Solvent Extraction by Rashmi Joshi

Rashmi Joshi
Dept. of pharmaceutical Chemistry
Govt. Holkar Science college

1. -- BY Rashmi joshi Dept. Of Pharmaceutical Chemistry Govt. Holkar Science College Indore Solvent Extraction

2. Liquid-Liquid Extraction or solvent extraction is one of the separation technique and it is the most common method adopted in the field of analysis. Extraction is the process of transfer of constituent from one liquid phase to another liquid phase by contact. This process is also as called Partitioning or distribution. In pharmaceutical field solvent extraction method is adopted in separation and isolation of various ingredients from their complex formulation. Introduction

3. Solvent Extraction Generally one of the two methods are used for extraction purpose 1. Removal of interfering or unwanted substance from preparation by crystallization, filtration, sublimation or distillation method. II. Separation or isolation of active ingredient from preparation i.e. extraction technique. There are two types of extraction techniques 1. Solid phase extraction 2. Liquid-Liquid extraction

4. liquid-liquid extraction liquid-liquid extraction has been employed predominantly and effectively not only for the pre-concentration and isolation of a 'single' chemical entity just before its actual estimation, but also for the extraction of classes of organic compounds or groups of metals, just prior to their usual estimation either by instrumental techniques.

5. Theory The concept of "like dissolves like" works well in LLE. A hydrophobic molecules prefers an organic medium whereas an ionic compound prefers to remain in aqueous solution. When shaken, with two immiscible solvents, the compound will distribute itself between the two solvents. Normally one solvent is water and the other solvent is a water-immiscible organic solvent.

6. Theory Consider a single solute(A) distributed between two immiscible solvent then the resulting equilibrium can be written as A aq A org Solute in lower phase Solute in upper phase At equilibrium the molecules naturally distribute themselves in the solvent where they are more soluble . Distribution of solute in upper and lower phase is depending on the affinity of the drug towards solvents.

7. Nernst distribution law Liquid liquid extraction method is based on nernst law which states that the ratio of activities of solute material in the two immiscible solvent at equilibrium is remain constant. Usually concentrations are substituted for activity, then distribution law is written as When solute in dissolved in two solvents which are immiscible in each other the solute distribute itself in both solvents and ratio of conc. of two solution remains constant and it is called as partition coefficient

8. distribution or partition coefficient(KD) Quantitative measure of the how an organic compound will distribute between aqueous and organic phases is called the distribution or partition coefficient. It is denoted by equilibrium constant K. It is the ratio of the concentrations of the solute in the two different solvents once the system reaches equilibrium.

9. Distribution or partition coefficient if also denoted as KD K (Note that K is independent of the actual amounts of the two solvents mixed but it is dependant on temperature.) If K, large, the solute will tend toward quantitative distribution in organic solvent.  

10. K D Benzoic acid is a weak acid in water with a particular ionisation constant K a . The distribution constant is given by e is ether solvent and a represents the aqueous solvent. (note that benzoic acid in aqueous layer exist as Bz depending on magnitude of Ka and pH of the aqueous layer)

11. Distribution ratio This equation predicts that when [H+]a >Ka, D is nearly equal to K, , and if K, is large the benzoic acid will be extracted into the ether layer; Dis maximum under these condition. If on the other hand, (H+] < Ka, then D reduces to K, (H+]a/Ka, which will be small and the benzoic acid will remain in the aqueous layer. i.e. in alkaline solution the benzoic acid is ionized and cannot be extracted, while in acid solution it is largely undissociated. In solvent extraction the separation efficiency is usually independent of the

12. Extraction of drug The distribution ratio D is a constant Independent of the volume ratio. However the fraction of the solute extracted will depend on the volume ratio of the two solvents. If larger volume of organic solvent is used, more solute must dissolve in this layer to keep the concentration ratio constant and to satisfy the distribution ratio. The fraction of the solute extracted is equal to the milimoles of the solute in the organic layer divided by the total no of milimoles of solute.

