the start of development. In the interest of faster drug development and reduced drug usage, preformulation studies should not be undertaken on a check-list basis. Rather, they should be conducted on a need-to-know basis. 

N.K. Ebube, C. Owusu-Ababio, and C.M. Adeyeye, Preformulation studies and characterization of the physicochemical properties of amorphous polymers using artificial neural networks, Int. J. Pharmaceut., 196, 27-35, 2000. 

Based on the major goal of preformulation—identification of possible failure in future development—numerous studies are performed to fully characterize prospective drug candidates. The major analytical technique in each preformulation group is liquid chromatography. Ninety percent of all analytical equipment in preformulation groups are HPLC systems equipped with UV and MS detection systems. HPLC is a fast and reliable method for concentration and identity determination by UV and/or MS detection, respectively. The type of HPLC methods differ based on the specific preformulation tests that will be described below. 

Additional preformulation and physicochemical characterization of the candidate compound are performed and stress stability studies may be initiated. Ideally, the optimal solid state (polymorphic) and chemical (salt) form of the molecule are identified as part of clinical candidate selection. Selection of the most stable and bioavailable form will expedite subsequent development. The methods for testing the drug substance are refined and additional methods may be developed. 

Solid-state characterization is one of the most important functions of the preformulation group, which is assigned the responsibility of making recommendations for further formulation work on a lead compound. Physical properties have a direct bearing on both physical and chemical stabilities of the lead compound. Much of the later work on formulation will depend on how well the solid state is characterized from the decisions to compress the drug into tablets to the selection of appropriate salt forms. The studies reported in this section, of course, apply to those drugs that are available in solid form, crystalline or amorphous, pure or amalgamated. 

There is no doubt that isothermal microcalorimetry has the potential to be very useful in studies of chemical degradation. The success will be greatest for solution-state reactions for which the reacting concentration is known, but even these can be limited by physical artifacts by, for example, the slow diffusion of oxygen into the liquid from the head space. The use of this technique for solid-state reactions is certainly not impossible, but is an area where great care is needed. The technique may therefore be used readily in a preformulation environment for solution systems, but is perhaps better applied in a QC (quality control) role for well-characterized solid-state processes. 

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