Isolating More Product in Organic Synthesis by Crystallization when the Most Significant Minor Impurity is More Polar:

Trituration with a Modified Water Phase as a Potential Chemical Process Development Method

A reaction may proceed quite well to give an 80% yield of the desired product but be very difficult to work up if it is a mixture of neutral compounds. In this situation, acid-base extraction cannot help to obtain some partitioning between organic and aqueous phases.

 Furthermore, most often the two compounds making up the reaction mixture are both essentially insoluble in water.  When there is 20% by weight of impurity, even when you can find a solvent that gets the major compound to selectively crystallize, the recovery is usually quite poor, simply because by the time you have crystallized 60% of the major compound the mother liquors are a 1:1 mixture of desired and undesired compounds. At this point, the rate of crystallization normally becomes impractically slow. The crystallization has essentially stopped. 

Usually, thin-layer chromatography in more than one solvent system can quickly tell you whether the main impurity, which most probably is the one blocking the crystallization, is, by and large, less polar or more polar than the desired major component.  When the minor component is the more polar, what we intuitively would like to do is triturate with water, modified so that it can dissolve more of the mixture, hoping that the additional material dissolved into the water-rich phase will be disproportionately the more polar impurity component. 

A co-solvent for water to be effective must prefer to mix with the water rather than forming an oily phase with the products.  Only experimentally can we find something guaranteed to work, but perhaps KiloMentor can propose a rule of thumb, that could increase the likelihood of success: this aqueous phase modifier should be completely miscible in all proportions with water.  If a diluent is only partially miscible with water it is more likely that when mixed with the neat reaction oil it will simply migrate into the oil. 

The most lipophilic solvents that are completely miscible in all proportions with water are acetone, methyl ethyl ether, methyl acetate, and t-butanol. The lower homologs of each of these function group types will also be completely miscible. That is: methanol, ethanol, propanol, and isopropanol are also completely miscible and could also be used as diluents. For esters, ethyl formate is not completely stable in water so it cannot be used. Acetonitrile is completely miscible but propionitrile is not. Nitromethane is not completely miscible, while dimethylformamide, N-methyl formamide, formamide, DMSO, and pyridine are.

In addition to adding small quantities of these solvents to a large excess of water to increase the leaching power of the polar phase, recrystallization from the less polar of these at least: acetone, t-butanol, pyridine or methyl acetate by the gradual addition of water could be fruitful.

Once the level of the impurity is reduced below 10% from the 20% range, crystallization in general can be expected to give a superior recovery.  From a mixture containing just 10% impurity, one could crystallize 80% before the mother liquors would be 50:50 product: impurity.  

Even at scale, a reaction mixture can be freed of organic solvent by concentration in the presence of a water phase to give a reaction product oil as an oil in water. The aqueous phase modifier could be added to this mixture.

When trituration is not working an alternative is to dissolve the compounds into isooctane and extract with some mixture of acetonitrile, water, and ethylene glycol.

Second Crops of Crystals are Easily Available from a Gas-Expanded, Mixed-Solvent System

 One of the advantages of performing crystallization of a substrate from a single solvent by cooling as opposed to causing crystallization by diluting a first solvent with a miscible anti-solvent is that one can try for a second crop simply by reducing the volume of the filtrate, recool the reduced volume to yield more solid. One can do this because the solvent composition isn't being modified. This advantage would be retained if the crystallizing solvent is a lower-boiling binary azeotrope.

In the alternative, where an anti-solvent is being mixed in to create the required supersaturation considerable tedious work is required to remove all the anti-solvent and concentrate that first pure solvent before a second crop can be attempted.

But if the anti-solvent is a gas under plant conditions, this re-establishment of a single solvent and its concentration is simple. Take for example a mixed-solvent recrystallization that was originally being performed by dissolving the substrate in toluene and then decreasing the overall solubility by adding hexane and then cooling. Suppose instead one dissolves the substrate in toluene cools the solution but instead now bubbles in butane gas. The butane will dissolve in the toluene but the solubility of the substrate will decline in just the same fashion that occurs by adding hexane. The product will crystallize. You cannot filter using a vacuum since this would drive off the butane. Filtration must instead be done by pushing the slurry through the filter cloth with pressure. When the crystallized substrate has been caught on a filter, evacuating the system will easily remove the butane from the filtrate leaving the toluene which can be further concentrated. A second crop can be isolated by repeating the gas expansion with butane.

Furthermore, although mixed solvents are not normally recycled and reused in multi-purpose fine chemical plants, Gas-expanded liquids are an exception since simple distillation rather than fractional distillation is sufficient to do the job.

Any mixed solvent recrystallization that uses cyclohexane, hexane, heptane or petroleum ether can be rejigged as a gas-expanded liquid mixed solvent recrystallization using butane thereby enabling taking a second crop of crystals to raise the yield.