13. Extraction If the partition coefficient for a solute between two solvents is known, it is possible to calculate the fraction of the solute that is present in each phase at equlibrium . Let P be the fraction of that solute in the upper phase and q is the fraction in the lower phase at equilibrium. The quantity p is defined by  

14. Fraction of drug in lower phase The equation relates the fraction of solute extracted into upper phase to the partition coefficient and ratio of phase volumes ,since P is the fraction extracted into phase volume, 1 00P is % extracted into upper phase. P+q = 1 , q= 1 -p, q= 1 - [KU/KU+ 1 ] q= 1 /KU+ 1 q= (KU + 1 ) -KU /KU+ 1 q= 1 /KU+ 1 The larger the partition coefficient, large amount of solute will be the extracted in upper phase

15. %P A solute is known to have a partition coefficient of 4 between water and ether. If 15 ml of an aqueous solution of the compound is extracted with one 20 ml portion of ether what % of original solute will be found I the ether K=4 U=20/15= 1.33 P=KU/KU+1 = 4 x1.33/4x 1.33+ 1 =5.32/5.32+1= 0.842 In percentage it is 84.2%

16. Multiple extraction Unless K is extremely large, a significant portion of solute will not get in both phases after extraction. Therefore at that time we have to re-extract the solute for maximum recovery. if very less amount of solute is extracted in 1 " extraction so to remove all the remaining solute we have to re-extract with additional portion of fresh extractant.

17. During every extraction calculate the fraction of solute extracted or calculate no of extraction required to achieve desired extent of extraction. State of extraction after one equilibrium is mention below. 1= p+q total fraction extracted (p) =1-q In multiple extraction p=1-q TABLE

18. Comparison of single and multiple extraction Compare the efficiency of extraction or 10ml aqueous solution of compound with a) one 40 ml portion of ether b) four 10 ml portions of ether. if K is 4 in ether water system. Single extraction a) K=4, U= ether layer vol/ aq layer vol=40/10=4 P=KU/KU+1 =4x4/4x4+1=16/173=0.9412 =94.12%b) b) Multiple Extraction K=4,U=ether layer vol/ aq layer vol= 10/10=1 (q=1/KU+1=1/4x1+1=0.2) So total fraction extracted in 4'extraction= 1-q'1-(0.2)4 =1-0.0016=0.9984 in percentage it is 99.84%

19. comparison of single and multiple extraction Results indicate that more efficient extraction is achieved with several extraction than single extraction utilizing same total volume of extractant. In multiple extraction Only 20 ml (2 portions of 10-10 ml ) can extract more than 96% than that of 40 ml used in single extraction

20. Types of Liquid Liquid extraction A Single extraction (Batch) Batch extraction is carried out using set of separating funnel. A solution from which a substance is to be extracted and immiscible solvent are introduced into separating funnel. Two phases are mixed thoroughly in order to extract the substance from one phase to other phase. For more efficiency fresh extractant is added to raffinate and extraction is continued several times. Extraction by this method is carried out when partition coefficient of solute is high. Method is simple and quick. Hence widely used for extraction on small scale. For extraction on a large scale, a continuous extraction procedure is used.

21. Single extraction (Batch)

22. Continuous Extraction In some cases, it is difficult to efficiently remove a solute unless a large number of extractions are conducted. An alternate approach is a continuous extraction. With an appropriate setup, an efficient extraction can be conducted with a minimum of extracting solvent. Advantages Only uses a small amount of solvent Can remove a high percent of a solute. Can work unattended for long periods

23. Continuous Extraction The continuous extraction method is carried out when the partition coefficient of solutes is low. An immiscible extracting liquid is kept flowing continuously through the solution from which a solute is to be extracted. Although there is not enough time for the equilibrium to reach, a solute is extracted continuously in this extraction method. This method requires a special kind of extractor, depending on whether the solvent used for extraction is lighter or heavier than sample solution

24. Extracting solvent lighter than the sample solution Apparatus used for this type of extraction is shown in fig

25. It is similar to that of the Soxhlet apparatus but instead of one solvent, two solvents are used in this case. The extracting solvent (e.g. a non-aqueous solvent), which is lighter than the sample solution (e.g. an aqueous solution), is placed in a container (A) It is connected to a container (B) holding the Sample solution to half its capacity. A glass tube (C), having a funnel shaped opening at one end and a glass bulb with holes at another end, is placed inside container B. This body is then connected to a condenser (D), which is attached at the upper end of the container B.

26. The extracting solvent being lighter than sample solution when extracting solvent in the container (A) is heated. Vapor of the extracting solvent passes to the condense where it get condense. The droplets of extracting liquids enter the glass tube ( and then escape through the holes in the glass bulb. It passes through the sample solution and extract the solute and accumulated on the top of the sample solution. When sufficient quantity of extracting solution ge collected in container B, it overflows in to the flask (A from the side arm (S) the process is continued till the extraction is complete.

