Drug characterization, early

With the advent of modern LC/MS instrumentation and sophisticated software, metabolic profiling has gradually become a significant tool to support drug discovery. Early identification of active or toxic metabolites and characterization of metabolic liability of a particular structural series will significantly reduce the cycle time of the lead opti-... 

It was apparent that the FDA recognized the ability of the pharmaceutical industry to develop chiral assays. With the advent of chiral stationary phases (CSPs) in the early 1980s [8, 9], the tools required to resolve enantiomers were entrenched, thus enabling the researcher the ability to quantify, characterize, and identify stereoisomers. Given these tools, the researcher can assess the pharmacology or toxicology and pharmacokinetic properties of enantiopure drugs for potential interconversion, absorption, distribution, and excretion of the individual enantiomers. 

At the point a compound is recognized and then considered for potential pharmaceutic or therapeutic usefulness, researchers will be both consumers of and contributors to the data-information-knowledge cycle that characterizes science. Initially, in the synthesis and purification phase of drug development, information about the compound s chemistry and physical properties may be both sought and created. Whether or not the compound has been of interest to other researchers may be determined by searching public records of grant and contract awards and also by searching resources that cover preliminary and early research results. The patent status of the compound may need to be established. 

Phase II investigates the compound s efficacy and safety in controlled clinical trials for a specific therapeutic indication. To eliminate as many competing factors as possible, Phase II trials are narrowly controlled. They are characterized as small—several hundred subjects with the indicated disease or symptoms—and are closely monitored. The control may be either a placebo study arm or an active control arm. The endpoint measured may be the clinical outcome of interest or a surrogate. Phase II trials may last for several months or even several years. Early pilot trials to evaluate safety and efficacy are called Phase Ila. Later trials, called Phase lib, are important tests of the compound s efficacy. These trials may constitute the pivotal trials used to establish the drug s safety and efficacy. At least one pivotal trial (most frequently a large, randomized Phase III study) is done. Only about one third of compounds entered into Phase II will begin Phase III studies [61],... 

It may be envisioned that a protocol for the complete physical characterization of a solid material could easily be developed. At the early stages in drug development, each lot of active drug, excipients, and formulated blends would be characterized as fully as possible. A feedback loop would be established after each formulation run, in which the physical characteristics of the input materials were correlated with the quality of formulated product. Out of these studies would come an understanding of what particular properties were essential to the production of an acceptable formulation. 

The other main approach to solubility is to measure the concentration of the drug substance after an equilibrium has been reached with the solvent in question. This work is also conducted very early during the development process, normally at the stage of preformulation characterization [7]. A full discussion of the various aspects of solution theory is beyond the scope of the present chapter, but it is available [68]. Only a few salient points will be addressed in the following paragraphs. 

It was recognized very early that diffuse reflectance spectroscopy could be used to study the interactions of various compounds in a formulation, and the technique has been particularly useful in the characterization of solid state reactions [24]. Lach concluded that diffuse reflectance spectroscopy could also be used to verify the potency of a drug in its formulation. In addition, studies conducted under stress conditions would be useful in the study of drug-excipient interactions, drug degradation pathways, and alterations in bioavailability owing to chemisorption of the drug onto other components in the formulation [24]. 

The two methods are complementary in that each can provide information inaccessible to the other. When these techniques are used in conjunction, substantial characterization of a solid material becomes possible. This information can be extremely useful during the early stages of drug development, since only a limited amount of the drug candidate is normally available at that time. 

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