Pyridine-Water Selective Precipitation with Pyridine Recovery

 

Dissolution of a solute in a water-miscible solvent followed by crystallization or precipitation of the solute by gradual or portion-wise addition of water is an established method of separation and purification.  It is frequently applied to the separation of mixtures of different polymers.

 Solvents commonly used are methanol or ethanol. When lower alcohols are used with small molecule substrates it amounts to the same thing or at least strongly resembles crystallization from mixed alcohol-water solvent. When more expensive organic liquids are used as solvents to be practical at scale there must exist a cheap straightforward method to recover that solvent.

Pyridine is miscible with water in all proportions. It can be used to purify solutes or separate mixtures of solutes by the gradual addition of water so as to cause fractional precipitation. Typically one starts with something like a mixture of 5 parts pyridine and 1 part solute which can be warmed to dissolve what may be a solid or oily mixture; then, one gradually adds water with vigorous stirring until faint turbidity persists. At this point, optionally, a small amount of pyridine (a drop or two at the laboratory scale) can be added to just clear the haziness. Crystallization may begin after some time. In Aleksandra Smoczkiewiczowa and Jan Bielawny's paper in  P. Zakresu Towarozn. Chem.,Wysza Szk. Ekon. Poznaniu, Zesz. Nauk., Ser. 1 1970 No. 36, 149-62, it says that their cholesterol oxidation mixture was dissolved in a 5-fold amount of pyridine and by addition of water fractionally precipitated about 15% androstenolone acetate.

 Pyridine is somewhat expensive as solvents go. No obvious simple means to recover the pyridine when the precipitation is complete makes this an infrequently used methodology  Pure pyridine cannot be recovered by distillation because pyridine/water forms an azeotrope. Fortunately, there is a technical trick that does achieve this separation. Pyridine is not particularly soluble when sodium hydroxide is dissolved into the aqueous pyridine so the addition of enough caustic causes pyridine-water to separate into two phases. The pyridine layer can be separated and the mostly- layer discarded.

Exhaustive Digestion as a Simple Prelude to High Yield Crystallization

 

This article is about the technique I call ‘exhaustive digestion’. This is a phrase that I used in my blog entitled, Getting Better Recovery from Crystallization. In this blog, I make the point that chemists scaling up a laboratory process often fail to do adequate preliminary purification of a solid and as a consequence get a lower recovery from their crystallization than is possible if a preliminary treatment were done. I proposed digestion or trituration as pretreatments before crystallization. I don’t know whether there are any widely accepted differences in meaning between the words digestion and trituration but, when used in my blogs, ‘trituration’ can be understood to apply equally to oils or solids while ‘digestion’ will only be applied to solids. Second, ‘trituration’ can be done with either hot or cold solvent while ‘digestion’ and particularly ‘exhaustive digestion’ as described hereunder is to be done with hot, boiling liquid, usually a rather poor solvent for the desired product. 

Exhaustive digestion is related to swish trituration which I have written about earlier. The difference is that the swish trituration employs its anti-solvent system at ambient temperature and does not measure the boiling point depression of the liquid to assess the extent of purification. 

In the old literature, the progress of purification by digestion on the laboratory scale was followed by observing the change in the boiling point of the digesting solvent or solvent mixture using a Beckmann thermometer, which is a thermometer that can measure differences as small as one-tenth of one Centigrade degree. I don’t know how long it has been since I have seen anyone use a Beckmann thermometer but, at least in my undergraduate Phys. Chem., (over 50 years ago) it was done quite often. The scale on a Beckmann thermometer is only 10-20 degrees but its range can be adjusted by removing or adding mercury to the column of mercury used for measurement by moving mercury back and forth from an attached mercury reservoir. Today a digital thermometer is more likely to easily achieve the same or better precision of measurement without managing liquid mercury.

I will illustrate exhaustive digestion by quoting from an experiment taken from Laboratory Technique in Organic Chemistry by Avery Adrian Morton, First Edition, McGraw-Hill, 1938,  pg. 128-229.

“The apparatus consists of a tube or flask of such size that a large part of the bulb is covered by the solid material being extracted, a thermometer graduated in tenths of a degree, a reflux condenser, and a water or oil bath. Place the sample in the container, insert the thermometer so the bulb is immersed in or covered by the sample, and add solvent to cover the solid and the thermometer bulb. The solvent is usually one that will dissolve impurities without appreciable quantities of the desired material. Petroleum ether or ligroin is often suitable. A mixture of solvents may be employed without affecting their utility in this experiment, as long as the composition of the mixture is not varied. Reflux the solution [I think slurry is intended] using a water or oil bath as a source of heat. After about 20 minutes the temperature has reached a constant level. Usually, no trouble will be experienced from superheating as long as a solid phase is present, although a little agitation with the thermometer is sometimes needed. Filter either by pouring into a Buchner funnel or by using a filter stick. Add more of the same solvent, reflux once more, and observe the temperature after equilibrium conditions have been reached. Continue the operation until the temperature of two or more successive operations is identical. The more soluble impurities have now been removed, and the solution contains only the pure compound or the compound with [less soluble type] impurities that have not been entirely removed…. The operation may be continued if desired until all the product has been dissolved. A change of solvent [may be implemented at some point for further purification]….. Constancy in the boiling points of successive portions constitutes further evidence of the purity of the material, whereas a drop in the boiling point is evidence of the exhaustion of still another component. Usually, the final portions of exhaustive digestion are pure materials.”

