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Posted on 2009 09:26 Maximizingchemical yield by recycling mother liquors from crystallizations isunderutilized in chemical and pharmaceutical processing, particularly outsidethe developing world. One of the few articles on this subject is Alan A.Smiths,A Model for Mother Liquor Recycle in Batch Processing, Org. Process Research& Development 1997, 1, 165-167. Kilomentorsdiscussion here is indebted to this paper. Whencrystallizing or recrystallizing product (i) from a reaction mixture, or (ii) apartially treated work up solution, or (iii) from a crude solid isolate, noneof the impurities’ concentrations exceeds their solubility product in thesolution. That is, more of each impurity could be dissolved in the filtratewithout precipitating any solid. The solution has the potential to extract moreof the impurities from the desired product. Besides having residual capacity todissolve impurities, the filtrate is saturated with the desired product, whichis going to be lost if the filtrate is sent as waste. Both of thesesituations can very often be improved upon if a portion of the crystallizationfiltrate from a first batch can be used as part of the crystallization solventin a subsequent batch. There are othersituations, easily identified, where filtrate recycling is not promising. Forexample, when an anti-solvent has been added to cause crystallization and thisanti-solvent is not easily removed. The reason is easy to understand. Addingthis modified filtrate back into a second batch will not reproduce theprecipitation conditions of the first batch. It is unreasonable to expect anequivalent product. A similarunpromising situation occurs with crystallization from mixed solvents when theproduct is dissolve in a first solvent and then the solution achieved dilutedwith a second solvent before awaiting crystallization. In general it iscrystallization achieved with the assistance of cooling that is amenable topartial filtrate recycling because the original condition can be recreatedsimply by reheating to the original dissolution temperature. If x is thefraction of mother liquors you contemplate recycling in place of an equalvolume of solvent and 0 < x < 1, the paper referenced above shows thatthe impurities in the mother liquors of each subsequent batch will tend towardsa limit that at infinite batches becomes Iinfinite = I1 X 1/(1- x) Thus with x=0.5and the level of impurity in the first batch I1 = 2% Iinfinite = 2% X 1/(1-0.5)= 4% Or with x=0.7and the level of impurity in the first batch I1 = 3% Iinfinite = 3% X 1/(1-0.7)= 10% Or with x=0.6and the level of impurity in the first batch I1 = 0.8% Iinfinite = 0.8% X1/(1-0.6) = 2% Of course if yourecycle all the mother liquors no matter what the level of I1 is Iinfinite = number X 1/(1-1.0)= infinite; that is to say the impurities come out on the product. The motivationfor recycling some of the mother liquors is not of course usually to savesolvent but to increase the recovered yield of the desired product. Toillustrate this, for simplicity let us suppose that what Kilomentor defines asthe 'reaction yield’ (the assay of the desired product in the isolationsolution as a % of the theoretical quantity of desired product) is 100%. The‘recovery yield’ (the weight % recovered product as a percentage of the weightof desired product based on the assay yield) in this situation becomes equal towhat we all call the reaction yield (the weight of product isolated over thetheoretical weight of product possible as a percentage). If under these circumstancesthe reaction yield is 70%, there will be 30% of the material left in thesaturated mother liquors (so long as no degradation has occurred). If half ofit is recycled, the overall yield will be increased by ½ X 30% = 15% and willbecome 85%. Now even if thesolubility product limit of all the different impurities in the mother liquoris never exceeded, the desired product which is isolated by crystallizationusing some mother liquor recycling will be less pure than when the technique isnot used. One reason for this is that the mother liquors do contain a higherconcentration of impurities and more of these by-products will eitherco-precipitate or be adsorbed on the pure solid crystalline product. Anotherpossibility is that separation of the desired crystalline solid from motherliquor solution is incomplete. Mother liquor solution is trapped on the surfaceof the solid and evaporates there or is deposited there when the crystals areplace in the drier. Certainly the wash solution used on the filtered crystalproduct becomes more critical both to preserve the yield improvement achieved(by not dissolving the product) and by removing this film of mother liquorwithout precipitating impurities. Thecrystallization from a solution in which a portion of mother liquors is beingrecycled will likely be different from an isolation without recycling. Optimalcrystallization temperature, and cooling time will change as the percentage ofimpurities changes. Typically crystallization proceeds more slowly in thepresence of a higher concentration of impurities and greater care needs to betaken to prevent co-precipitation. It would beunusual to recycle more than 50% of the mother liquors from one run of acampaign to the next. Remember to save all the mother liquors from run A untilthe product of run B certified to be trouble free. If run B has a problem andneeds to be investigated, you will not want to use run B mother liquors in runC. You still want to have at least 50% of the mother liquors from run A to usewhile you check to see if there is some deviation in run B. If you intend touse mother liquor recycling in a validated process, you will need to use motherliquor recycling in the validation batches and have in place the analyticaltesting protocols required to show that the mother liquors you are transferringfrom one batch to the next meet preset standards, have been stored for avalidated time under validated conditions.
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