kilomentor

kilomentor http://kilomentor.chemicalblogs.com/55_kilomentor kilomentor 2010-03-17T12:52:00Z kilomentor Contemplates a New Adventure http://kilomentor.chemicalblogs.com/55_kilomentor/archive/1149_kilomentor_contemplates_a_new_adventure.html In one year time, I think it is likely that I will be retiring from my present position at ratiopharm. For one thing, I will be 65 years old, and for another, ratiopharm, by that time, will have been sold off to some other organization. Most likely ratiopharm will be part of either Teva, Pfizer or Actavis. Anyway, those, Reuters reports are the front-running contenders. Since the ratiopharm organization did not itself produce any active pharmaceutical ingredients but sourced everything outside, the organization didn’t mind me writing a blog whose purpose was to mentor process development chemists anywhere in the world. I do not suppose these new people will feel the same way.I am still in good health and cannot imagine doing anything else as enjoyable as chemistry. The action to-day is in the developing world, so I wouldn’t mind getting back into process development /research management / mentoring there with a vigorous team of young scientists determined to efficiently deliver significant projects. My wife, who is Chinese, favors China which clearly moving the fastest. As a Canadian with British roots, I may be inclined somewhat more towards India, where I have visited and appreciated what I saw. Of course there are other potential destinations as well. Any suggestions from out there in cyberspace?Regards,Dr. Clarke Slemon<a href="mailto:kilomentor@sympatico.ca">kilomentor@sympatico.ca</a>The Kilomentor General 2010-03-15T05:24:32Z kilomentor Transition Metal Complexes for Chemical Process Development http://kilomentor.chemicalblogs.com/55_kilomentor/archive/1107_transition_metal_complexes_for_chemical_process_development.html Kilomentor takes the position that, in the present state of the chemical art, electronic database searching has enabled chemists of ordinary skill to design ingenious reactions schemes by little more than electronically searching for reactions to string together. It is isolation and purification procedures where there is the least technical support to support individual ingenuity. Isolation methods cannot be searched because the search terms are the solution to the problem not the starting point.Therefore Kilomentor wants to emphasize where inexpensive transition metal complexes such as those with Chromium (III) and Cobalt (III) can simplify the work-up of chemical process steps. Chromium (III) is the most stable and important oxidation state of the element in general and particularly in the aqueous chemistry. Advanced Inorganic Chemistry 1966 pg. 823 states, “The foremost characteristic of this state is the formation of a large number of relatively kinetically inert complexes. Ligand displacement reactions of Cr (III) complexes are only about 10 times faster than those of Co(III), with half-times in the range of several hours. It is largely because of this chemical inertness that so many complex species can be isolated as solids and that they persist for relatively long periods of time in solution, even under conditions where they are thermodynamically quite unstable.” Note that it is the kinetically inert property of chromium complexes that makes them valuable. What this is saying is that complexes that are not the thermodynamically most stable nevertheless can be isolated. This means that many more compounds are in principle accessible. Advanced Inorganic Chemistry 1966 pg. 873 says about cobalt chemistry that “The complexes of Cobalt (III) are exceedingly numerous. Because they generally undergo ligand exchange reactions slowly, but not too slowly, they have, from the days of Werner and Jørgensen, been extensively studied and a large fraction of our knowledge of the isomerism, modes of reaction and general properties of octahedral complexes as a class is based upon studies of Co (III) complexes.” What I take this to be saying is that many different complexes of cobalt would also be readily accessible in principle. Iron also appears to be promising in terms of offering multiple potential complexes. Iron (III) forms a large number of complexes, mostly octahedral ones, and octahedron may be considered its characteristic coordination polyhedron. The affinity of iron (III) for amine ligands is very low. No simple amine complexes exist in aqueous solution; addition of aqueous ammonia only precipitates the hydrous oxide. Chelating amines, for example, EDTA, do form some definite complexes among which is the 7 coordinate [Fe(EDTA)H2O]ion. Also, those amines such as 2,2’-dipyridyl and 1,10-phenanthroline which produce ligand fields strong enough to cause spin-pairing form fairly stable complexes, isolable in crystalline form with large anions such as perchlorate. Transition metals now have an extensive application as catalysts in organic chemistry. Nickel, palladium and platinum complexes are today extensively used to catalyze reactions for which there is no uncatalyzed equivalent. An extensive chemistry has also been established centering on the practical question of the recovery and recycling of the noble metal catalysts, mainly palladium and platinum, since these represent expensive inputs into a process. From the Kilomentor perspective of using of transition metal complexes for isolations the complexes of the wide variety of less expensive chromium, cobalt and iron complexes would seem most promising. As a first example let us consider Reinicke and Rhodalilate Salts: The Chromium Salt NH4[Cr(NH3)2 (SCN)4] is red in color. It is soluble in ethanol or hot water and is reported to dependably yield precipitates with primary and secondary amines. The implication of many reference books seems to be that the salt does not form precipitates with t-amines, but this is untrue. According to Cotton & Wilkinson’s Advanced Inorganic Chemistry Comprehensive Text, it can be used, in general, to precipitate large cations, either organic or inorganic. It seems likely however that although, thermodynamically, precipitation of Reinecke salts may not be as selective as has been publicized, fractional precipitation based on rates of precipitation can provide purification as suggested for the closely related Rhodanilate salts (see later for rhodanilate definition). The Reinecke and the related Rhodanilate salt possibly could be used to precipitate particular amines in the presence of others. One idea is that because the Reinicke salt is soluble in alcohol alone, a useful separation could be done on a substrate, which is sensitive to water. An example of this is that the possible difference in rates of precipitation might be useful in the case of alkylating of an amine where an excess of the starting amine could perhaps be selectively precipitated.Amines are frequently used as reagents to neutralize acidic co-products of a reaction and thereby drive any equilibrium towards completion in a particular direction. The most frequently used amine in this regard is triethylamine. Some advantages of triethylamine are that even if it is employed in excess any unused base isi) volatile enough to be removed by vacuum ii) water soluble enough to be carried away in a water wash<ul><li><div class=" " style="TEXT-INDENT: -36pt">iii) inexpensive enough to be discarded and </div></li><li><div class=" " style="TEXT-INDENT: -36pt"></div></li><li><div class=" " style="TEXT-INDENT: -36pt">iv) easily made anhydrous. </div></li></ul>Disadvantages are that it is volatile enough to escape from reactions that require heating and nucleophilic enough to compete in some displacements and deprotonations. Employing the Reinicke or Rhodalinate salts in a work-up of mixtures containing more complex amines may make them recoverable and recyclable and so practical as traps for acidic co-products. Another possibility is that initial formation of an easily isolable amine salt of a complex anion X could