Solubility studies

When compounds are selected for preliminary PK studies, the identification of an appropriate dosing vehicle for iv studies requires solubility studies in various vehicles. Also, the study of thermodynamic solubility is useful as this more closely reflects the environment experienced by compounds on oral dosing. Higher throughput thermodynamic solubility assays have been introduced recently [23] so it will be possible to introduce this type of assay earlier in the discovery process. 

Taub, M. E., L. Kristensen, and S. Frokjaer. Optimized conditions for MDCK permeability and turbidi-metric solubility studies using compounds representative of BCS classes I-IV, Eur. J. Pharm. Sci. 2002, 15, 331-340... 

Huuskonen and coworkers [11] published a study on 211 drugs, all of which were solids. The solubility data were taken from the literature. We will discuss this work further in 10.7. Klopman et al. [16] published a water-solubility study on 483 literature compounds, but unless one orders the accompanying Supplementary Material it is difficult to know the physical states of the substances they studied. 

For highly permeable, poorly soluble drugs given in lower doses, the dissolution rate rather than the saturation solubility is the limiting factor. An increase in dissolution rate due to in vivo solubilization mediated by food intake could theoretically be obtained, but this situation is not always found in vivo. For example, food does not affect the rate and extent of bioavailability for candesartan cilexitil, a very poorly soluble compound [78], An in vitro dissolution and solubility study of this compound in simulated intestinal media provided a potential explanation it was revealed that the solubility was increased as a function of bile concentration as expected, whereas the dissolution rate was not increased by the higher bile concentrations being representative for the fed state (see Fig. 21.14). Thus, although... 

In 1988, Terry and coworkers attempted to homopolymerize ethylene, 1-octene, and 1-decene in supercritical C02 [87], The purpose of their work was to increase the viscosity of supercritical C02 for enhanced oil recovery applications. They utilized the free radical initiators benzoyl peroxide and fert-butyl-peroctoate and conducted polymerization for 24-48 h at 100-130 bar and 71 °C. In these experiments, the resulting polymers were not well studied, but solubility studies on the products confirmed that they were relatively insoluble in the continuous phase and thus were not effective as viscosity enhancing agents. In addition, a-olefins are known not to yield high polymer using free radical methods due to extensive chain transfer to monomer. 

PVA Particles. Dispersions were prepared in order to examine stabilization for a core polymer having a glass transition temperature below the dispersion polymerization temperature. PVA particles prepared with a block copolymer having M PS) x 10000 showed a tendency to flocculate at ambient temperature during redispersion cycles to remove excess block copolymer, particularly if the dispersion polymerization had not proceeded to 100 conversion of monomer. It is well documented that on mixing solutions of polystyrene and poly(vinyl acetate) homopolymers phase separation tends to occur (10,11), and solubility studies (12) of PS in n-heptane suggest that PS blocks with Mn(PS) 10000 will be close to dissolution when dispersion polymerizations are performed at 3 +3 K. Consequently, we may postulate that for soft polymer particles the block copolymer is rejected from the particle because of an incompatibility effect and is adsorbed at the particle surface. If the block copolymer desorbs from the particle surface, then particle agglomeration will occur unless rapid adsorption of other copolymer molecules occurs from a reservoir of excess block copolymer. 

Fig. 2 Dynamic solubility study in water at 37°C for untriturated digoxin powders (A), freshly triturated digoxin (O), and digoxin triturated and stored for 2-5 months ( ). (Reproduced from Ref. 9 with permission of the copyright owner, the American Pharmaceutical Association.)...

Pigheadedness in interpretation. Usually a case of, I know what this peak is so don t confuse me with facts. Infrared is an extremely powerful technique, but there are limitations. You don t have to go hog wild over your IR, though. I know of someone who decided that a small peak was an N—H stretch, and the compound had to have nitrogen in it. The facts that the intensity and position of the peak were not quite right, and neither a chemical test nor solubility studies indicated nitrogen, didn t matter. Oh well. 

The existence of solvates of lanthanide halides may be taken as an indication of favorable interaction between the halides and solvent in question. Evidence of this type may suggest solvents which could prove useful or interesting for calorimetric or solubility studies. However, the existence of stable solvates is no guarantee of marked solubility for the halide in the solvent in question. One need look no further than lanthanide fluorides and water for cautionary examples, for despite their very low solubility in water these fluorides form a series of stable hemihydrates, LnF3-V H20. 

Ion-Activity Products. As in the determination of the amount sorbed through Equation 2, the characterization of surface precipitates often utilizes measurements made solely on the aqueous solution phase. Solubility studies limited in this way run a risk of being ambiguous as to mechanism because of the lack of direct information about the solid phase (10). In respect to the aqueous solution phase, ambiguity can be minimized if equilibrium is approached both from supersaturation and from undersaturation if the equilibration time is varied... 