27. Extracting solvent heavier than the sample solution Apparatus used for this type of extraction is shown in fig

28. The extracting solvent placed in RBF (A) and is heated. The sample solution to be extracted is present in a container (B) Vapor of the extracting solvent passes into the condenser andfalls as droplets into the funnel type glass tube (C), and pasthrough the sample solution. In this process it extracts the solute and get accumulated at the bottom of the container 8. When volume of extractant rises to sufficient height it overflows in to the flask (A) from the side (S) and the process is continued till the extraction is complete. Continuous extraction method is used when the material to bu extracted has low partition coefficient fora pair of solvents.

29. Countercurrent Distribution Generally for simple extraction separating funnel method is used but if sample solution contains 2 or more substances having similar distribution coefficients then their separation using single batch extraction is very poor. So by a technique of succesive extraction with fresh solvent, complex mixture with similar distribution coefficient may be separated. Eg counter current extraction technique CCD is basic liquid-liquid extraction that permits separation of sub with very similar partiton coefficient.

30. Working of CCD Term counter current indicates that 2 phases move in apposite directions. In this one phase is stable and other phase is in moving state. The countercurrent distribution process involve train of tubes each containing two separate chamber within which the individual equilibrium occur. Chamber A in all tubes filled with solvent A (which is denser than extracting solvent) Tube one contain sample and extracting solvent (2) is introduced into first through inlet B

31. Working of CCD After shaking back and forth and then allow the phase to separate. Then tube is tilted to 90'. The less dense solvent flow through tube C into chamber D then assembly is rotated to original position and solvent flows out through tube E into next tube leaving solvent 1 in chamber A of first tube. Fresh solvent 2(lighter solvent extractant) is added to first tube and process is repeated.

32. Working of CCD Solute originally extracted into solvent 2 (extractant or less denser solvent) has been transferred to second tube containing solvent 1 (no sample) where it is redistributed. This procedure is repeated several times depending on separation efficiency or no of tubes. In this way transfer of solute in the direction of motion of upper phase (solvent 2) takes place. If sample contains 2 solutes with different partition coefficient they will pass through tube with different rate i.e. sub with larger partition coefficient will travel faster. Counter current is very efficient process for separation of closely related compounds

33. Solid liquid extraction Soxhlet apparatus Continuous hot percolation process. The apparatus consists of three parts A flask: For boiling of solvent. A Soxhlet extractor: Having the drug in thimble A side tube & siphon tube A reflux condenser: For condensation of vapors

34. Soxhlet extraction Typically soxhlet extraction is only required where the desired compound has limited solubility in a solvent. Extraction carried out by distillation and condensation of the solvent. Apparatus allows multiple extractions to be done repeatedly using same volume of solvent. Soxhlet extraction has been a standard method of extraction of solids from crude material. Extraction of solid is imp step in preparation of many pharmaceuticals.

35. Soxhlet extractor Soxhlet extractor is used only for thermostable compounds. A finely ground drug is held in a porous bag or thimble (made up of filter paper) is placed in chamber E. Extracting solvent is placed in flask A and heated to boiling vapors rise through side arm B are condensed in condenser D. The condensed extractant drips into the thimble containing crude drug extracting it by contact. When level of extractant in chamber E rises to top of siphon tube c extractant come back to flask A and process is repeated several times to achieve max extraction of solute.

36. Factors affecting LLE Separation of pair of substances is much influence by their distribution behavior. The feasibility of resoling two subs is explained in terms of separability factor . A= K1/K2 Where K is partition coefficient of two substances in LLE. If value of a is unity means two subs can not separated by extraction. So greater the deviation of a from unity more feasible is the separation. In separation of two substances by LLE requires that one of the solute has small k, so other sub is extractable from

37. Number of Factors affect distribution coefficient of solute which affect extraction and these can be utilized for effective separation. K can be increase by considering following points : Choice of solvent pH effect Salting out effect Control of hydrophobicity

38. Conditions of a choice of solvent which is used as extractant Criteria for Selection of solvent The density of extractant should be difference from water density. Low Boiling point . Should be selective. High distribution coefficient. Should have the minimum viscosity. Should be inexpensive and of low toxicity.