be followed by the switch from the amine salt to the inorganic metal salt via a Rienecke or or Rhodalinate reagent which could precipitate the intermediate amine.For example, a salt of an amine with a complex anion X might be converted into the salt of a metallic cation MX by adding that M in the form of acetate and precipitating the amine (here R3N) as the Reinicke salt precipitate.M+ - OAc + R3NH+ X- + NH4[Cr(NH3)2 (SCN)4] going toR3NH [Cr(NH3)2 (SCN)4] (insoluble) + NH4 OAc + M XI do not know of any experimental examples of this, however. Amine Recovery from lithium amide reagentsThe lithium salts of many sterically hindered secondary amines, lithium diisopropylamide for example, are used for quantitative deprotonation in chemical synthesis. Because they are sterically hindered the resulting secondary amine co-products do not interfere in subsequent reactions of the carbanions they helped create. These sterically hindered secondary amines may need to be separated from desired product in the reaction work-up and if they are expensive recovered for recycling.Reinicke Salts, Rhodanilate salts or Trisoxalatochromate salts can potentially be used to precipitate these secondary amines and remove them as filterable solids. Diisopropylamine, dicyclohexyl amine, 2,2,6,6-tetramethylpiperidine, isopropyl-cyclohexylamine, and pentamethylpiperidine need to be examined to see whether they can be quantitatively or semi-quantitatively precipitated.According to Max Bergmann’s article in J. Biol. Chem.109, 471 (1935) proline and hydroxyproline can be precipitated from gelatine hydrolysates using Reinecke’s salt and the amines liberated by forming a complex with N,N-dimethylaniline or pyridine. This liberation shows that all amines can react.In this Bergmann article the formation of what he regards as more selective complexing agents can be achieved replacing the ammonia ligands with other amines. Displacing the two ammonia with aniline what is called ammonium rhodanilate is formed About this Bergmann says, “ Rhodanilic acid forms rose-coloured, well crystallized salts with basic nitrogen compounds, and in particular with alkaloids and with amino-acids. Although rhodanilic acid lacks definite specificity, the various rhodanilates differ greatly in their solubilities, crystalline form, and rate of crystallization. It is therefore often possible to separate from mixtures of amines, amino acids , or peptides, single homogeneous products by fractional precipitation with rhodanilic acid. In most cases where several rhodanilates form simultaneously, a separation by fractional crystallization is often possible.”With regard to the amount of ammonium rhodanilate in the fractional precipitation Bergmann says that “The quantity necessary was determined by examining the precipitate under the microscope in the course of successive additions.” I interpret this to mean that the precipitation was controlled by the kinetics and the fastest precipitating compound came out first followed by other compounds and the precipitate was collected in fractions that were subsequently combined on the basis of their microscopic crystal shape.In the case of preparing proline rhodanilate, the free amino acid was simply achieved using excess pyridine. “In order to obtain the free amino acid from proline rhodanilate, advantage was taken of the fact that pyridine rhodanilate is very difficultly soluble in water. It is therefore sufficient to suspend the solid proline rhodanilate in water and to add a little pyridine in order to precipitate almost instantly the entire rhodanilic acid as pyridine salt. On filtration a faintly colored aqueous solution of l-proline is obtained.The by-product of such a purification is pyridine rhodanilate. It may easily be recycled and reconverted into ammonium rhodanilate with ammonia and so recovered for further use.Thus ammonium rhodanilate can be used to precipitate a complex amine, the amine rhodaniliate can be freed from the complex with pyridine to precipitate the very poorly soluble pyridine rhodanilate and then the ammonium rhodanilate can be reformed from the pyridine salt by treatment with excess ammonia.In a finl use, of the Reinicke salt, if mercuric acetate bound to an ion exchange resin is used as a source of mercuric ions in a reaction. Water from such a reaction, that could contain small amount s of mercury ion, can be decontaminated with Reinicke Salt which precipitates the mercury ion. General 2010-01-21T07:48:40Z kilomentor The Use of the Diisopropyl ether (DIPE) Water Azeotrope as a possible means to dry high boiling dipolar aprotic solvents http://kilomentor.chemicalblogs.com/55_kilomentor/archive/1102_the_use_of_the_diisopropyl_ether_dipe_water_azeotrope_as_a_possible_means_to_dry_high_boiling_dipolar_aprotic_solvents.html Dipolar aprotic solvents such as N-methylpyrollidone, dimethyl formamide, N-methyl formamide, dimethyl acetamide and dimethyl sulfoxide are often drowned out with water and then extracted to isolate organic products. No cheap and convenient method has been worked out to separate these polar organics from the bulk of the water and return them to an anhydrous condition suitable for reuse. Kilomentor at his present employment does not have access to a chemical laboratory where experimentation could be done so the following idea has not been tested, but on the basis of the physical properties of the chemicals it might be workable. Diisopropyl ether (DIPE) forms an azeotrope with water that is reported to boil at 62.2 C. This is a heterogeneous azeotrope that according to the Chemical Rubber Handbook splits into a water-poor DIPE upper phase and a water rich lower phase. Addition of DIPE therefore to one of these higher boiling solvents and water, and boiling of the ternary mixture under a Dean-Stark trap with continuous return of the top DIPE phase should gradually separate a lower water rich phase which could be periodically drained away. The high boiling dipolar aprotic solvent that is being dried should theoretically be confined to the still pot at the low azeotropic boiling point. In the real laboratory situation, however, a small amount of dipolar solvent vapour entrained in the reflux stream could be all that is needed to prevent the distillate from separating into two phases in the trap and this would scupper the procedure. It is crucial for a practical process that the DIPE be recycled since the distillate is 97% DIPE and only 3% water. Recycling is essential to be able to remove a large amount of water using only a small amount of DIPE. Other solvents that boil above 100 C that can potentially be separated from water and dried are: nitromethane, acetic acid, dioxane, ethylene diamine, sulfolane and isoamyl alcohol. After the water has been completely removed continued distillation will separate the DIPE. Even if small amounts of DIPE might remain they are usually unreactive. If particular importance they are inert towards organometallic reagents. For safety remember that DIPE needs to be worked with under inert gas to prevent the accumulation of explosive peroxides. The solvent very readily forms peroxides. General 2009-12-28T19:17:52Z kilomentor Nitriles Separated by Competitive Reaction and then Simple Extraction http://kilomentor.chemicalblogs.com/55_kilomentor/archive/1100_nitriles_separated_by_competitive_reaction_and_then_simple_extraction.html Although mixtures of carboxylic acids or mixtures of amines are each fit for separations based on extractions at controlled pHs, most functional groups are not so easy to isolate from each other. Kilomentor thinks a good deal about how to simplify separating molecules with the same functional group in slightly different structural environments. Although it has not been demonstrated in the literature yet, two different molecules each with a nitrile functionality but differing in the steric environments around them can likely be separated by selective reaction followed by a simple acid-base extraction. Nitriles are known to react smoothly with azide in a 3+2 cycloaddition to give 1,2,3,4 tetrazoles. This is a ‘click chemistry’ reaction . Cycloadditions are typically quite sensitive to steric environment. Thus, although these reactions are generally fast, it is likely that conditions can easily optimized to get good selectivity between cyanide groups in different molecules using an insufficient amount of azide. The result will leave a nitrile in one substrate untouched and the nitrile in the other substrate converted essentially completely to tetrazole. The beauty of this is that these tetrazoles have the acidity of carboxylic acids and can be extracted into water with alkali. Thus the tetrazole derivative removes the reactive nitrile substrate from the organic phase leaving the unreactive nitrile substrate clean for a simple recovery. Two references that I could loctate concerning the kinetics of the reaction of nitriles with azide are: Khimiya Geterotsiklicheskikh Soedinenii (1992) (9) 1214-17, which is in Russian [C.A. 11; 8945a, 8948a]; and Inorganica Chimica Acta (1985). 