Recycling Mother Liquors in Chemical Process Development to Raise Yields and Reduce Solvent Usage

Maximizing chemical yield by recycling mother liquors from crystallizations is underutilized in chemical and pharmaceutical processing, particularly outside the developing world. One of the few articles on this subject is Alan A.Smith’s, A Model for Mother Liquor Recycle in Batch Processing, Org. Process Research & Development 1997, 1, 165-167. Dr. Smith himself, in the comments, recommends a further reference.

Kilomentor’s discussion here is indebted to this first paper.

When crystallizing or recrystallizing product (i) from a reaction mixture (ii) a partially treated workup solution or (iii) from a crude solid isolate, none of the impurities’ concentrations exceed their solubility product in the solution. That is, more of each impurity could be dissolved in the filtrate without precipitating any of that solid.  The liquid solution can extract more of the impurities from the crude product. Besides having the residual capacity to dissolve impurities, the filtrate is saturated with the desired product, which is going to be lost if the filtrate is sent as waste.

Both of these situations can very often be improved upon if a portion of the crystallization filtrate from a first batch can be used as part of the crystallization solvent in a subsequent batch.

There are other situations, easily identified, where filtrate recycling is not promising. For example, when an anti-solvent has been added to cause crystallization and this anti-solvent is not easily removed.  The reason is easy to understand. Adding this modified filtrate back into a second batch will not reproduce the precipitation conditions of the first batch.  It is unreasonable to expect an equivalent product.

A similar unpromising situation occurs with crystallization from mixed solvents where the product is dissolved in a first solvent and then that homogeneous solution is diluted with a second solvent to induce crystallization.

In general, it is crystallization achieved by cooling alone that is amenable to partial filtrate recycling because the original condition can be recreated simply by reheating to the original dissolution temperature.

If x is the fraction of mother liquors you contemplate recycling in place of an equal volume of solvent and 0 < x < 1, the paper referenced above shows that the impurities in the mother liquors of each subsequent batch will tend towards a limit that at infinite batches becomes

                                    I_infinite = I₁  X 1/(1- x)

Thus with x=0.5 and the level of impurity in the first batch I₁ = 2%   I_infinite = 2% X 1/(1-0.5) = 4%

Or with  x=0.7 and the level of impurity in the first batch I₁ = 3%                 I_infinite = 3% X 1/(1-0.7) = 10%

Or  with x=0.6 and the level of impurity in the first batch I₁ = 0.8%               I_infinite = 0.8% X 1/(1-0.6) = 0.2%

Of course, if you recycle all the mother liquors no matter what the level of I₁ is Infinite = number  X 1/(1-1.0) = infinite; that is to say the impurities come out on the product.

The motivation for recycling some of the mother liquors is, of course, not usually to save solvent but to increase the recovered yield of the desired product.  To illustrate this, for simplicity let us suppose that what Kilomentor defines as the ’reaction yield’ (the assay of the desired product in the isolation solution as a percentage of the theoretical quantity of desired product) is 100%. The ‘recovery yield’ (the weight % recovered product as a percentage of the weight of desired product based on the assay yield) in this situation becomes equal to what we all call the reaction yield (the weight of product isolated over the theoretical weight of product possible as a percentage). If under these circumstances the reaction yield is 70%, there will be 30% of the material left in the saturated mother liquors (so long as no degradation has occurred).  If half of it is recycled, the overall yield will be increased by ½ X 30% = 15% and will become 85%.

Now even if the solubility product limit of all the different impurities in the mother liquor is never exceeded, the desired product which is isolated by crystallization using some mother liquor recycling will be less pure than when the technique is not used. One reason for this is that the mother liquors do contain a higher concentration of impurities and more of these by-products will either co-precipitate or be adsorbed on the pure solid crystalline product.  

Another possibility is that separation of the desired crystalline solid from mother liquor solution is incomplete. Mother liquor solution is trapped on the surface of the solid and evaporates there or is deposited there when the crystals are placed in the drier. Certainly, the wash solution used on the filtered crystal product becomes more critical both to preserve the yield improvement achieved (by not dissolving the product) and by removing this film of mother liquor without precipitating impurities.

The crystallization from a solution in which a portion of mother liquors is being recycled will likely be different from an isolation without recycling.  Optimal crystallization temperature and cooling time will change as the percentage of impurities changes. Typically crystallization proceeds more slowly in the presence of a higher concentration of impurities and greater care needs to be taken to prevent co-precipitation.

It would be unusual to recycle more than 50% of the mother liquors from one run of a campaign to the next. Remember to save all the mother liquors from run A until the product of run B certified to be trouble-free. If run B has a problem and needs to be investigated, you will not want to use run B mother liquors in run C. You still want to have at least 50% of the mother liquors from run A to use while you check to see if there is some deviation in run B.

If you intend to use mother liquor recycling in a validated process, you will need to use mother liquor recycling in the validation batches and have in place the analytical testing protocols required to show that the mother liquors you are transferring from one batch to the next meet preset standards and have been stored for a validated time under validated conditions.