Marshall s extensive review (16) concentrates mainly on conductance and solubility studies of simple (non-transition metal) electrolytes and the application of extended Debye-Huckel equations in describing the ionic strength dependence of equilibrium constants. The conductance studies covered conditions to 4 kbar and 800 C while the solubility studies were mostly at SVP up to 350 C. In the latter studies above 300°C deviations from Debye-Huckel behaviour were found. This is not surprising since the Debye-Huckel theory treats the solvent as incompressible and, as seen in Fig. 3, water rapidly becomes more compressible above 300 C. Until a theory which accounts for electrostriction in a compressible fluid becomes available, extrapolation to infinite dilution at temperatures much above 300 C must be considered untrustworthy. Since water becomes infinitely compressible at the critical point, the standard entropy of an ion becomes infinitely negative, so that the concept of a standard ionic free energy becomes meaningless. 

Marshall has extended his high temperature solubility studies (39,40,41) and has begun some work on liquid-vapour critical temperatures of solutions (42,43) which should prove valuable. 

Solubility is highly influenced by the solid-state form (e.g., crystalline or amorphous) of the drug. Rigorous solubility studies using the final solid form (i.e., salt form or crystal form) as a function of temperature (i.e., 25 and 37°C) and pH (range 1 to 7.5) are conducted during preformulation. Solubility in nonaqueous solvents is also screened. Solubility in simulated gastrointestinal fluids is also important. 

Zhang, C.M., Adesina, A. A., and Wainwright, M.S. Solubility studies of isobutene in tertiary butyl alcohol-t water mixtures,/ Chem. Eng. Data, 47(6) 1476-1480, 2002. 

While the solubility parameter can be used to conduct solubility studies, it is more informative, in dealing with charged polymers such as SPSF, to employ the three dimensional solubility parameter (A7,A8). The solubility parameter of a liquid is related to the total cohesive energy (E) by the equation 6 = (E/V) 2, where V is the molar volume. The total cohesive energy can be broken down into three additive components E = E j + Ep + Ejj, where the three components represent the contributions to E due to dispersion or London forces, permanent dipole-dipole or polar forces, and hydrogen bonding forces, respectively. This relationship is used... 

Preformulation testing provides a basic dossier on the compound and plays a significant role in identifying possible problems and suitable approaches to formulation. Such dossiers already exist for the common excipients. The requirement for aqueous solubility is paramount and preformulation can identify salt forms that are appropriate for further development. Stability and solubility studies wiU indicate the feasibility of various types of formulation such as parenteral liquids and their probable shelf lives. Similar information can be garnered for solid products from the solid physical properties. By performing these studies on a series of candidate compounds, the optimum compound can be identified and further biological and chemical studies guided to provide the best results. 

At other times the compound is found to have significant protein binding. Again this can lead to an increase in the solubility of the compound. If the binding occurs in the blood, it could lead to reduced elimination rate constants. Whenever the pharmacology studies indicate some type of interaction is happening additional studies should be conducted to try and elucidate the interactions. If the compound has a particularly low solubility it can lend itself to solubility studies which can be used to determine the interaction equilibrium constants and effect on the overall solubility. 

E.C. Morino, T. Aoba, Comparative solubility study of human dental enamel, dentin and hydroxyapatite, Calcif. Tissue Int. 49 (1991) 6-13. 

A solubility study coupled with IR and titrameric measurements and ab initio molecular orbital calculations was performed on 2,3-pyrazinedicarboxylic acid <2000JST(526)191>, demonstrating that the dicarboxylic acid exists in the solid as such and not in a zwitterionic form. In addition, one internal and one external 0---0=C hydrogen bond per molecule were proposed. 

Leturcq, G., Advocat, T., Hart, K., Berger, G., Lacombe, G. Bonnetier, A. 2001. Solubility study of Ti,Zr-based ceramics designed to immobilize long-lived radionuclides. American Mineralogist, 86, 871-880. 

Parameters describing a particular thermodynamic equilibrium system are derived from experimental quantities obtained by a variety of methods, for example, calorimetry, potentio-metry, and solubility studies. In the ideal case, critical examination of well-studied systems reveals high-quality experimental data that lead to a unique set of thermodynamic constants, which are internally consistent, not only formally, but also from a chemical point of view. In the course of our reviews, however, we encountered several cases of conflicting experimental data that resisted any attempt to cast them into a unique set of thermodynamic parameters. The following summarizes the conflicting data and our pragmatic solutions. 

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