102(2), 157-62 that does the condensation with the nitrile coordinated in a Co(III)complex. The synthesis of tetrazoles from nitriles and azide has been studied intensively because of its relevance to the preparation of the sartan family of drugs. Relevant patents are US5744612, US6040454, WO2005014602, WO2007054965 and CN1718574 General 2009-12-15T18:55:46Z kilomentor Crystallization of miconized pharmaceuticals from impinging stream technology will soon be free to use. http://kilomentor.chemicalblogs.com/55_kilomentor/archive/1099_crystallization_of_miconized_pharmaceuticals_from_impinging_stream_technology_will_soon_be_free_to_use.html Crystallization is a process step that has for a very long time generally defied attempts to scale it up. A solution is to crystallize by continuous micromixing small volumes and accumulating the resulting slurry in a large reservoir for isolation at scale. One standard crystallization variant contacts a supersaturated solution of the substrate with an appropriate anti-solvent in a stirred vessel. The anti-solvent initiates primary nucleation as it mixes into the supersaturated solution of active and these seeds then grow. The process is adaptable to using preformed seed crystals and/or further aging of the solid, once formed, which digests the crystals to change their initial sizes and/or polymorphic forms. Using such a methodology, in order to get the smaller crystals preferred for enhanced bioavailability, the saturated solution needs to be added into the anti-solvent to get many tiny seeds forming rapidly. Using this reverse addition technology a concentration gradient cannot be avoided in a large reactor because the introduction of feed solution into the anti-solvent in the stirred vessel does not afford a thorough mixing of the two fluids prior to the initiation of crystallization. The presence both of the concentration gradients and a heterogeneous fluid environment interferes with optimal crystal structure creation and allows greater entrainment of impurities. On scale even the fastest bulk mixing cannot smooth out the microenvironments in which the seeds form. Furthermore, in a large bulk reactor the number of seeds present at the beginning of the nucleation process is very different from the seeds present in the bulk when the last of the supersaturated solution enters the tank. On scale stirring cannot handle the micromixing requirement.Another standard crystallization procedure cools a solution of the desired product in order to bring the solution to its supersaturation point but cooling in batch processing is a slow process that becomes even slower as the batch size increases. Although the solvent gradient is abolished, it is replaced by a themal gradient. In any case the crystals are undesirably larger with the slower process. The characteristics of size, purity and stability are difficult to control with the technology. Technology is now coming off patent that may solve this problem in may cases. Particle size is more important for drug substances because of te relationship with bioavailability. Most drugs are provided as pharmaceutically acceptable salts and consequently it is the particle size of these salts that is of most commercial importance.CA2044706, Crystallization Method to Improve Crystal Structure and Size, expires June 14th, 2011 in Canada and the corresponding US5314506 expires May 24th 2011. The invention addresses the general problem, how to obtain a reproducible micronization of a pharmaceutical compound without milling. The patents are assigned to Merck.The technology taught in CA2044706 teaches pumping both solution and antisolvent in impinging jets of fluid that because of their small volumes and high velocities create almost instantly, where they collide, a region of high intensity micromixing. Once the fast crystallization has occurred the mixture of solution and antisolvent can be accumulated and filtered when all the material has been processed or it can be collected after any other appropriate time.This impinging jet technology removes the problem of scale. Larger scale just translates into a longer period pumping the same streams together. The heterogenous slurry in which the seed crystals form becomes a function of the pumping rates, the concentration of solute in solvent and anti-solvent and the radii of the columnar jets of colliding fluids. All these parameters are within engineering control. Because of this the surface area, crystallinity, stability and purity can be optimized. Because the equivalent of a milled material is available directly, a step is saved and the noise, dust, yield loss, equipment cost and exposure hazard of milling are all by-passed.Preparation and Crystallization of Pharmaceutical Salts using Impinging Jet Micromixing Technology.Some bimolecular reactions proceed in superior yield if both reactants are added simultaneously to a pot of solvent so that the concentrations of both reactants is kept low. Formation of pharmaceutical salts can benefit from such a process. Two impinging jets of solutions, one containing the substrate molecule and the other either the pharmaceutical acid or pharmaceutical base required to make a pharmaceutical salt can be implemented. As above, where the jets collide the intense micromixing both form the salt and cause nucleation into small seed crystals. This is taught in CA2349136. The advantages are the same. The process is completely under control of the engineering, product can be synthesized in micronized form in a single step with a single piece of equipment.. The US equivalent, US6558435B2, expired May 6th 2003. The Canadian family member application died August 15th 2007. They are now free to use.Crystallization of micron sized controlled particle size may be becoming easier not harder on scale! General 2009-12-12T15:06:55Z kilomentor The Possibility of Using Solid Alumina or Silica Gel Catalysis in Development of an Organic Synthetic Step http://kilomentor.chemicalblogs.com/55_kilomentor/archive/1085_the_possibility_of_using_solid_alumina_or_silica_gel_catalysis_in_development_of_an_organic_synthetic_step.html It has long been known that some chemical reactions that proceed slowly or not at all in solution can become predominant when the reactants are adsorbed on solid adsorbants. This can be dramatically demonstrated if we perform preparative chromatography and leave the material on the prep plate or in the column overnight. Very often you would discover the next day that the anticipated product had at least partially decomposed. Fieser & Fieser’s Reagents for Organic Chemistry has numerous entries for reactions on alumina or silica. For alumina, these are Vol.1 pg. 19-20; Vol. 2 pg. 17; Vol.3 pg. 6; Vol. 4 pg. 8;Vol. 6 pg. 16-17; Vol7, pg. 5-7; Vol. 8, pg. 9-13; Vol. 9, pg. 8-11; Vol.14, pg. 20-21;Vol. 16, pg. 16-17; Vol. 18 pg 16-17. For Silica, (also alternatively indexed as silic acid), the entries are Vol. 6, pg. 510; Vol. 9, pg 4`10; Vol. 