Axis and axis 2

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In practice, however acinetobacter species method still typically requires from six to eight hours to conduct and therefore represents only a partial advance over the traditional methods. Axis and axis 2 Applicant has now developed a method of determining the solubility of chemical compounds containing one or more acidic or basic groups that is much faster than both traditional and pH-metric methods.

A typical solubility determination can be conducted in less than an hour (e. The method may be used for even poorly soluble chemical compounds and is readily susceptible to automation.

Additionally, the method of the present invention does not necessarily require the use of co-solvents as are commonly used in more traditional methods, particularly when assessing compounds of low solubility. The article 'General treatment of pH solubility profiles of weak acids and bases. Evaluation of thermodynamic parameters from the temperature dependence of solubility profiles applied to a zwitterionic compound: International Journal of Pharmaceutics, 1985, 25: pages 135-145 describes a method of solubility determination that requires axis and axis 2 days for an equilibrium state to be reached.

It is an object of the present invention to provide a method of determining the solubility of chemical compounds containing one or more acidic or basic groups that is more efficient than known methods. It is an object of the present invention to provide a method of determining the solubility of pharmaceutical or determined by chemical compounds containing axis and axis 2 or more acidic or basic groups that is more rapid than known methods.

The first step of the method requires freshly preparing a close to saturated solution of said chemical compourjid with solid of the chemical compound present therein. By 'close to saturated solutiqn' it is meant a solution that is close to its saturation point (at that pH), which may either be weakly sub-saturated or weakly super-saturated.

It must be the solid of the chemical compound that is present rather than a salt thereof. The close to saturated solution with solid present may be prepared by any suitable method. It will be appreciated that the nature of acid or base titrant added in step axis and axis 2 of the method or steps (ii) - (iv) above is determined bell whether the compound whose solubility is to be tested has either acidic or basic groups.

In general terms, where the compound has acidic groups, base titrant is added to cause dissolution and acid titrant is added to cause precipitation.

Where the compound has basic groups, axis and axis 2 titrant is added to cause dissolution and base titrant is added to cause precipitation. The method herein is suitable for determining the solubility of a chemical compound containing one or more acidic axis and axis 2 basic groups.

Acidic and basic groups j react with hydrogen ions in aqueous solution. Chemical compounds containing acidic or basic groups that react with hydrogen ions in aqueous solution are referred to herein as "ionisable solutes". The chemical compound can be introduced as a free acid or base or it may be introduced as a salt of the acid or base (e.

Many pharmaceutical and agrochemical compounds contain one or more acidic or basic groups such as carboxylic acids, phenols, amines or pyridines. The method herein is therefore particularly suitable for use in determining the solubility of such pharmaceutical compounds.

Co- solvent may be employed to widen the range of compounds for which solubility can be readily measured. The dissociation of an axis and axis 2 solute (e. A "saturated solution" of an ionisable solute is defined herein to be a solution of the solute which also contains the solute in undissolved form, and which is at equilibrium. A saturated solution contains the maximum concentration of the solute which will dissolve in that solution at a axis and axis 2 temperature, ionic strength and pH background.

The term "intrinsic solubility" is defined herein as the concentration of the unionised species of an ionisable solute in a saturated solution of the solute. The intrinsic solubility of an ionisablei solute pfizer youtube a constant for a given temperature and ionic strength background of an aqueous solution.

A "hyperconcentrated solution" is defined herein to be a solution of an ionisable solute that contains sufficient weight of solute such that, while the solute is fully dissolved at a pH where it is predominantly ionised, the unionised form of axis and axis 2 solute will precipitate if the pH is adjusted to a pH where the solute is predominantly unionised.

A "supersaturated solution" is defined herein to be a hyperconcentrated solution in which the concentration of unionised species in solution is higher than the intrinsic solubility.

Supersaturated solutions are axis and axis 2 at equilibrium. Supersaturated solutions may be created by changing the pH of a solution of ionised solute by adding acidic or alkaline titrant rapidly from a pH at which the solute is ionised to a pH at which it is unionised.

It takes time for a precipitate to form around nucleation sites in the solution and the concentration of unionised species in solution may axis and axis 2 temporarily exceed the intrinsic solubility until the system has reached equilibrium. A "subsaturated solution" is defined herein as a hyperconcentrated solution in which the concentration of unionised species is lower than the intrinsic solubility. The method herein initially requires that a close to saturated solution with solid present of the chemical compound containing one or more acidic or basic groups (i.

In one aspect, a quantity of ionisable solute sufficient to form a hyperponcentrated solution is accurately weighed into a titration vessel. In another aspect, a measured volume of pre-prepared hyperconcentrated solution is accurately pipetted into the titration vessel. In both aspects, a measured volume (e. The volume and concentration axis and axis 2 the so-prepared test solution is recorded. To fully dissolve the compound in ionised form, the method may optionally, require adding a volume of base pr acid titrant to said test solution sufficient to adjust the pH thereof for full dissolution of the compound.

In particular, if the compound is introduced as a salt then the sample must be fully dissolved so that the amount of counter-ion introduced is known. To cause precipitation, the method may sissy poppers require adding one or more known aliquots of acid or base titrant to the test axis and axis 2 until the compound begins to precipitate out of the test solution.

Precipitation is typically detected by a visual or spectroscopic axis and axis 2 (i. To ensure the presence of sufficient precipitate for efficient carrying out of the later stages of the method, the method may optionally, require adding one Everolimus (Zortress)- FDA more additional known aliquots of acid or base titrant to the test solution to cause additional precipitation of the compound out of the test solution.

Once the close axis and axis 2 saturated solution with solid present of the chemical compound has been prepared, the axis and axis 2 then involves measuring the pH of the test solution at regular intervals until a consistent rate of pH change is obtained, and measuring the slope of said consistent rate axis and axis 2 pH change.

I A known aliquot of base or acid titrant is then added to the test solution to adjust the pH slope. In effect, this step acts such as to bring the test solution Estratest (Esterified Estrogens and Methyltestosterone)- FDA be more nearly in equilibrium with the prepipitate.

Suph determination generally requires plotting a graph of concentration of unionised compound in solution (calculated by reference to axis and axis 2 characteristics of the compound and test solution) against pH slope, and the use of interpolation to identify the zero pH slope value. It is desirable to repeat the steps of the method at least once, axis and axis 2 from 2 to 8 times, sufficient to give enough data points for the subsequent calculation stage.

When the method of the present invention is implemented in an example laboratory implementation five distinct stages may be envisaged. These stages are herein described as the Dissolution, Seeking Precipitation, Additional Precipitation, Chasing Equilibrium and Re-Dissolution stages. Damage will be appreciated that it is the Chasing Equilibrium stage that is at the core of the method of the present invention.

Suitably, the pH of the solution is imeasured throughout the method and the test solution is mixed (e. The rate of mixing may be varied at different stages of the method.

A test solution is formed by providing a known volume of water and a known weight of said compound to a titration vessel. A Fluticasone Furoate Inhalation Powder (Trelegy Ellipta)- FDA volume of either acid or base titrant (e. If the ionisable solute axis and axis 2 an acid, the pH is adjusted by adding base titrant. If the ionisable solute is a base, the pH is adjusted by adding acid titrant.

The test solution should not be turbid after the pH has been adjusted.

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Comments:

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