美国药典溶解性

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1、DESCRIPTION AND SOLUBILITYDescription and Relative Solubility of USP and NF ArticlesThe descrip tion| and solubi lity| stat emen ts per taining to an arti cle (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 Odor Organ

3、oleptic characteristics are indicated in many instances because they may be 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 among other descriptive properties may aid in identifying the causa

4、tive 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

5、 a volatile 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 may be encountered if the characteristic

6、s of a 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 cavity likewise is apparent if traces of residue mater

7、ials on fingers are inadvertently brought into contact with the tongue or adjacent mucosal tissues.SolubilityOnly where a special, quantitative solubility test is given in the individual monograph, and is designated by a test heading, is it a test for purity. The approximate solubilities of Pharmaco

8、peial and National Formulary substances are indicated by the descriptive terms in the accompanying table.The t erm miscible| as used in t his Pharmacopeia per tains to a subs tance that yields a homogeneous mixture when mixed in any proportion with the designated solvent.Descriptive TermParts of Sol

9、ve nt Required for 1 Part of SoluteVery solubleLess tha n 1Freely solubleFrom 1 to 10SolubleFrom 10 to 30Spari ngly solubleFrom 30 to 100Slightly solubleFrom 100 to 1000Very slightly solubleFrom 1000 to 10,000Practically in soluble, or In soluble10,000 and overSoluble Pharmacopeial and National Form

10、ulary articles, when brought into solution, may show traces of physical impurities, such as minute fragments of filter paper, fibers, and other particulate matter, unless limited or excluded by definite tests or other specifications in the individual monographs. 1171 PHASE-SOLUBILITY ANALYSISPhase-s

11、olubility 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 respect t

12、o 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 temperature

13、 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 indicate

14、s the presence of an impurity or impurities.Phase-solubility analysis is applicable to all species of compounds that 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 of s

15、ix 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) dete

16、rmination 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) extrapolation a

17、nd calculation.SolventsA proper solvent for phase-solubility analysis meets the following criteria: (1) The solvent is of sufficient volatility that it can be evaporated under vacuum, but is not so volatile that difficulty is experienced in transferring and weighing the solvent and its solutions. No

18、rmally, solvents having boiling points between 60” and 150” are suitable. (2) The solve nt does not adversely affect the substance being tested. Solvents that cause decomposition or react with the test substance are not to be used. Solvents that solvate or form salts are to be avoided, if possible.

19、(3) The solvent is of known purity and composition. Carefully prepared mixed solvents are permissible. Trace impurities may affect solubility greatly. (4) A solubility of 10 mg to 20 mg per g is optimal, but a wider working range can be used.Apparatus*Constant-Temperature Bath Use a constant-tempera

20、ture bath that is capable of maintaining the temperature within 0.1 and that is equipped with a horizontal shaft capable of rotating at approximately 25 rpm. The shaft is equipped with clamps to hold th e Ampuls. Alternatively, the bath may contain a suitable vibrator, capable of agitating the ampul

21、s at 100 to 120 vibrations per second, and equipped with a shaft and suitable clamps to hold the ampuls. Ampuls Use 15-mL ampuls of the type shown in the accompanying illustration. Other containers may be used provided that they are leakproof and otherwise suitable.Ampul (left) and Solubility Flask

22、(right) Used in Phase-Solubility Analysis Solubility Flasks Use solubility flasks of the type shown in the accompanying illustration.ProcedurenoteMake all weighi ngs within 10 pg.System Composition Weigh accurately, in g, not less than 7 scrupulously cleaned 15-mL ampuls. Weigh accurately, in g, inc

23、reasingly larger amounts of the test substance into each of the ampuls. The weight of the test substance is selected so that the first ampul contains slightly less material than will go into solution in 5 mL of the selected solvent, the second ampul contains slightly more material, and each subseque

24、nt ampul contains increasingly more material than meets the indicated solubility. Transfer 5.0 mL of the solvent to each of the ampuls, cool in a dry ice-acet one mixture, and seal, using a double-jet air-gas burner and taking care to save all glass. Allow the ampuls and their contents to come to ro