Continuously measuring and recording the changes, in real-time, of the boiling point without any actual sampling makes this an early application of Process Analytical  Technology (PAT). The improvements in the size and sensitivity of temperature measuring devices for following small changes in boiling point under conditions where superheating does not occur deserve more frequent consideration.

Exhaustive digestion if used at scale would require a more rugged method for measuring small changes in the boiling point of the slurry than the old Beckmann thermometer. Fortunately, modern digital thermometers meet that need.

Exhaustive digestion, similar to swish trituration, may profit from using either water-rich or hydrocarbon-rich binary azeotropes,  as the anti-solvents, as the desired product’s solubility dictates. Some are suggested in the following list:

97.0% water 3.0% acetic acid azeotrope bp 76.6ºC

91.0% water 9.0% benzyl alcohol azeotrope bp 99.9ºC

87.1% heptane 12.9% water azeotrope bp 79.2ºC

94.4% hexane 5.6% water azeotrope bp 61.6ºC

95.5% hexane 4.5% allyl alcohol azeotrope bp 65.5ºC

97.0% hexane 3.0% 1-butanol azeotrope bp 67.0ºC

91.5% cyclohexane 8.5% water azeotrope bp 69.8ºC

83.7% acetonitrile 16.3% water azeotrope bp 76.5 C

72.9% allyl alcohol 27.1% water azeotrope bp 88.2ºC

66.0% allyl cyanide 34.0% water azeotrope bp 89.4ºC

77.5% formic acid 22.5% water azeotrope bp 107.1ºC

Methods for Forming and Crystallizing Organic Salts particularly Pharmaceutical Salts

 

Most Common Method for Forming Salts

Mixing  stoichiometric proportions of acid and base in a suitable solvent; then

1. Cooling to a lower temperature
2. Adding a miscible anti-solvent or liquefied gas
3. Adding an immiscible  or partially miscible anti-solvent
4. Drowning out in a miscible anti-solvent
5. Slowly adjusting the pH
6. Use of the common ion effect to decrease the salt’s solubility

Other Methods

1. Exchange of Ammonium Salt with Nonvolatile Base

An exchange between ammonium salt and another non-volatile cation to give a more insoluble salt of an anionic drug.

2. Exchange of formate or acetate or thiocyanate salt with a non-volatile acid

3. Double Decomposition Reactions

Metathetical reactions between a salt solubilize by the presence of a particular cation and a second salt solubilized by the presence of a particular anion giving one insoluble salt and one soluble salt from which the insoluble salt is recovered by filtration and washing.  

The use of metal salts of 2-ethyl hexanoic acid for the basification of organic acids is an example.

Methods for 

1. Direct addition

Addition of a solution of the salt-forming acid or base slowly into a solution or slurry of the pharmaceutical product whose salt is sought.

2. Inverse addition

Addition of the pharmaceutical salt capable species, either as a solid or as a solution into at least a full equivalent quantity of the salt-forming reagent.

3. Slow addition of poorly soluble neutral species by extraction

Extraction of the pharmaceutical salt capable species from a Soxhlet extractor by hot solvent and quench of the extracted species by an excess of the salt-forming reagent in the boiler of the extraction apparatus.

4. Impinging Streams of Salt Solution and Anti-solvent

5. Impinging Streams of Acid and Base
   

Methods for Precipitating Pharmaceutical Salts

Crystallization by Diffusion of an Ant-iSolvent

Dissolution of the salt in a mixture of solvents followed by the addition of an immiscible third solvent creating two phases in both of which the salt is insoluble.

Partial Evaporation of a Single Volatile Solvent

Partial Evaporation of a Mixed Solvent System

      Dissolving the pharmaceutical salt in a mixed solvent of a less volatile poorer solvent and a more volatile better solvent and then removing the better solvent by distillation of evaporation..

Lyophilization/Inorganic Salt Removal

Lyophilisation (freeze-drying) of a solution. Dissolution in methanol and filtration to remove inorganic salts.

Slurry to Slurry

Transformation from a slurry of the slightly soluble pharmaceutical acid or base candidate into a slurry of the desired salt form until a method of solution analysis shows equilibrium.