15, pg 282; and Vol. 18, pg 319. Closer inspection of these references, however, would reveal that they deal mostly with reactions that don’t occur in the absence of the solid phase. This it seems to me is misleading for the true potential of the methodology. If presence of a catalytic surface can activate new reaction pathways, logically, it might improve the energetics for processes that already proceed to some extent. One can significantly ask whether a useful augmentation of the product can be delivered through this pathway. Adding alumina or silica gel to an otherwise homogeneous reaction system has the potential to selectively catalyze one out of several competing reactions and lead to an optimization of a process step. Even if the possibility is a long shot iit is easy to test this at the process investigation stage. Supposing that a required transformation is not proceeding either at all or fast enough and if raising the reaction temperature is not an option,( perhaps because the bp of the solvent is limiting,) rather than tossing the trial reaction into the waste, we could try adding alumina or silica and observe. There is no down-side because you are working with what will be discarded. In the test, add as much solid as possible consistent with maintaining stirring. The goal is to see something desirable happen. Economics and material handling problems, which are real issues for such a solid catalyzed protocol, are not an issue unless something promising happens. All that needs to occur is that the rate limiting mechanistic step have its transition state energy reduced by adsorbing an intermediary on the solid; but there must be enough solid to provide adequate sites. Another possible mechanism that would lead to a success is for a reversible reaction to be driven forward by the removal through adsorbtion of the product or a co-product. Filtration and washing are easy isolation steps that completely removed the added adsorbant. The ease of work-up in the event of success are the potential advantages. It might be that one should try adding silica gel and alumina together instead of one or the other. Because they are solids they cannot intermingle on the molecular scale so any catalytic sites on one solid are isolated so that if either or both adsorbants produce any beneficial or deleterious effects, their influences will be additive and one will see that something is occurring. One can then sort out whether one or the other or both are having an influence. If you see nothing then both have been removed from consideration with a single experiment! General 2009-11-26T19:04:42Z kilomentor Recent Assessments of Organic Synthesis as expressed in Chemical Process Development http://kilomentor.chemicalblogs.com/55_kilomentor/archive/1075_recent_assessments_of_organic_synthesis_as_expressed_in_chemical_process_development.html Kilomentor tries to keep up with opinions expressed concerning chemical process development. Girish Malhotra recently wrote an article, Less is More in API Process Development published electronically at PharmaManufacturing.com. He asked the question, Why does U.S. pharmaceutical industry persist in using complex manufacturing processes to make active pharmaceutical ingredients? He cites as examples US6037483, US6245913, US6867306, US6835848 and US6331638. Am I missing something? None of these applications is from the laboratory of an American company. The authors are without exception Indians either working in India or in one case working in Ireland. I would dispute many of the contentions made in the article; for example, I think the priorities of innovative manufacturing chemists and generic manufacturing chemists may explain an enormous part of the differences he tries to assert. However, with such examples, I think a discussion need go no further. General 2009-10-25T17:32:08Z kilomentor Selective Ester Hydrolysis as a Process Isolation Tool for Work At Scale http://kilomentor.chemicalblogs.com/55_kilomentor/archive/1073_selective_ester_hydrolysis_as_a_process_isolation_tool_for_work_at_scale.html Organic synthesis activity devotes a substantial amount of time searching for reactions, which proceed selectively so that difficult separations are not needed to obtain pure products. At the same time it is known that acids and bases, nd most frequently represented as carboxylic acids or amines, are characheristically easier to separate from each other because of the sensitive effect of substituent patterns in their pKas. It would be very useful if more functional groups could be similarly dependably purified. Esters are common derivatives of carboxylic acids and esters can be hydrolyzed easily in high yield in moist solvents to the carboxylic acids. These free acids can be esterified in high yield. Is there a capacity to purify reaction product mixtures, comprising esters by selective hydrolysis? This is not a question typically asked by organic synthesis chemists. Yhe answer, although it was known to us during our undergraduate or graduate studies, has probably since faded away. Esters are quite sensitive both to electronic and to steric factors in their relative rates of hydrolysis. Newman’s Rule of Six states that the rate of hydrolysis of an ester is substantially dependent upon the sum of the number of atoms bonded to the combination of those atoms, which are six bonds away from the nucleophile attacking at the carbonyl. From example, in the literature, it can be seen that isomeric compounds differing significantly (i.e. a difference of four substituents six atoms away) can have rates of hydrolysis under the same conditions differing by a factor of 50 or more. W shall examine the case in which two esters in two molecules of a product mixture differ in reactivity by a factor of 50. As we shall see the difference in reactivity is variable. Additionally and for simplicity we shall assume that the conditions of hydrolysis are selected to give unimolecular reaction kinetics for both the major and minor isomer. In the case where the mechanism of hydrolysis of the esters are different the separation is often solved simply by the intuitive application of this information. For the development of a general mathematical treatment, Let [A]t be the concentration at time t of the major substanceLet [B]t be the concentration at time t of the minor substanceLet [A]to be the concentration at time0 of the major substanceLet [B]to be the concentration at time 0 of the minor substance -d[A]t/dt = k [A]t -d[B]t/dt = 50 k [B]t This would be true as we have postulated if the rate of hydrolysis of B is 50 times that of A. By integrating and subtracting these equations from each other we see how time is related to the ratios of esters at the beginning of hydrolysis and at any time during the hydrolysis log {[A]t/[B]t} = (50-1) kt/2.303 + log {[A]to/[B]to} 49kt/2.303 = log {[A]t/[B]t} - log {[A]to/[B]to} t = 2.303 {log ([A]t[B]to/[B]t[A]to)}/49 k Thus we can calculate the time required to achieve any particular ratio of esters remaining. Given that for a unimolecular reaction the rate is related to the half time by k=0.693/ t½[A] where t½ is the half life of the major, slower hydrolyzing reaction constituent under the hydrolysis conditions we can substitute and get t = 2.303 t½[A] { log ([A]t[B]to /[B]t[A]to)}/( 49(0.693)) The half life of a hydrolysis can be approximated without knowing the structure or the concentration of an ester or even separating it from its mixture with the minor ester. The material is simply hydrolyzed until its residual spot is equivalent to a spot of one-half the original concentration when quantitatively equal volumes are spotted. This can be done simply by following the reaction by tlc. The original molar ratio of the mixture can be estimated either by tlc , by integration of appropriate signals in the nmr or by other means convenient for the particular case. We know the ratio of esters present in the mixture before hydrolysis which is [B]to / [A]to Let it be 9/1 or 90% the major