美國(guó)藥典溶解性

1、DESCRIPTION AND SOLUBILITYDescription and Relative Solubility of USP and NF ArticlesThe “ description ” and “ solubility ” statements pertaining to an article (formerly included in the individual monograph) are general in nature. The information is provided for those who use, prepare, and dispense d

2、rugs, solely to indicate descriptive and solubility properties of an article complying with monograph standards. The properties are not in themselves standards or tests for purity even though they may indirectly assist in the preliminary evaluation of the integrity of an article.Taste and OdorOrgano

3、leptic characteristics are indicated in manyinstances because they maybe useful and descriptive properties of substances. However, they are not meant to be applied as tests for identifying materials.The inclusion of odor or taste amongother descriptive properties may aid in identifying the causative

4、 agent following accidental exposure to or contact with a substance. This information is provided as a warning or to make an individual aware of sensations that may be encountered. The use of odor or taste as a test for identification or content is strongly discouraged.The characteristic odor of a v

5、olatile substance becomes apparent immediately on opening a container of it. The odor may be agreeable (e.g.,Peppermint Oil), unpleasant (e.g., Sulfur Dioxide), or potentially hazardous on prolonged exposure (e.g., Coal Tar). Moreover, an unexpected odor maybe encountered if the characteristics of a

6、 substance are not known or if a container is incorrectly labeled. Consequently, containers of such substances should be opened cautiously, preferably in a well-ventilated fume hood. A characteristic taste or sensation produced in the oral cavitylikewise is apparent if traces of residue materials on

7、 fin gers arein adverte ntly brought into con tact with the ton gue or adjace nt mucosaltissues.SolubilityOnly where a sp ecial, qua ntitative solubility test is give n in thein dividual monograph, and is desig nated by a test head in g, is it a testfor pu rity.The app roximate solubilities of P har

8、mac op eial and Nati onal Formularysubsta nces are in dicated by the descri ptive terms in the acco mpanyingtable. The term “ miscible ” as used in this Pharmacopeia pertains to asubstanee that yields a homogeneousmixture when mixed in any proportionDescri ptive TermP arts of Solve nt Required for 1

9、 Part of SoluteVery solubleLess tha n 1Freely solubleFrom 1 to 10SolubleFrom 10 to 30Sparin gly solubleFrom 30 to 100Slightly solubleFrom 100 to 1000Very slightly solubleFrom 1000 to 10,000P ractically in soluble, or In soluble10,000 and overwith the desig nated solve nt.SolublePharmacopeial and Nat

10、ional Formulary articles, when brought intosoluti on,mayshow traces of physical impurities, such as minute fragmentsof filterpaper, fibers, and other p articulatematter, uni ess limited orexcluded by defi nite tests or other sp ecificati ons in the in dividualmonographs.1171PH ASE-SOLUBILITY ANALYSI

11、SPhase-solubility analysis is the quantitative determination of the purity of a substance through the application of precise solubility measurements.At a given temperature, a definite amount of a pure substance is soluble in a definite quantity of solvent. The resulting solution is saturated with re

12、spect to the particular substance, but the solution remains unsaturated with respect to other substances, even though such substances may be closely related in chemical structure and physical properties to the particular substance being tested. Constancy of solubility, like constancy of melting temp

13、erature or other physical properties, indicates that a material is pure or is free from foreign admixture except in the unique case in which the percentage composition of the substance under test is in direct ratio to solubilities of the respective components.Conversely, variability of solubility in

14、dicates the presence of an impurity or impurities.Phase-solubility analysis is applicable to all species of compoundsthat are crystalline solids and that form stable solutions. It is not readily applicable to compounds that form solid solutions with impurities.The standard solubility method consists

15、 of six distinct steps: (1) mixing, in a series of separate systems, increasing quantities of material with measured, fixed amounts of a solvent; (2) establishment of equilibrium for each system at identical constant temperature and pressure; (3) separation of the solid phase from the solutions; (4)

16、 determination of the concentration of the material dissolved in the various solutions; (5) plotting the concentration of the dissolved materials per unit of solvent ( y-axis or solution composition) against the weight of material per unit of solvent ( x-axis or system composition); and (6) extrapol

17、ation and calculation.SolventsA proper solve nt for p hase-solubility an alysis meets the followi ngcriteria: (1) The solve nt is of sufficie nt volatility that it can beeva po rated un der vacuum, but is not so volatile that difficulty isexp erie need in tran sferri ng and weighi ng the solve nt an

18、d its soluti ons.Normally, solve nts hav ing boili ng p oi nts betwee n 60and 150 aresuitable. (2) The solve nt does not adversely affect the substa nee beingtested. Solvents that cause decomposition or react with the test substaneeare not to be used. Solvents that solvate or form salts are to be av

19、oided,if p ossible. (3) The solve nt is of k nown pu rity and comp ositi on.Carefullyprep ared mixed solve nts are p ermissible. Trace imp urities may affectsolubility greatly. (4) A solubility of 10 mg to 20 mg per g is op timal,but a wider work ing range can be used.App aratus *Con sta nt-Te mp er

