Minimum acceptable solubility

Fig. 10.1 Minimum acceptable solubility (in pgmt ). Bars show the minimum solubility for low, medium and high permeability (KJ at a clinical dose. (From Ref [17].)...

Aqueous solubility, potency and permeability are three factors under medicinal chemistry control that must be optimized to achieve a compound with acceptable oral absorption. Typically, a lead (chemistry starting point) is deficient in all three parameters. The inter-relationships of these three parameters has been described in a series of publications from Pfizer researchers [7, 8]. Figure 9.1 depicts graphically the minimum acceptable solubility as a function of projected clinical potency and intestinal permeability. A minimum thermodynamic aqueous solubility of 52... 

Figure 22.2 is a bar graph illustrating the minimum acceptable solubility as a function of compounds projected clinical potency and permeability in medicinal chemistry. The middle set of bars show that a compound has to have a minimum thermodynamic solubility of 52mg/mL when the permeability is average (avg and the projected clinical potency is 1 mg/kg. 

Figure 8.19 Minimum acceptable solubilities for compounds with low, medium, and high permeability at a clinical dose. The middle three bars are for a 1 mpk dose where, with medium permeability, a solubility of 52 p,g/mL is required (Reproduced with permission from Lipinski, C. Aqueous Solubility in Discovery, Chemistry, and Assay Changes , Chapter 9 in van de Waterbeemd, H., Lennernas, H., Artursson, P., Eds. Drug Bioavailability, (Wiley-VCH Verlag GmbH Co. KGaA) p. 222, copyright 2003.).

Figure 16.1. Minimum acceptable solubility in pg/mL. Bars show the mimimum solubihty for low, medium, and high permeability (Ka) at a cMnical dose. The middle three bars are for a 1-mg/kg dose. With medium permeability you need 52-pg/mL solubility.

Alcohol-soluble/water-soluble extractives—sets thresholds for minimum acceptable amount of aqueous-, alcohol-, or aqueous alcohol-soluble extractives. 

FIGURE 22.2 Minimum acceptable drag solubility as a function of projected clinical potency (O.l-lOmg/kg) and intestinal permeability (low-avg-high K. ... 

Generally, the clients give the specifications as a numerical value for acceptable quality (minimum purity %, solubility %, viscosity as centipoises). While a product may meet the criteria for minimum purity, it is possible that it may contain a component which is not acceptable. 

If a polymer(s) or resin(s) is dissolved in a true solvent and then titrated with a known diluent, there comes a point when the binder just starts to precipitate out of solution. In most cases, this point is sharply defined and the solution takes on a definite turbidity. The composition of the solvent at this point is assumed to be able to just dissolve the binder and its solubility parameters therefore indicate the absolute minimum acceptable solvent power at this point. By performing this titration and calculation with a variety of solvents and diluents, the limits of solubility of the binder are accurately defined. The construction of a map is then quite straightforward by using the following procedure ... 

In report separately discuss the peculiarities of determination of the anion composition of the solid solutions, that conditioned by ability of diphosphate anion to destruction in water solutions. In given concrete case by most acceptable method of control of the diphosphate anion in the hydrated solid solutions is a traditional method of the quantitative chromatography on the paper. Methodical ways which providing of minimum destruction of the diphosphate anion in the time of preparation of the model to analysis (translation in soluble condition) and during quantitative determination of the P.,0, anion are considered. 

Acceptable yields have been obtained for dialkyl 3,3-dimethoxycyclobutane-l,l-dicarboxylates which are functionalized at Cl and C3 by reaction of l,3-dibromo-2,2-dimethoxypropane (10) with malonic esters.22 In these reactions, dimethylformamide proves to be the solvent of choice, because it allows the volume of the reaction mixture to be kept to a minimum.22 High temperature (120 to 130 C) is also necessary for these reactions due mainly to the solubility... 

Most experiments were performed with cotton or cotton linters as highly crystalline celluloses. Table I shows conditions leading to complete dissolution. A minimum amount of an acid which forms a cellulose ester (sulfuric or trifluoromethylsulfuric acid) (Entries 5 7-14) is necessary for the reaction. The dissolution is accelerated by a temperature increase (Entries 10-12 13, 14) and leads to water-soluble cellulose acetate hydrogensulfate. Whereas this primary hydrolysis can be achieved within 1-5 min, the deesterification and complete hydrolysis of the soluble cellulose derivative proved to be much more difficult. This is in contrast to the generally accepted view that the main resistance to the hydrolysis of cellulose lies in the crystalline nature or low accessibility determining the heterogeneous first step of the reaction. 

Older biodiesel processes are essentially batchwise. The oil is submitted to transesterification in a stirred-tank reactor in the presence of a large amount of methanol, and base catalyst, mostly NaOH or KOH. An excess of methanol is necessary chiefly to ensure full solubility of triglyceride and keep the viscosity of the reaction mixture low, but also for shifting the chemical equilibrium. A minimum molar ratio methanoktriglyceride of 6 1 is generally accepted [16, 17, 29], The reaction... 

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