isomer for example. We can choose the desired enrichment or the ratio of major ester to minor ester at the end of enrichment, that is [A]t / [B]e. Let us set it at 50/1 that is 98% pure. Now the log term becomes simple number and we can solve for time of hydrolysis required to reach that enrichment in units of the half time for the hydrolysis of the major isomer. In the case of a 90 to 10 molar composition where the half time for the major A components hydrolysis was 300 minutes, the time for enrichment to 98% purity would be just under 54 minutes. We can intuitively see that only a small amount of the desired A component would be destroyed in that time, so it would be a useful separation. The degree of enrichment/purification that is needed before the main component of the mixture will purify itself further, (during crystallization for example), is estimated based on experience with similar compounds; then the time for the competitive hydrolysis can be calculated as a fraction of the hydrolysis half time of the major component. After this period, acid-base extraction is applied to separate the mixture of esters and acids and the enriched material recovered. The acid fraction of course will be enriched in the minor, more easily hydrolyzed material. The same thing is stated in more qualitative terms in the statement that among aliphatic carboxylic acids those of primary structure are esterified readily with an alcohol and a mineral acid catalyst whereas those in which the carboxyl is joined to a quartenary carbon react sluggishly, probably because the alkyl groups dominate so much of the space in the neighbourhood of the carboxyl group that they block the formation of a protonated intermediate. The alkyl groups combine to break up the required solvation shell around the charged activation intermediate and raise its free energy slowing the reaction. This is even more striking among benzoic acid or heterocyclic acid systems when there are two ortho substitutuents. Meyer in 1894 investigated the response of aromatic acids to attempted esterification under the conditions of refluxing 3-5 hours a solution of aromatic acids in methanol containing 3% hydrogen chloride or by saturating a methanol solution with HCl in the cold and allowing the solution to stand overnight. Doubly ortho substituted materials yielded little or no ester. Even a single ortho substitutent exerted a significant blocking effect compared to benzoic acid. The carboxyl of salicyclic acid which has an ortho hydroxyl must be performed five times as long to give methyl salicylate in reasonable quantity. This difference in reaction rates may be able to be increased further by using a larger alcohol in the esterification. This would add an unfavorable equilibrium to the already slow forward reaction rate. Fieser & Fieser’s Organic Chemistry Third Edition. pg.671-673. Although one might think that such thinking is only applicable to simple aromatic substitution problems, when structures become even more complex carboxyl and amines can be hindered by even quite remote parts of a structure in terms of intervening bond distance and steric hindrance can come into play. Of course, the best means for differentiating between esters is an enzyme. We are familiar with using enzymes to hydrolyze one enantiomer of a pair of mirror image compounds in a racemate. It follows from this, however, that enzymes should be able to even more easily distinguish esters of distinctly different structures. In the past this was not a productive path because the most likely result would have been that both esters were not substrates for the enzyme. Today many more esterases are available and it is quite likely that an appropriate one can be found to selectively hydrolyze one ester structure in the presence of another. Of course if the compound that hydrolyzes is chiral, the enzyme may only hydrolyze one of the chiral pair. Besides a separation one would achieve a resolution in the same pot! General 2009-10-09T03:52:18Z kilomentor Explaining Process Intensification to Process Chemists http://kilomentor.chemicalblogs.com/55_kilomentor/archive/1069_explaining_process_intensification_to_process_chemists.html In the 1980s, Colin Ramshaw at ICI coined the term “process Intensification” to describe his engineer rethink about gas/liquid mass transfer. That resulted in aiming for much smaller chemical plants that would be markedly cheaper and safer than existing ones. Ramshaw’s zero-based thinking moved away from existing equipment. He started thinking afresh. Distillation for example he saw as fundamentally a gas liquid mass transfer for which the key cost drivers for a given system were well established: <ol><li><div class=" " style="LINE-HEIGHT: 110%; TEXT-INDENT: -18pt; BACKGROUND: white">· Well mixed liquid and gas phases </div></li><li><div class=" " style="LINE-HEIGHT: 110%; TEXT-INDENT: -18pt; BACKGROUND: white">· Lots of interfacial surface area </div></li><li><div class=" " style="LINE-HEIGHT: 110%; TEXT-INDENT: -18pt; BACKGROUND: white">· Thin liquid film </div></li><li><div class=" " style="LINE-HEIGHT: 110%; TEXT-INDENT: -18pt; BACKGROUND: white">· Counter-current operation </div></li></ol>In general gases mix well in all conditions as do low viscosity liquids in thin films. Simple geometry teaches us that smaller, finer, packing gives us more surface area so that would be the obvious way to go - a column with very fine packing with counter-current gas flow. However, a liquid film running through a bed of fine material floods when the film thickness becomes approximately equal to the clearance between the bits of packing. The limiting factor is the thickness of the liquid film and most of the factors determining film thickness are physical properties of the fluid and are not open to modification. Only gravity was independent. The higher the applied gravity the thinner the film and the smaller the packing could be. If gravity could be varied that would give a lot of mass transfer surface area for volume i.e. an intensified plant. To increase virtual gravity the centripetal effect of rotating the packing in a “high-g” machine was demonstrated to deliver an order of magnitude reduction in size. The idea was a major announcement at the time. An article appeared in Chemistry & Engineering News, Novel Separation Technology May Supplant Distillation Towers March 7, 1983, but the high-g machine never became popular.Even so, this zero-based engineering that starts afresh from first principles exemplied the essential process of science and had appeal as a creative process. Understanding a process (a reaction, a crystallisation etc.) with sufficient depth so that the key rate controlling steps are understood and then matching that process to the right processor was seen as potentially breakthrough innovation. Heat exchangers are another example. Obviously one of the keys to performance is heat transfer area so it is surprising that many heat exchangers are based on pipes that have a minimum surface area! It has been proposed that this reflects mechanical engineering considerations rather than process ones. Clearly the plate heat exchanger is a much more effective way of providing area, albeit with some mechanical downsides. This is 180 degrees opposed to the normal approach in the chemical and pharmaceutical process industry, which creates a process to match standard equipment. Although there are good economic reasons for this in a batch process industry, there was a feeling not to lose sight at the design stage of the possibility that intransigent difficulties operating in the standard way may become trivial with different equipment. For example, the ubiquitous batch reactor might be used to carry out a polymerisation in the laboratory but the recipe used on plant scale will be adjusted to match the relatively poor heat transfer performance of a larger reactor. Here, the process has been tuned to match a characteristic of the processor. Perchance in some particular instance, the rationale