Precipitation by pH Adjustment

Dissolving of the pharmaceutical candidate in a partially aqueous solution followed by adjustment of the pH gradually by the hydrolysis of a solution component. For example: methyl acetate and base giving acetate and methanol; ethyl carbamate and acid giving ammonium carbon dioxide and ethanol.

Solvent Expansion

Dissolving the pharmaceutical salt or making the pharmaceutical salt in solution and then exposing the solution to a volatile anti-solvent so that the composition slowly becomes more insoluble

Diphenylphosphine Oxide Containing Compounds: Intermediates almost guaranteed to be Crystalline

 

 Stuart Warren, in an article in Accounts of Chemical Research 11 (11) 401 (1978), wrote that almost all diphenylphosphine oxide-containing compounds are highly crystalline white solids. KiloMentor is, therefore, proposing the use of compounds containing the diphenylphosphine oxide substructure as one of the preferred intermediate types in ‘paper’ syntheses.

It is well known that the reaction of a primary alkyl halide with triphenylphosphine produces a quaternary phosphonium salt that is both an ionic salt and crystalline. Hydrolysis of such a compound in aqueous base liberates benzene and provides the phosphine oxides. These compounds in turn can be alkylated with other alkyl halides using butyllithium and TMEDA as co-solvent. [J. Chem. Soc. Perkin Trans. I, 550 (1977)] Warren predicts that these also will be highly crystalline solids.

The KiloMentor strategy for paper synthesis route design emphasizes the advantages of selecting a route that can easily be scaled up. To be preferred, intermediates need to have an increased likelihood of being easily separated and purified, preferably by acid-base extraction. This is proposed to be an overarching advantage over competing routes, whose intermediates almost always have to be purified by crystallization. The problem with these competing routes is that the crystallizability of an intermediate from a paper synthesis cannot be dependably predicted.  

Besides those intermediates, purifiable by extraction, other intermediates would also be preferred if, even when still unknown and existing only ‘on paper’, they contained a functional group that could pretty well guarantee they would be found to be crystalline. There are not many of these and they are not celebrated for this property. Usually, the ease of crystallization for a compound depends upon the entire molecular structure and cannot be predicted, but diphenylphosphine oxide appears to be one that should come with a guarantee.  

Impinging Jet Micromixing to Solve the Problem of Small Crystal Size without Milling.

CA2044706, Crystallization Method to Improve Crystal Structure and Size expired June 14^th 2011 in Canada and the family member US5314506 expired May 24^th 2011 in the United States. The invention addresses the general problem, how to obtain a reproducible micronization of a pharmaceutical compound without milling.

Crystallization is a process step that has for a very long time has only been scaled up empirically.  

One standard crystallization procedure 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 can be modified by 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. In order to get the smaller crystals, preferred for their greater bioavailability, the saturated solution needs to be added into the anti-solvent in order to get very rapid formation of many tiny seeds. Using this reverse addition methodology 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 of these concentration gradients and heterogeneous fluid environment both 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 solved, there is a thermal gradient and in any case the crystals are larger with the slower process. The characterisrtics of size, purity, and stability are difficult to control.

The technology taught in CA2044706 pumps both solution and anti-solvent as two impinging jets of fluid that because of their small volumes and high velocities create almost instantly a region of high intensity micromixing where they collide. Once the fast crystallization has occurred, the mixture of solution and anti-solvent 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 heterogeneous 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 the parameters come within engineering control.  Because of this, the surface area, crystallinity, stability and purity can be optimized. Because a milled quality material is available directly, a step is saved and the noise, dust, yield loss, equipment cost and worker exposure hazard of milling are by-passed.

The entry of this manufacturing technology into the public domain in 2011 was a significant development. 

CA2349136 is still more interesting. This is the same inventive idea but incorporates a reaction involving elements from each of the two impinging liquid jets. For example this could be used to form a salt from the free base form of a pharmaceutical in one stream and a solution of an appropriate acid in the second stream. Thus we can intuit the formation and instantaneous crystallization of a desired salt and its crystallization into micro crystals.  The US equivalent US6558435B2 expired May 6^th 2003. The Canadian attempt became a dead application August 15^th 2007.

Crystallization and Recrystallization from Polar Water-Miscible Organic Solvents

Dissolution for Recrystallization by Adding Small Amounts of Water to Increase Solubility in a Water-Miscible Organic Solvent

It is well known that small amounts of water have a marked influence on the solubility of many solutes when mixed into less polar organic liquids. An example is the difference in dissolving power between well dried acetonitrile and acetonitrile that has picked up just the moisture it gets standing near a steam bath for a few minutes. Years ago, Dr. Renuka Misra, an extraordinary natural products chemist then working at the University of Toronto, demonstrated this to me when I was having trouble doing a particular recrystallization.

