Physicochemical constraint

Finally, the 3D-LogP descriptor may be used for the 3D screening of virtual molecular conformation libraries wherein the selection of candidate molecules might not only be driven by pharmacophoric but also by physicochemical constraints. Similarly, we anticipate that the 3D-LogP descriptor will also become useful for the design of chemical libraries in which the description of the conformational space is taken into account in the description of the constituent molecules. We are currently enhancing the descriptor by implementing the last atom type classification system proposed by Wildman and Crippen (54). 

In situ Biosparging Most cost efficient Physicochemical constraints See above... 

A kinetic expression that is selected should satisfy certain statistical tests and physicochemical constraints, before it can be indicated as an adequate model. These tests often cannot be applied together, due to lack of information, but should be considered as far as possible in the evaluation and selection of the best rate expression. When still a set of competitive expressions are left some model discrimination techniques may be applied or additional experiments should be conducted, based on a careful, efficient planning. 

Initial dosage forms are usually those that are most easily developed, most stable and at least reasonably acceptable to adult patients. Such formulations can often be improved upon, whether for matters of convenience (e.g. a bioequivalent melt-in-the-mouth wafer that, unlike a tablet, does not require access to water for its administration) or to enlarge the patient population that might use the product (e.g. a linctus instead of a tablet for use in children or to permit smaller increments in dose adjustment). Again, when there are serious physicochemical constraints on formulations, the discovery of a new one can itself be patentable. 

Metabolic networks can be quantitatively and qualitatively studied without enzyme kinetic parameters by using a constraints-based approach. Metabolic networks must obey the fundamental physicochemical laws, such as mass, energy, redox balances, diffusion, and thermodynamics. Therefore, when kinetic constants are unavailable, cellular function can still be mathematically constrained based on the mass and energy balance. Flux balance analysis (FBA) is a mathematical modeling framework that can be used to study the steady-state metabolic capabilities of cell-based physicochemical constraints. ... 

Eq. (7) defines the mass, energy, and redox balance constraints on the metabolic system. However, additional physicochemical constraints are typically placed on the metabolic network. For example, the value of the flux through each of the metabolic reactions can be constrained based on reversibility, transport limitations, and/or maximum allowable fluxes. Irreversibility constraints are enforced by placing a lower limit of zero on the respective irreversible metabolic reactions ... 

There are special physicochemical constraints, such as chelation, complex formation, or crystallization to consider (see 21CFR320.33). 

Terpenoids can be found in various plant organs. Concentrations of terpenoids in plant tissues are controlled by the availability of substrate and the activity and type of biosynthesis enzymes. Emission rates of volatile terpenoids from plant leaves are controlled by their synthesis rates and compound-specific physicochemical characteristics, mainly their solubility, volatility and diffusivity. These are affected by physicochemical constraints caused by temperature, stomatal conductance and leaf structure. Storage of terpenoids could be isolated from other plant tissues with specialized structures such as secretory cavities, resin canals (Fig. 94.1), latex canals (lactifers), and glandular trichomes. 

Physticochemical coiiatrainla Further constraints can be imposed on the atoms and bonds of the reaction center, such as those physicochemical factors calculated by the PETRA package (see Section 7.1). For example, the partial charges calculated by the PEOE method can be used to extract the chemically feasible reaction from the two conceivable ones as illustrated in Figure 10.3-11. 

Modification of an introduced cysteine is both time- and concentration-dependent. It is therefore possible to measure the rate of sulfhydryl modification by applying low concentrations of MTS over short periods of time. The rate of reaction depends on the following factors (1) the permeability of the access pathway to the substituted cysteine, (2) electrostatic potentials, (3) the degree of ionization of the thiol, and (4) local steric constraints (Karlin and Akabas, 1998). The rate constant provides important information about the physicochemical environment of the introduced cysteine residue, relative to other accessible residues within... 

Two of the recognized limitations of in situ technologies are (1) physicochemical restraints (e.g., bioavailability, desorption kinetics), and (2) a need for extended treatment time as compared to ex situ biotreatment approaches. Inherent geological parameters such as permeability, vertical and horizontal conductivity, and water depth can also represent constraints that are critically important to recognize and appreciate (Norris et al., 1993 Norris Falotico, 1994). Another widely recognized limitation inherent to in situ processes is that the systems are difficult to monitor and thus effective and complete treatment is difficult toascertain and validate. 

The chemical constraints related to physical chemistry in the origin of petroleum should be more clearly defined than in the other subdisciplines, but the complexity of the situation becomes overwhelming. Physicochemical aspects are widespread, fitting into two major areas one dealing with reaction kinetics and thermodynamics, and the other with physical relationships including colloid chemistry. 

The stratum corneum forms an excellent barrier to penetration and thus transdermal delivery is only feasible for drugs where the total daily dose is less than one or two milligrams. This corresponds to plasma concentrations of the order of nanograms per milliliter. There is thus a restriction that the drug must be very potent. Using the above model it is possible to identify further constraints which are based on the physicochemical properties of the drug. 

Firstly the drug must partition into the lipids of the stratum corneum. Thus ionic compounds will not be successful unless they can be formulated as ion pairs. It is important, therefore, to consider only drugs or their complexes which have appropriate physicochemical properties for partitioning from the topical formulation into the skin lipids. Assuming this process is favourable are there any further constraints These can be identified by considering two drugs which are potential candidates... 

---