39. Choice of solvent The partition coefficient is influenced by chemical nature of the solvent So choice of solvent is important factor to achieve good recovery. Widely used extractant are diethylether , chloroform and hydrocarbons. Ex: separation of sodium benzoate(SB) and caffeine(C)Mixture of SB and C is dissolved in water both are soluble. Extraction is carried out with chloroform(C is quite soluble but SB is insoluble). Final result is total C is present in Chloroform layer and SE remains in water layer. Separated constituents is then quantitatively analyzed using spectrophotometric technique

40. Control of ionic strength Salting out effect If the salt concentration of an aqueous solution is made very high, the solubility of non-electrolyte will be decreased. The reduction of solubility by an increase in ionic strength is called as salting out effect. This is because due to high salt conc. in water, availability of water molecule to act as solvent for non-electrolyte get reduced. The ions of the salt tying up much of water (through strong ion dipole force) so solute due to unavailability of water get extracted in to organic solvent. This helps to increase extraction efficiency of solute having greater solubility in

41. pH effect pH plays an important role in extraction process. Many comp. encountered by pharmaceutical analyst are weak acids or bases. Solubility of these subs depends upon their ionic form. Generally ionized species are soluble in polar solvents and non- ionoised in nonpolar solvents. These form can be Inter-converted by adjusting pH of medium. Hence pH control is most powerful means for influencing the value of partition coefficient.

42. Effect of p H on separation of mixture of acid and base Acetylsalicylic acid (acid and antihistamine(base)Both drugs are separated by dissolving in water. They acidify the solution using HCl and extracting the Acetylsalicylic acid (unionized in HCl)completely with ether. Then antihistamine which is in its salt form(due to reaction of basis drug with HCL) in aqueous layer can be extracted by adding base to release the drug in free form. Finally using other organic solvent extract antihistamine

43. Pka of weak neutral acid =5 i.e at pH 5 equal amount of acid are present in the anion and neutral form. At pH 6 about 10 % remains in neutral form. At pH 7 1% in neutral form and at pH8 0.1 %present as the acid.

44. Control of hydrophobicity The partition coefficient of an ion can be altered by making the ion more hydrophobic. In two phase system ( aq.and org. phase) ions are normally expected to partition almost completely to aq. Phase. If hydrophobic counter ions are added, so ion pair may be hydrophobic enough to partition into org. phase. Another way is use of macrocyclic sequestering agent such as crown ether.

45. Ex benzene water system, KMnO4 partitions completely into aq layer and benzene layer is colorless. In presence of crown ether, benzene layer becomes colored indicating that some of KMnO4 have distributed in benzene layer. This is because permanganate ion is complexed within the cavity of the crown ether, which thus masks the high polarity of ion, presenting hydrophobic external surface.

46. Applications of extraction in the drug analysis Separation of elements. Concentrating impurities. Clearings of the basic component from impurities in the process of synthesis of substances of drugs. Definition of the basic component from impurities in the process of synthesis of substances of drugs . For identification and quantitative definition of chemical agent or substances-markers in the process of the analysis of Phyto genesis drugs. Increase of sensitivity and selectivity of reactions

47. Studying of formation constant of complex's. Studying of substance condition in a solution (a charge, polymerization degree) Separation - controlled by pH which controls ionization and complex formation. Clean up before analysis . Preconcentration: Extract from a large aqueous volume into a much smaller organic volume. Treatment of extracts, tinctures, antibiotics, preparations from a different biological material

48. Difference between continuous and multiple extraction Continuous extraction Multiple extraction Ex. Soxhlet apparatus Ex. Counter current distribution Multiple extraction is one phase system i.e.Single solvent is used CCD is two phase system i.e. Two solvents are used Not suitable for thermolabile compound suitable for thermolabile compound Multiple extraction method can separate only one constituent at a time CCD method can separate two constituent at a time It is solid liquid extraction technique It is Liquid-liquid extraction technique Technique is used when K value is quite differ. Technique is used when K values of 2 drugs in solvents are almost similar. Same extracting solvent is used repeatedly for extraction . Fresh extracting solvent is used

49. Difference between Single and multiple extraction Single Extraction Multiple Extraction Used when partition coefficient of solute between two solvents isextremely large Used when partition coefficient of solute between two solvents is almost same Maximum recovery is not possible single extraction. Maximum recovery is possible in multiple extraction Extraction efficiency is less as compared to single extraction. Extraction efficiency is more as compared to single extraction. Suitable for thermolabile compound Not suitable for thermolabile compound Total volume of extractant required in single extraction technique is more as compared to multiple extraction Total volume of extractant required in multiple extraction technique is less as compared to single extraction. Ex. Separating funnel Ex. Soxhlet apparatus

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