 Removing Water from a Solvent Mixture with a Miscible Polar Solvent to Causing Crystallization by Distilling an Azeotropic Composition

Another way to access the solubilizing power of water is with water azeotropes. Co-solvents that form azeotropic mixtures with water can be used to recrystallize polar materials by first dissolving them in the co-solvent assisted with some water and then distilling the azeotropic composition to remove the water as its azeotrope leaving the solute in the less polar, pure organic solvent from which it can crystallize or precipitate, often in excellent yield.

Precipitation and Isolation of Organic Carboxylic Acids, Sulfonic Acids and Sulfinic Acids from Solution or Reaction Media.

Arylmethylisothiuronium Salts

Ionizable acids are intermediates preferred by KiloMentor in organic synthesis schemes because they are more easily separated in pure form whether by extraction of the anions into water or precipitation of insoluble salt compounds.

Arylmethylisothiuronium salts are useful intermediates for precipitating these organic acids, particularly if (i) the molecular target contains another functionality that is sensitive to aqueous alkali or (ii) the entire target molecule is water-soluble. The arylmethylisothiuronium salt reagents themselves are decomposed by aqueous alkali to liberate arylmethylthiols, so conditions must be kept slightly acidic during all operations using them. 

Carboxylic Acids

Carboxylic acids are first converted into sodium salts by reaction with sodium alkoxide in alcohol and then mixed with a solution or slurry of the arylmethyl-isothiuronium halide in alcohol. The salt crystallizes out. It is important for carboxylic acids that the liquid be water-free and the pH not at all basic.  Salts of weak acids such as the carboxylic salts, in the presence of any water, can partially hydrolyze back to free acid and sodium hydroxide which creates a basic solution which then will degrade the isothiuronium reagent. 

The isothiuronium derivative can be formed in water so long as the formation of the carboxylic acid salt is never completely neutralized. This is accomplished by only adding alkali until methyl red changes color. Another literature citation proposes that the neutralization be done to the point of the color change of phenolphthalein followed by the readdition of acid until the color disappears.

Sulfonic and Sulfinic Acids

Salts both of sulfonic acid and sulfinic acid anions and arylmethyl-isothiuronium cation are preferably formed by mixing aqueous solutions of the reagent and the alkaline metal salt of one of these acids. These precipitations can be done in water which gives much higher yields of these crystalline products. Degradation from adventitious base is less likely because for these stronger acids there is no propensity to hydrolyze the salts to create an alkaline solution.

The regeneration of all  the purified acids is done the same way. In a mixture of an organic solvent immiscible with water and water acidified with hydrochloric acid, the isothiuronium salt is added and stirred vigorously. The strong mineral acid partially or completely protonates the organic acid whereupon it dissolves into the immiscible organic layer leaving the regenerated arylmethyl-pseudothiuronium chloride in the aqueous hydrogen chloride mixture. Heating the aqueous acid phase dissolves the regenerated reagent which then crystallizes when the solution is cooled.

The purified organic acid is recovered from the organic solution by any convenient means.

It seems likely that carboxylic acids in these isothiuronium salts can be liberated by the more acidic alkylsulfonic acids; for example by methanesulfonic acid.

It might well be that any O-acid with at least two tautamerically equivalent oxygens could form these derivatives: such as alcohol sulfonic acids, sulfamic acids, or phosphonic acids. This is something that can be explored further. I do not have any information on these.  

Liquid-Liquid Extraction using Hydrotropes as an Alternative to Fractional Crystallization for Purification at Scale

How does one purify a mixture of structurally similar neutral compounds that is about 80% one isomer and 20% the other? If you adopt fractional crystallization the most likely outcome is that you do purify the major compound but the recovery is about 60%. The lost material is in the mother liquors in an approximate 50:50 w/w ratio with the minor constituent.

You could try liquid-liquid partition, even trying several of these in series resembling a rough counter-current extraction. The problem is that there aren’t that many liquid phases that are mutually immiscible and more frequently at least one component of any pair that is immiscible will exhibit poor solubility for most of the multifunctional organic compound mixtures that you want to separate. Yes- water and hydrocarbons are immiscible but neither one dissolves most organics well. Yes- acetonitrile and hydrocarbons are immiscible, but most organic mixtures do not partition competitively between them. Yes, hydrocarbons and perfluorocarbons are immiscible but again distribution between them is usually overwhelmingly into one or the other. Then there are less well-known ones such as MIBK/sulfolane which might be promising, but these are few.

What is needed is a way to modify water so that it has an increased capacity to dissolve organic compounds of interest while still remaining substantially immiscible with those common organic solvents which also have a good ability to dissolve a target mixture. This is what hydrotropes can do.

Two important strengths of the methodology: (i) the solubilization capacity of the hydrotrope is a strong function, usually exponential, of the hydrotrope concentration and 
(ii) mere dilution of the hydrotrope with water is enough to recover dissolved materials.

