美国药典溶解性.pdf

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1、DESCRIPTION AND SOLUBILITY Description and Relative Solubility of USP and NF Articles The“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 drugs,solely

2、 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 Organoleptic chara

3、cteristics 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 agent followi

4、ng 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 volatile substanc

5、e 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 substance are not known o

6、r 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 appare nt if traces of residue materials on fin gers are in adverte ntl

7、y brought into con tact with the ton gue or adjace nt mucosal tissues.Solubility Only where a special,qua ntitative solubility test is give n in the in dividual mono graph,and is desig nated by a test head in g,is it a test for purity.The approximate solubilities of Pharmacopeial and Nati onal Formu

8、lary substa nces are in dicated by the descriptive terms in the accompa nying table.The term“miscible”as used in this Pharmacopeia pertains to a substanee that yields a homogeneousmixture when mixed in any proportion with the desig nated solve nt.Descriptive Term Parts of Solve nt Required for 1 Par

9、t of Solute Very soluble Less tha n 1 Freely soluble From 1 to 10 Soluble From 10 to 30 Spari ngly soluble From 30 to 100 Slightly soluble From 100 to 1000 Very slightly soluble From 1000 to 10,000 Practically in soluble,or In soluble 10,000 and over Soluble Pharmacopeial and National Formulary arti

10、cles,when brought into solution,mayshow traces of physical impurities,such as minute fragments of filter paper,fibers,and other particulate matter,uni ess limited or excluded by defi nite tests or other specificati ons in the in dividual mono graphs.1171 PHASE-SOLUBILITY ANALYSIS Phase-solubility an

11、alysis 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 to the particula

12、r 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 or other physical

13、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 indicates the presence of an i

14、mpurity 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 of six distinct steps:(1)mix

15、ing,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)determination of the concentration of t

16、he 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 and calculation.Solvents A proper solve nt f

17、or phase-solubility an alysis meets the followi ng criteria:(1)The solve nt is of sufficie nt volatility that it can be evaporated un der vacuum,but is not so volatile that difficulty is experie need in tran sferri ng and weighi ng the solve nt and its soluti ons.Normally,solvents having boiling poi

18、nts between 60 and 150=are suitable.(2)The solve nt does not adversely affect the substa nee being tested.Solvents that cause decomposition or react with the test substanee are not to be used.Solvents that solvate or form salts are to be avoided,if possible.(3)The solve nt is of k nown purity and co

19、mpositi on.Carefully prepared mixed solve nts are permissible.Trace impurities may affect solubility greatly.(4)A solubility of 10 mg to 20 mg per g is optimal,but a wider work ing range can be used.Apparatus*Con sta nt-Temperature Bath Use a con sta nt-temperature bath that is capable of maintainin

20、g 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 the Ampuls.Alter natively,the bath may con tai n a suitable vibrator,capable of agitati ng the ampuls at 100 to 120 vibrations per second,an

21、d equipped with a shaft and suitable clamps to hold the ampuls.Ampuls Use 15-mL ampuls of the type show n in the accompa nying illustrati on.Other containers may be used provided that they are leakproof and otherwise suitable.Ampul(left)and Solubility Flask(right)Used in Phase-Solubility An alysis S

22、olubility Flasks Use solubility flasks of the type show n in the accompa nying illustratio n Procedure NOTL Make all weigh ings with in 10 卩 g.System Composition Weigh accurately,in g,not less than 7 scrupulously cleaned 15-mL ampuls.Weigh accurately,in g,increasingly larger amounts of the test subs

23、ta nee into each of the ampuls.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 sec ond ampul contains slightly more material,and each subseque nt ampul contains increasingly more m

24、aterial than meets the indicated solubility.Tran sfer 5.0 mL of the solve nt to each of the ampuls,cool in a dry ice-acet one mixture,and seal,using a double-jet air-gas bur ner and taking care to save all glass.Allow the ampuls and their contents to come to room temperature,and 7&mm 25 mm 1 19mn 丄

25、weigh the in dividual sealed ampuls with the corresp onding glass fragme nts.Calculate the system compositi on,in mg per g,for each ampul by the formula:1000(W-W)/(W-W)in which Wis the weight of the ampul plus test substanee,Wis the weight of the empty ampul,and W is the weight of ampul plus test su

26、bsta nee,solve nt,and separated 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 temperature.Normally,equilibrium is obtained more rapidly by the vibration method(1 to 7 days)than by the rotational method(7 to

27、14 days).In order to determine whether equilibration has been effected,1 ampul,o i.e.,the next to the last in the series,may be warmedto 40 to produce a supersaturated solution.Equilibration is ensured if the solubility obtained on the supersaturated solution falls in line with the test specime ns t

28、hat approach equilibrium from an un dersaturated solutio n.Solution Composition After equilibration,place the ampuls vertically in a rack in the con sta nt-temperature bath,with the n ecks of the ampuls above the water level,and allow the contents to settle.Open the ampuls,and remove a porti on grea

29、ter tha n 2 mL from each by means of a pipet equipped with a small pledget of cotton membraneor 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 the weight of the soluti on.Cool the f

30、lasks in a dry ice-acet one bath,and the n evaporate the solve nt in vacuum.Gradually in crease 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 g,by the formula:1000(F3-FJ/(F2-F3)in whi

31、ch F3 is the weight of the flask plus residue,R is the weight of the solubility flask,and F2 is the weight of the flask plus soluti on.Calculati on For each porti on of the test substa nee take n,plot the soluti on compositi on as the ordin ate and the system compositi on as the abscissa.As show n i

32、n the accompa nying diagram,Typical Phase-Solubility Diagram the points for those contain ers,freque ntly only one,that represe nt a true solution fall on a straight line(AB)with a slope of 1,passing through the origin;the points corresponding to saturated solutions fall on another straight line(BC)

33、,the slope,S,of which represents the weight fraction of impurity or impurities present in the test substanee.Failure of points to fall on a straight line indicates that equilibrium has not bee n achieved.A curve in dicates that the material un der test may be a solid solution.Calculate the percentag

34、e purity of the test substanee by the formula:100-100 S.The slope,S,maybe 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 extending the solubility line(BC)through the y-axis.The point

35、of interception on the y-axis is the extrapolated solubility,in mgper g,and is a constant for a given compound.Purification Technique Since 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 imp

36、urities 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 compoundsas well as concentrates of impurities from substances otherwise considered pure.A simpl

37、e 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 nonreactive solvent of suitable composition and amount so that about

38、 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 liquor is then drawn off and evaporated at or near room temperature t

39、o 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 specimen taken to the weight of solids dissolved in the volume of solvent

40、used.USP3-NF27Page 687 The undissolved crystals remaining after withdrawal of the mother liquor are usually sufficie ntly pure to be used as a refere nee sta ndard after appropriate rinsing and drying.Available from Hanson Research Corp.,19727 Bahama St.,P.O.Box 35,Northridge,CA 91324.Auxiliary Information Please cheek for your question in the FAQsbefore con tacti ng USP.Topic/Questi on Con tact Expert Committee Gen eral Chapter Horacio N.Pappa,Ph.D.Senior Scientist and Latin America n Liais on 1-301-816-8319(GC05)General Chapters 05 USP3-NF27Page 687