20、ature Bath Use a con sta nt-te mp erature bath that iscap able of mai ntaining the temp erature within 0.1 and thatis equippedwith a horiz on talshaft cap able of rotat ingat app roximately25 rpm. Theshaft is equipped with clamps to hold the Ampu Is. Alter natively,the bathmay con tai n a suitable v

21、ibrator, cap able of agitati ng the amp uls at 100to 120 vibrationsper second, and equipped with a shaft and suitable clampsto hold the ampuls.Ampuls Use 15-mL ampuls of the type show n in theacco mpanyingillustration. Other containers may be used provided that they areleak proof and otherwise suita

22、ble.25nvnTSmmTOmEAmpul (left) and Solubility Flask (right) Used in P hase-SolubilityAn alysisSolubility Flasks Use solubility flasks of the type show n in the acco mpanying illustrati on土 10 卩 g.P rocedureNOTL Make all weigh ings with inSystem Composition Weigh accurately, in g, not less than 7 scru

23、pulouslycleaned 15-mL ampuls. Weigh accurately, in g, increasinglylarger amounts of the test substa nee into each of the ampu Is. The weight of the test substa nee is selected so that the first ampul contains slightly less material tha n will go into soluti on in 5 mL of the selected solve nt, the s

24、ec ond ampul contains slightly more material, and each subseque nt ampulcontains increasinglymore material than meets the indicated solubility.Tran sfer 5.0 mL of the solve nt to each of the ampu Is, cool in a dry ice - acet one mixture, and seal, using a double-jet air-gas burner and taking care to

25、 save all glass. Allow the ampuls and their contents to come to room temp erature, and weigh the in dividual sealed amp uls with the corres ponding glass fragme nts. Calculate the system comp ositi on, in mg per g, for each ampul by the formula:1000(W - W) / ( W - W)in which Wis the weight of the am

26、pul plus test substanee, Wis the weightof the empty amp ul, andW is the weight of ampul plus test substa nee, solve nt, and sep arated glass.Equilibrati on The time required for equilibrati on varies with the substa nee, the method of mixing (rotati on or vibrati on), and the temp erature. Normally,

27、 equilibrium is obta ined more rap idly by thevibrati onmethod (1 to 7 days) tha n by the rotati onalmethod (7 to 14 days).In order to determ ine whether equilibrati on has bee n effected, 1 amp ul, i.e., the next to the last in the series, may be warmedto 40 to produce a sup ersaturated soluti on.

28、Equilibrati on is en sured if the solubility obta ined on the sup ersaturated soluti on falls in line with the test sp ecime ns that app roach equilibrium from an un dersaturated solutio n.Solutio n Comp ositi on After equilibrati on,pl ace the amp uls vertically and dry the residue to constant weig

29、ht. Calculate the solution composition.in a rack in the con sta nt-te mp eraturebath, with the n ecks of the ampulsabove the water level, and allow the contents to settle. Open the amp uls,and remove a p orti on greater tha n 2 mL from each by mea ns of a pipetequipped with a small pledget of cotton

30、 membraneor other suitable filter.Transfer a 2.0-mL aliquot of clear solution from eachampul to a marked,tared solubility flask, and weigh each flask plus itssolutionto obtainthe weight of the soluti on. Cool the flasks in a dry ice-acet one bath,and the n eva po rate the solve nt in vacuum. Gradual

31、ly in crease thetemperature to a temperature consistent with the stability of the compound,in mg per g, by the formula:1OOO(F3 - FJ / ( F2 - F3)F1 is the weight ofin which F3 is the weight of the flask plus residue,the solubility flask, andF2 is the weight of the flask plus solutio n.Calculati onFor

32、 each p orti on of the test substa nee take n, plot the soluti on comp ositi on as the ordin ate and the system compo siti on as the abscissa.As show n in the acco mpanying diagram,5VSTEM COMPOSITION, MG PER 0 UOTyp ical P hase-Solubility Diagramthe points for those contain ers, freque ntly only one

33、, that rep rese nt a true soluti on fall on a straight line (AB) with a slope of 1, p ass ingthrough the origin;the points corresponding to saturated solutions fall on another straight line (BC), the slope, S, of which represents the weightfraction of impurity or impuritiespresent in the test substa

34、nee. Failure of points to fall on a straight line in dicates that equilibrium has not bee n achieved. A curve in dicates that the material un der test may be asolid solution.Calculate the percentage purity of the test substanee by the formula:100 - 100 S.The slope, S, maybe calculated graphically or

35、 by least-squares treatment for best fit of the experimental values to a straight line.The solubility of the main component is obtained by extending the solubility line (BC) through the y-axis. The point of interception on the y-axis is the extrapolated solubility, in mgper g, and is a constant for

36、a given compound.Purification TechniqueSince the solvent phase in all combinations of solvent and solute that are used to construct segment BC of a phase-solubility diagram contains essentially all the impurities originally present in the substance under analysis, whereas the solid phase is essentia

37、lly free from impurities, phase-solubility analysis can be used to prepare pure reference specimens of desired compoundsas well as concentrates of impurities from substances otherwise considered pure. A simple modification of this technique can be used to accomplish these purposes with considerably less effort than is usually required for rigorous phase-solubility analysis.In practice, a weighed amount of test specimen