Water-Organic Solvent Mixtures for Crystallization or Recrystallization

It is well known that small amounts of water have a marked influence on the solubility of many solutes when mixed into less polar organic liquids. An example is the difference in dissolving power between well dried acetonitrile and acetonitrile that has picked up just the moisture it gets standing near a steam bath for a few minutes. Years ago, Dr. Renuka Misra, an extraordinary natural products chemist then working at the University of Toronto, demonstrated this to me when I was having trouble doing a particular recrystallization. Another way to access the solubilizing power of water is with water azeotropes. Co-solvents that form azeotropic mixtures with water can be used to recrystallize polar materials by first dissolving them in the co-solvent assisted with some water and then distilling the azeotropic composition to remove the water as its azeotrope leaving the solute in the less polar, pure organic solvent from which it can crystallize or precipitate, often in excellent yield.
For example suppose you want to recrystallize a compound that dissolves in acetonitrile so long as some water is added. Acetonitrile/water have an azeotrope with bp. 70.6 C; five degrees less than acetonitrile itself. Slowly distilling this water/acetonitrile solution will remove this azeotrope leading the pot solution itself towards pure acetonitrile. The compound will start to crystallize at some point in the distillation.  

Crystal Engineering-Optimization of a Generic Drug Synthesis

Improved Crystallizability of Intermediates

A generic version of a drug is often prepared following different chemistry from that used by the originator. This may arise because some of the intermediates in the originator’s process may be still protected by patents while the drug substance itself can have become free to use. so the generic route must proceed by a new route that avoids the patented intermediates. Such a process would have been worked out for the API provider by its chemists. Although the route may be ‘optimized’ according to what can be done in the laboratory, it is not optimized for the scaled up version. One of the areas where improvements can be made without changing the overall chemistry including the trace solvent analysis, is to make improvements in the efficiency of crystallization of isolated intermediates.

By this I do not mean improvements in the crystallization yield because changes in the crystallization solvent or in the degree of precipitation of the product can have unacceptable effects, in the former case, on the trace solvent analysis and in the latter upon the level of impurities.

I am thinking here of reducing the time for crystallization and filtration. These improvements can be particularly significant for crystallization of intermediates from the early steps of the process where the number of batches of each step can be large. Yet, starting out, synthetic chemists attach little importance to the time spent crystallizing, filtering or drying before they have matured into process chemists.
The size and shape of crystals of a process intermediate are the main factors determining the rate of filtration, the efficiency of washing away impurities, and the rate of drying of the solid.

Crystal Habit Modification for Pharmaceuticals

CA2509796 (WO2004064806A2; US20060122265A1)

PROCESS FOR MODIFYING DRUG CRYSTAL FORMATION

Published 2004-08-05

The patent application teaches a method increasing the bulk density of acicular (needle-like) crystals by cyclical temperature programming of a solid only partially dissolved in a recrystallization solvent.

Generic API manufacturers may be missing out both on a competitive advantage and a cost reducing methodology by not working to control the crystal habits of the general products they manufacture.

CA2509796 (WO2004064806A2; US20060122265A1) is from a family of patent applications filed by Novartis. The alleged invention proposes to use a cycle of temperature fluctuations applied to the recrystallized slurry of a pharmaceutical product to convert needles into more compact solid forms.  The general claims of these applications are unlikely ever to issue. The authors have adopted the strategy of ignoring the prior art rather than trying to distinguish themselves from it.  Novartis is attempting to monopolize something closely akin to the ancient technique called aging, digestion, or Oswald ripening which is known to produce more easily filterable precipitates. This method has been routine in gravimetric analysis for a very long time. I learned it in my undergraduate days reading Inorganic Vogel.

Some additional time ‘ripening’ a product before filtration can more than pay for itself in shorter filtration and drying times. Saving time in a drying step can save plenty of energy. Additionally ripened crystals frequently contain lower levels of impurities. 

Crystallization from a Separation Perspective

Crystallization is the most frequently used method for isolating organic solids. Recrystallization is the most frequently used means to purify them. But this phase switching from a solute in solution to an ordered solid is one of the most unpredictable methods both for isolation and purification in the sense that it is impossible to predict melting point, solubility, or lattice energy much less the comparative values of these for the desired product versus t the most troublesome by-products which one is trying to remove from the reaction mixture from which it was synthesized. This unpredictability is exactly what led KiloMentor to focus on other ways to switch phases to achieve purification in a chemical process chain.

This is not to say that once a certain molecular architecture has been achieved one cannot prove that the target compound is a solid. I am saying first, that no reliable prediction can be made of how to get it separated sufficiently pure that it is not an oily mixture, and second, no reliable prediction is possible of what recrystallization conditions will be needed to purify it from its most predominant and intransigent impurities and, third, what yield of pure product can be anticipated. 

The following generalizations have some logical basis:

The lower the melting point of an intermediate, the more difficult it will be to crystallize. 