25、om temperature, and weigh the individual sealed ampuls with the corresponding glass fragments. Calculate the system composition, in mg per g, for each ampul by the formula:1000(世- W)/ (W 一 W)in which W is the weight of the ampul plus test substance, W is the weight of the empty ampul, and W3 is the

26、weight of ampul plus test substance, solvent,3and separated glass.Equilibration The time required for equilibration varies with the substance, the method of mixing (rotation or vibration), and the temperature. Normally, equilibrium is obtained more rapidly by the vibration method (1 to 7 days) than

27、by the rotational method (7 to 14 days). In order to determine whether equilibration has been effected, 1 ampul, i.e., the next to the last in the series, may be warmed to 40 to produce a supersaturated solution. Equilibration is ensured if the solubility obtained on the supersaturated solution fall

28、s in line with the test specimens that approach equilibrium from an undersaturated solution.Solution Composition After equilibration, place the ampuls vertically in a rack in the constant-temperature bath, with the necks of the ampuls above the water level, and allow the contents to settle. Open the

29、 ampuls, and remove a portion greater than 2 mL from each by means of a pipet equipped with a small pledget of cotton membrane or other suitable filter. Transfer a 2.0-mL aliquot of clear solution from each ampul to a marked, tared solubility flask, and weigh each flask plus its solution to obtain t

30、he weight of the solution. Cool the flasks in a dry ice-acet one bath, and the n evaporate the solve nt in vacuum. Gradually increase the temperature to a temperature consistent with the stability of the compound, and dry the residue to constant weight. Calculate the solution composition, in mg per

31、g, by the formula:1000(F -F) / (F -F)3 1 2 3in which F is the weight of the flask plus residue, F is the weight of the solubility flask, and F2 is the weight of the flask plus solution.CalculationFor each portion of the test substance taken, plot the solution composition as the ordinate and the syst

32、em composition as the abscissa. As shown in theTypical Phase-Solubility Diagram(0 HIJJd zpEsodsauNOLtmOSthe points for those containers, frequently only one, that represent a true solution fall on a straight line (AB) with a slope of 1, passing through the origin; the points corresponding to saturat

33、ed solutions fall on another straight line (BC), the slope, S, of which represents the weight fraction of impurity or impurities present in the test substance. Failure of points to fall on a straight line indicates that equilibrium has not been achieved. A curve indicates that the material under tes

34、t may be a solid solution. Calculate the percentage purity of the test substance by the formula:100 -100 S.The slope, S, may be calculated graphically or by least-squares treatment for best fit of the experimental values to a straight line.The solubility of the main component is obtained by extendin

35、g the solubility line (BC) through the y-axis. The point of interception on the y-axis is the extrapolated solubility, in mg per g, and is a constant for a given compound.Purification TechniqueSince the solvent phase in all combinations of solvent and solute that are used to construct segment BC of

36、a phase-solubility diagram contains essentially all the impurities originally present in the substance under analysis, whereas the solid phase is essentially free from impurities, phase-solubility analysis can be used to prepare pure reference specimens of desired compounds as well as concentrates o

37、f 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 is suspended in a nonr

38、eactive solvent of suitable composition and amount so that about 10% of the material is dissolved at equilibrium. The suspension is sealed (a screw-cap vial is usually adequate) and shaken at room temperature until equilibrium is attained (usually 24 hours is sufficient for this purpose). The mother

39、 liquor is then drawn off and evaporated at or near room temperature to dryness. Since the mother liquor contained essentially all the impurities that were present in the specimen, the residue has been concentrated with respect to the impurities roughly in proportion to the ratio of the weight of sp

40、ecimen taken to the weight of solids dissolved in the volume of solvent used.The undissolved crystals remaining after withdrawal of the mother liquor are usually sufficiently pure to be used as a reference standard after appropriate rinsing and drying.* Available from Hanson Research Corp., 19727 Ba

41、hama St., P. O. Box 35, Northridge, CA 91324.Auxiliary Information Please check for your question in the FAQs before contacting USP.Topic/Questi onCon tactExpert CommitteeGen eral ChapterHoracio N. Pappa, Ph.D.(GC05) Gen eralChapters 05Senior Scientist and Latin America n Liais on 1-301-816-8319USP32 -NF27 Page 687