for this matching process may even be lost in corporate history. Perhaps a batch takes a certain length of time to complete because many years ago it was matched to a particular reactor or type of reactor. Just as important is the corrollary that the process that has been matched to a particular processor cannot be simply transferred to a different processor without adjustments. For example, for exothermic reactions rate is proportional to temperature. A reaction temperature is selected so that the heat can be removed and the reaction condition kept under control. One can make an order of magnitude change in the rate and still disipate heat , by going to a plate reactor. Thus a higher operating temperature can be held in control and a much shorter reaction time becomes practicable. The reaction time may become so short that continuous processing becomes possible. In fact, the new reactor will not work unless the process conditions are changed to harmonize with its new character. In the above example of an exothermic reaction, the matching of process temperature is key. Other characteristics that might need adjustment are mass transfer, mixing, diffusion etc. Often the controlling step is obvious, sometimes it is completely unknown and sometimes there are different rate controlling steps during the course of a reaction. What the critical variables are, constitutes fundamental understanding.Batch reactors or in their continuous form continuous stirred reactors (CSTR) will match a process that inherently needs long times (perhaps diffusion controlled with real maximum temperature limitations). Oscillating columns offer moderate residence times with better than batch heat transfer. Plate heat exchanger type reactors (HEX reactors) are a good match for clean high heat transfer duties. Spinning disc reactors offer good heat and mass transfer as well as good mixing. It is erroneous to claim that one is inherently better than another, anymore than to claim a Posidrive screwdriver is better than a crosshead. What is required is to match the process and the processor! All the benefits of process matching, precision processing or process intensification are not always obvious. Clearly capital cost saving is the classic rationale with smaller reactors, less civil costs, less safety systems but improvements in yield, higher conversions, less or no solvent use are also important along with energy reduction. Improvements to product properties and even novel products that competitors find difficult to match are other potential major benefits. As discussed above, the matching of the process to the processor is key to precision processing. It is also important to recognise that the way a business is run often reflects the processor. For example multi products on a batch reactor with the need to clean between batches usually means some form of campaign operation of the reactor and a warehouse is needed to meet customer delivery demands. The way the business works is matched to the characteristic of the processor. Change the processor to a low inventory continuous reactor and it might be possible to move to just-in-time (JIT) manufacturing with all those benefits. The business operation has been properly matched to the new processor characteristics. General 2009-10-03T17:14:27Z kilomentor Purification by Reaction: An Example of Removing a Serious Impurity by Purifying Starting Material http://kilomentor.chemicalblogs.com/55_kilomentor/archive/1057_purification_by_reaction_an_example_of_removing_a_serious_impurity_by_purifying_starting_material.html Kilomentor has suggested in other blog entries, that process chemists think ahead of time about possible impurities that could contaminate their products arising from impurities in starting material when these impurities are unlikely to be removed by the downstream reactions or process step separations. An example of such technology has appeared in a US patent application, US2005/0250961A1, authored by Muddasani Pulla Reddy, The application has since lapsed. The invention teaches methods for performing the Friedel-Craft reaction between glutaric anhydride and fluorobenzene catalyzed by aluminum chloride, so that even when standard commercial fluorobenzene containing 300-700 ppm of benzene is used as starting material, the isolated product will contain less than 0.05% of the unfluorinated, 4-benzoylbutyric acid as impurity in 4-(4-fluorobenzoyl)butyric acid. This 4-(4-fluorobenzoyl)butyric acid is an important intermediate for some syntheses of the medicine ezetimibe.The full disclosure does not explain how or why the procedures taught decrease the amount of the defluorinated impurity. The document in fact does not provide a comparative example of 4-(4-fluorobenzoyl)butyric acid made according to the prior art literature that shows clearly by contrast the improvement taught. All that is said is that benzene is about 5 times more reactive than fluorobenzene to Friedel-Craft acylation. The teaching does not describe how the benzene reacts, what product the benzene forms or what stage in the process the impurity(ies) is(are) removed.The requirement of a halogenated solvent such as methylene chloride or dichloroethane suggests to Kilomentor that the halogenated alkane solvent may react selectively with the benzene producing products that are more easily removed in one or more of the isolation steps. It appears that in each of the patent documents specific examples one-half the fluorobenzene is mixed with aluminum chloride and halogenated solvent before adding glutaric anhydride. In this mixing period before glutaric acid is introduced, the benzene impurity could have reacted with chloroalkane solvent catalyzed by the aluminum chloride. General 2009-08-27T17:23:38Z kilomentor The Yoshida Tag Methodology and the Kilomentor Synthesis Philosophy http://kilomentor.chemicalblogs.com/55_kilomentor/archive/1051_the_yoshida_tag_methodology_and_the_kilomentor_synthesis_philosophy.html The Kilomentor philosophy or strategy of process development ranks processes not only by the number of reaction steps and their anticipated approximate yields but additionally and with higher priority by the anticipated simplicity of the reaction work-ups and purifications expectd as part of the process step. A proposed ranking system for isolations is provided in an earlier Kilomentor blog. A consequence of this selection principle is that process steps which involve phase switching as taught be Curran tend to be preferred over steps in which starting materials, by-products, and co-products are not so easily separated. In particular, intermediates that are carboxylic acids or amines and that can be separated by acid-base extractions are preferred intermediates as contrasted to neutral intermediate substances. The same philosophy is taught by Jun-ichi Yoshida, Kenichiro Itami and coworkers in their article, Chem. Rev. 2002, 102, 3693-3716, Tag Strategy for Separation and Recovery. The key difference is that these authors are thinking about tagging products, reagents or by-products to simplify the separation in a process that has already been chosen and is just being optimized. In contrast, Kilomentor would be making the choice among different proposed paper syntheses based, to a fundamental extent, upon whether the intermediates in the process steps are easily separable because they are naturally ‘tagged’ by the functional groups they bear. These naturally tagged intermediates are those intermediates containing (most frequently) acidic and basic functional groups which enable simple acid-base extraction separations. Put another way, Kilomentor uses the concept of phase tags to select a preferred route, while Yoshida teaches the contribution tagging can make to improving the ease of separation in a previously selected route. Also, while Yoshida’s review encompasses phase tags that are contained within or can be attached to, any one of reagents, co-products and by-products and not just the desired products, Kilomentor