There is a positive correlation between melting point and ease of crystallization. 

The presence of impurities in a reaction mixture leads to a melting point depression and contamination of isolated samples of the desired product.  

The extent of the melting point depression depends upon the proportion of those impurities. 

The free energy of crystallization is roughly proportional to the enthalpy of crystallization and this is roughly proportional to the melting point.

The fewer the chemical conformations (the fewer the rotatable bonds) or the more symmetrical the compound, the more crystallizable the compound will be.  

I do not know whether this is latter claim is proven but it seems likely and agrees with some simple observations. Compounds with long hydrophobic chains as part of the structure tend to be lower melting than cyclic substances. Compounds with high symmetry seem to be higher melting than unsymmetrical compounds of the same molecular weight and functional group type (ie t-butanol vs 1-butanol).

This makes sense in physical terms.  There would be more entropic resistance to the crystallization of a molecule that can adopt multiple conformations than to one that because of its cyclic form or symmetry can adopt fewer.  If only one conformation can be accepted into a crystal lattice, the compound with fewer conformations has a statistically better chance of being added to the lattice.  Thus crystallization might be expected to be faster.

Crystallization is accelerated if one has seed crystals and it is for this reason that so much effort is expended to get the first crystalline material.  If an intermediate has never been prepared before one should anticipate the possibility that a considerable effort may be needed to obtain the first solid. The methods adopted to obtain the first batch of material sufficiently pure to crystallize do not need to be scaleable. Making these seeds is a valid use of chromatography in process development.  Column chromatography can quickly and dependably deliver a high-purity material, which should have a significantly enhanced tendency to crystallize.  If a chromatographically purified solid material does not readily crystallize one has good reason for pessimism.

Other classical methods which can lead to that initial crystallization are:

• scratching the flask containing the impure material with a glass rod while cooling the oil
• steam distillation to remove traces of solvent from the oil
• ultrasonic treatment in a sonification bath
• cooling to a low temperature to form a glass followed by slow warming
• trituration with a pure hydrocarbon fraction
• overnight cooling in a sealed vessel (to exclude moisture) in a deep freeze
• formation of a solid derivative, crystallization, followed by regeneration of the compound itself

It is apparent why this should happen if the initial crystallization is being inhibited by small amounts of a particular impurity.

The difficulty with the initial crystallization of a new substance is that two different physical processes must occur in each other's presence. First, initial crystal nuclei must be generated and this usually requires a low temperature AND then, second,  these nuclei must become bigger. This latter requires crystal growth. The optimum temperature for crystal growth is consistently more elevated than the best temperature for nucleation.  It is for this reason it is thought that raising and lowering the temperature or establishing a temperature gradient within the oil or solution can enhance this first crystallization. Seeds formed in one colder region of the oil or solution migrate into the warmer crystal-growth region.  

Once some crystals have been created, even when one performs a recrystallization there are always, it is hypothesized, trace amounts of the crystals remaining that, as seeds, provide a ‘memory’ when the bulk of the material is taken to conditions optimum for crystal growth. This explains a remarkable phenomenon. One form of crystal may reproducibly form from a substance for years but then by chance, a more stable form crystallizes and thereafter it is impossible to obtain any of the first form because there are always seeds around to catalyze the formation of this later-discovered but more stable form.

Coloured compounds which according to their structure should not be coloured are contaminated by small amounts of polyunsaturated impurities.  Charcoaling can remove the colour and at the same time often assist that initial crystallization.

Crystallization is an art. There are the virtuosos and then there are the rest of us.

Low-Temperature Crystallization

In the laboratory, crystallizing and then reducing the temperature of the crystal slurry to below zero and filtering below zero is quite likely to fail. The reason is that, at the laboratory scale, working with one's hands, it is difficult to maintain an inert atmosphere over the cold liquid and over the filtered crystals. This causes moisture to condense into the crystallizing mixture and onto the solid already collected on the filter funnel and this can lead to outright failure, oily crystals, or a solid that melts away on the filter or dissolves in the wash liquid.

At scale, however, these problems are eliminated. It is simple to retain an inert atmosphere which excludes moisture. It is simple to cool to sub-zero temperatures and hold that temperature; and it is much easier to hold the temperature of the filtered solid low and also keep cold the temperature of the wash liquid.  Using a temperature differential between the boiling point of the solvent on the upper side and –20 ℃ on the lower side can provide higher recoveries of crystalline product. Also, the greater temperature gap is less demanding on the solvent properties and allows more inexpensive solvents to function adequately.

Using less common solvents at scale should be more a case of selecting a solvent for improved purity rather than choosing a solvent for enhanced recovery.

Checking for the purification ability of a solvent operating on a particular reaction mixture

If the problem of obtaining crystals of the product from the mixture is resolved, it is useful to explore the ability of the solvent to distinguish between the desired intermediate and other impurities in the reaction mixture which one would expect. The following experiment might be very revealing and very simple to do, but frankly, I have never done it myself and I know of no one who has ever done it.  Take a crude solid contaminated with reaction contaminants and divide the solid into two equal portions.  Recrystallize the first portion from the solvent you have identified. Filter the solvent but do not allow any wash liquid to mix with the mother liquors but keep the mother liquors from this first crystallization separate. Dry the solid. Now use the mother liquors to recrystallize the second portion of the solid and isolate it in the exact same way. Now compare the recovery and purity of the two portions. The recovery of the second portion would be expected to be higher than the first. The second recrystallization presumably is done from solvent already saturated with the desired product. The purity of the first should be greater than for the second. There will be nearly twice the level of impurities in the second crystallization versus the first; however, the extent of these differences will be quite dependent upon the particular substance and its particular impurity levels. Thus, one experiment might provide a very good idea of how much recycling solvent could improve recovery for a process step.

A crystallization in two parts followed by a trituration or slurrying of both parts combined in an anti-solvent might be expected to give a better yield of a homogenous product in a single batch than some of the poor recovery recrystallizations that we often employ.

Another Way to Separate Phenolics by Crystallizing of Co-crystals?

When Kilomentor comes upon some very specific information that might have general utility for separations of a function group class, he saves it in his personal files, until an appropriate process chemistry situation arises.  The trick is (i) to have saved the information and (ii) to read these notes over sufficiently so that when the possible application comes up, some internal mental alert will sound to remind himself that he has some information that might be useful. Then, it is easy enough to retrieve it, examine it in more depth and see whether it really could be part of a rugged, time-saving, and even perhaps an elegant solution.

In this blog, I would like to examine the content of the patent US5081263 which on its face teaches an improved means to purify meta or para-substituted hydroxylphenyl or hydroxylnaphthyl carboxylic acids.

The inventive trick is that the authors have discovered that aryl carboxylic acids bearing a phenolic group, not in an ortho position to the carboxyl group, can be advantageously crystallized from p-dioxane because co-crystals are formed using this particular solvent.

The inventors explain that “the particular feature of the said adducts is that hydrogen bridge bonds exist between the hydroxyl groups of the aromatic compounds and the oxygen atoms of the dioxane, so that the adducts are 2:1 adducts…..and the carboxyl groups of two hydroxycarboxylic acid molecules are, in turn, dimerized, so that relatively long chain-like arrangements can form.”

In other words, (and this is my interpretation), the carboxylic acid functionality has a strong preference in this medium to exist as acid dimers leaving the phenol hydroxyls un-associated, and in p-dioxane they strongly prefer making two hydrogen bonds between the two phenols and the two ether oxygens of a single dioxane molecule.  This leads to high molecular weight co-crystals.

The patent provides information to suggest that the molecules that might do this can have other non-interfering functional groups and they propose fluorine, chlorine, bromine or a nitro group as potentially not interfering. Interestingly, this nitro can be ortho to the phenol and the dioxane co-crystal will still form. A specific example is a crystallization of 4-hydroxy-3-nitrobenzoic acid.  Other teachings in the patent indicate that the crystallization of the cocrystals can be from mixtures of dioxane and water or dioxane and ethanol, so it would seem that hydroxyalkyl is also a  non-interfering. 

Useful as all this might be for separating hydroxylaryl carboxylic acids, it would seem that the usefulness might be broader and more significant. Carboxylic acids are not typically difficult to purify. In many other articles, KiloMentor has argued that in fact carboxylic acids are preferred intermediates in synthetic process design precisely because if a mixture is produced during synthesis, they can be separated by simple acid-base extraction from all non-acids and a mixture of acids can be separated by pH-controlled extraction, or extractive crystallization or by reversible formation of a myriad of salt derivatives.

The gift the patent may be providing is the possibility that phenolic, diphenolic, or even polyphenolic compounds may form co-crystals with p-dioxane, and simple phenols may form simple 2:1 adducts with dioxane. Now the separation of diphenols, phenols, and non-phenols is a more challenging goal than the separation of a group of carboxylic acids. Yes, phenols are weakly acidic and some of the strategies for separating acidic compounds, in general, do work but it is not as rugged a methodology and interfering reactivity from the more alkaline conditions (such as oxidation) can raise several ugly problems. 

High molecular weight phenols, called pseudophenols because their alkali salts are not extracted into water, may be extracted from hydrocarbon solvents with Claisen's alkali. 

Phenols also can form O-sulfate water-soluble salts that are easily extracted and crystallized.

At the same time it is quite true that this idea may not work out in any particular situation, but the key pedagogical point is that if you have collected the concept and have sufficient familiarity to recall it in the appropriate situation, you get one more simple isolation possibility to evaluate. Choosing from more potential and distinctly different approaches increase your chances for simple, rugged, elegant solutions.