only looks at whether the desired intermediates themselves contain or could contain some tag. Yoshida sees tags as being similar modus operandi to protecting groups. Typically a protecting group is introduced into a molecule in one step, protects its corresponding functional group during some transformation(s) and then is removed in still another step. The protecting group protects a function group from undesired reaction. A tag is introduced intentionally before a process step, simplifies the isolation of pure product from the step and is subsequently removed. The tag is not an inherent part of the process but a functional add-on. Yoshida does not completely ignore the kind of tagging Kilomentor recommends but calls it the masking of tags. To quote: “Another approach to this issue is masking of tags (Scheme 7). In some cases, tags are masked so that tagged molecules retain their natural phase affinity. Thus reactions can be conducted under homogeneous conditions in organic solvents. After the reaction, however, the tag is converted into its active form to effect separation of the tagged molecule from untagged molecules. A typical example of this case is acid/base extraction. For example, an ammonium ion tag is unmasked by protonation of the corresponding amine tag and the tagged compound is extracted from the organic phase into acidic aqueous phase. Remasking the tag by neutralization enables reextraction of the tagged compound into the organic phase (phase switching). In such a case, the tag is not a simple tag, but a phase–trafficking tag or “phase shuttle” because it facilitiates the back and forth movement of molecules from one phase to another.” This explanation feels contrived because it makes the simple, complex, but if we must make reference to it, using this nomenclature, what Kilomentor is recommending is that, in making the initial route choice, higher consideration should be given to processes containing intermediates that comprise a phase-shuttle. General 2009-08-16T05:08:54Z kilomentor Understanding Distillation is still important for Chemical Process Development and Organic Synthesis At Scale. http://kilomentor.chemicalblogs.com/55_kilomentor/archive/1038_understanding_distillation_is_still_important_for_chemical_process_development_and_organic_synthesis_at_scale.html One of the non-obvious outcomes of structural identification using spectroscopy (particularly NMR and MS) is the decrease in experience with distillation, among organic synthetic chemists. Because even an inexperienced student researcher can now routinely identify a substance using milligrams of pure compound, flash chromatography high performance liquid chromatography or preparative gas chromatography can replace old-fashioned distillation for making samples for identification in most steps in a laboratory. Corroborating evidence of this trend is the virtual disappearance of boiling point as part of physical characterization in the chemical literature. Finally, as the catalogues of suppliers of chemical intermediates become thicker, more of the early steps in syntheses can simply be purchased. It is these lower molecular weight entities that used to be prepared and distilled in the lab. Standard distillation has an inherent problem that became further reason to abandon this technology in the laboratory. Unless a distillation column receives an input of heat that at small scale is usually supplied by vigorously boiling the liquid mixture in the still pot It cannot achieved liquid-vapour equilibrium. Thus on the lab scale, there is hold-up of distillate that is inevitably lost and this can be up to about 30%. Compounding this inherent difficulty is the annoyance that all glass laboratory distillation equipment is expensive and does not easily accommodate the particular amount of crude that you may have. That is, the amount of crude distillate must be selected to fit the size of the physical assembly that you have and not the other way round. Fractional distillation assemblies are not available in your lab drawer in 100 ml, 200ml, 500ml, 1 L 5L and 15L sizes, like round bottom flasks are! The days when distillation units were patched together with hardened cork or rubber stoppers between pieces of blown glass are long past. Now all glass assemblies are a single piece or pieces joined with ground glass joints. Because of this, now more than ever, distillation assemblies for vacuum distillation often use the same equipment as for simple distillation and don’t appreciate the special requirements imposed by the low-pressure condition. The boiling point of the fluid mixture in the still pot of a distilling assembly depends upon the pressure at the surface of the liquid, not the pressure recorded on a pressure gauge, which may be and usually is, closer to the vacuum pump. For pressures from 760 mm down to 15 mm of mercury, a regular distillation flask is satisfactory. For pressures below this level, and particularly pressures 2 mm or less, the diameter and location of the vapour port linking the distillation portion of the apparatus to the condensing portion becomes very important. This is not usually understood. The increment in vapour pressure at the surface of the boiling liquid, over and above the vacuum pressure reading taken at the receiver is proportional to the length and inversely proportional to the fourth power of the diameter in centimetres of that side arm plus any other narrow portion of the path between still pot and condenser. As Hickman, inventor of a famous low pressure still, pointed out many years ago, an experimenter may go to great lengths to produce a vacuum less than 1 micron, yet fail to benefit properly from his/her efforts because the pressure necessary to drive vapours from the distilling through neck and side arm is from 1 to 4 mm. The factor limiting te available vacuum is often the distilling assembly shape not the quality of the vacuum pump or vacuum pump oil. Take for example a vacuum distillation using a Liebig condenser attached by a ground glass joint to a simple distillation flask. A Liebig condenser has a narrow bore tube running inside a wide bore tube that serves to supply condenser water to the outside of the narrow bore tube. The vacuum is applied through the length of the condenser down the height of the distilling flask and column to the boiling liquid surface. Because the Liebig condenser tube is both long and narrow, it must add a large pressure to the reading of the vacuum guage at the receiver. Low pressure distillation is impossible. Bumping from super-heating of the still pot liquid is a great time waster and many solutions have been offered. When distilling at atmospheric pressure boiling chips can be used or a bleed from a glass capillary but the former fails under vacuum and the latter adds to the pressure and is really co-distillation with the gas being bubbled. A very old but effective solution is to place glass wool into the flask so that it is partly above the liquid surface. Using this method magnetic stirring is not possible and an oil bath is the preferred source of heat to avoid over-heating at the flask wall. When using ground glass jointed flask the glass wool must be inserted carefully to make sure that no wool strands get trapped on the ground glass joint where it will destroy the vacuum seal. When magnetic stirring is used anti bumping is usually not needed unless the stirring fails. When performing a fractional distillation in a packed column some people do not realize the importance of a near perfect vertical positioning of the column above the flask. Fractionation is achieved by the equilibration of rising vapours and the descending liquid film and that equilibration is a function of the surface area and thickness of that film. If the column is tilted the returning liquid is not spread over all the walls and packing and where it does run it is in a thicker less effective layer. In a tilted fractionating column the height equivalent of a theoretical plate is longer so there is less rectification. With low pressures where the pressure drop in the apparatus is damaging the effective rate of distillation, tipping the entire apparatus to the side can actually help by reducing the height that the gas must be driven to, to reach the side arm! This amounts to a patch when you are stuck with inadequate apparatus for a low-pressure distillation. General 2009-06-25T15:12:58Z kilomentor Chemical and Pharmaceutical Process Development Update Materials from the Earlier Kilomentor Articles (September 2007-September 2008) http://kilomentor.chemicalblogs.com/55_kilomentor/archive/1037_chemical_and_pharmaceutical_process_development_update_materials_from_the_earlier_kilomentor_articles_september_2007-september_2008.html I have seen a large increase in traffic to this blog after I reviewed the titles of some articles from April 2007 to September 2007. Therefore, I continue with this updating.Search engines have the shortcoming that they give higher rankings to recent material. This is appropriate for news, fashion and opinion but not nearly as appropriate for scientific educational materials. Thus with the passage of time it becomes harder to locate pertinent kilomentor blogs. To counteract this I am providing a review of the titles of some of the early Kilomentor articles. Regular readers can of course find all my articles in the Kilomentor archives in the kilomentor blog. The Use of Mesityl Oxide as a Dehydrating Agent by the Chemical Reaction of Water catalyzed by Primary AminesExtraction and Phase Switching Hydrolysis-Purifying Phenols.Avoiding the Impurity from Hell:(chemical process development; purification of organic chemicals; process optimization; impurity identification in organic synthesis)Reactions “On Water” (immiscible water makes a great heat sink)Kilomentor moves the discussion from Steam Distillation to other Co-distillationsPolymorphism in Organic Syntheses, Process Development and FormulationInverted Filtration: A chemical synthesis laboratory technique particularly helpful at 5-10 litre scales.Recovering More Product by Crystallization in Organic Synthesis:Trituration with a modified water phase as a potential Chemical Process Development MethodThe Complete Blog for the Preparation of Pharmaceutical SaltsKilomentor weighs in as “Pharmaceutical Manufacturing Goes Green”.Another Way to Separate Phenolics by Crystallizing of Co-crystals?Green /Recyclable Solvents: Low Vapour pressure compositions for storage and recycling of solvents that are highly volatile or gaseous at room temperatureSymmetrical Bis-N,N-(3-nitrophenyl)urea: A Super Co-crystal Former that might have applications in Product Purification.The Importance of the Molecular Weight of a Salt Former in choosing a Pharmaceutical Salt (the choice of salt is not as broad as you think)Pamoates or Embonates: crystalline Pharmaceutical Salts or Derivatives for Isolation and PurificationBiocatalytic Methods of Enantioselective Synthesis in Pharmaceutical Process DevelopmentSeparation by Substantial Differences in Chemical Reactivity of the Same Nominal Functional Group.Sulfate Pharmaceutical Salts General 2009-06-25T14:57:53Z kilomentor Kilomentor suggests some crazy purification ideas http://kilomentor.chemicalblogs.com/55_kilomentor/archive/1033_kilomentor_suggests_some_crazy_purification_ideas.html Reently Amelia sent Kilomentor a question. She wrote: Hi, I would like to know what is a good method to remove DMF from my compound. My compound is very polar (with acid and 2 phenol groups)and might not be very soluble in ether. As the compound is a sticky solid, I suspect a tiny amount of DMF is trapped in the solid as I tried freeze-dry vacuum and passing through silica gel column. Do you have a good idea? Thanks. It is always more difficult to recommend a purification strategy without knowing the full structure. At the same time there is usually good reason for confidentiality.You say, Amelia, that you think your compound might be insoluble in diethyl ether. If so then triturating with such antisolvent could be an excellent method to remove traces of DMF if present. DMF is miscible with diethyl ether so if your product is essentially insoluble the separation could be excellent and it would certainly be simple and rugged. If too much of your product is dissolved a mixture of ether and hexanewould further reduce the solubility of the diphenolic acid. Another off the wall idea is from the Kilomentor article “Another Way to Separate Phenolics by Crystallizing of Co-crystals?” 21 March, 2008. Carboxylic acids that are also phenols might be expected for structural reasons to form quite insoluble co-crystals from dry dioxane. The article points out an exception that ortho hydroxy benzoic acids would not be expected to work. Yet again, if the DMF is tightly complexed to your compound and this is suggested by the failure of freeze drying and passing it through a silica column you might need to make a hydrophobic derivative in order to remove the hydrogen bonds of that hypothetical complex. Complete silylation of your compound would attach at least three trimethylsilyl groups. The derivative would become more and could become soluble in hydrocarbon solvents. Hexane and acetonitrile are immiscible phases and DMF would I think prefer to be in the nitrille phase while your persilylated product may now prefer the hydrocarbon. Kilomentor has written an article about catalysts for quick persilylations and hydrolysis back to product would be facile. Finally, if your compound is soluble in benzene, you might try adding some sodium iodide to a solution in benzene or other similar solvent. in J. Am. Chem. Soc. 82, 2895 (1960) it is reported in footnote a of Table III that DMF and sodium iodide form an insoluble complex from benzene in a molecule ratio of 1:3! I do not know whether this is actually true and I have never tried this so I would test it out with some DMF in benzene but none of your compound first. General 2009-06-03T19:47:33Z kilomentor Recycling Mother Liquors in Chemical Process Development to Raise Yields and Reduce Solvent Usage http://kilomentor.chemicalblogs.com/55_kilomentor/archive/1031_recycling_mother_liquors_in_chemical_process_development_to_raise_yields_and_reduce_solvent_usage.html 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.Smiths, A Model for Mother Liquor Recycle in Batch Processing, Org. Process Research & Development 1997, 1, 165-167. Kilomentors discussion here is indebted to this paper. When crystallizing or recrystallizing product (i) from a reaction mixture, r (ii) a partially treated work up solution, or (iii) from a crude solid isolate, none of the impurities’ concentrations exceeds their solubility product in the solution. That is, more of each impurity could be dissolved in the filtrate without precipitating any solid. The solution has the potential to extract more of the impurities from the desired product. Besides having 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 when the product is dissolve in a first solvent and then the solution achieved diluted with a second solvent before awaiting crystallization. In general it is crystallization achieved with the assistance of cooling 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 Iinfinite = I1 X 1/(1- x)Thus with x=0.5 and the level of impurity in the first batch I1 = 2% Iinfinite = 2% X 1/(1-0.5) = 4%Or with x=0.7 and the level of impurity in the first batch I1 = 3% Iinfinite = 3% X 1/(1-0.7) = 10%Or with x=0.6 and the level of impurity in the first batch I1 = 0.8% Iinfinite = 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 Iinfinite = 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 not of course 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 % 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 bes 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 place 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, have been stored for a validated time under validated conditions. General 2009-05-18T09:26:56Z kilomentor