kilomentor

Does microwave heating have a place in process development? In June of 2008 I attended a conference that raised this question quite a lot. The question I kept asking anyone who cared to talk about it was simply, what can microwave heating do that other methods cannot?

Microwave heating heats liquids or solids that have polar bonds. The heating comes from the flipping back and forth that the bonds dipole does trying to stay aligned with the radiation.

This heat is generated right inside the solution so that it does not have to be transmitted from the heated walls of a reactor. Thus the walls of a vessel heated by microwaves are cooler than the bulk material.

If you have a reaction that requires a high temperature and which shows degradation/impurity formation from charring on the hot walls, microwave heating can help you. Small scale reactions display the largest wall effects because they have a greater proportion of wall area to total volume, so scaling up is likely to help you anyway, even without microwave heating. The problem is that as one scales up it takes longer to reach your desirable high operating temperature. Microwave heating can help because, since the entire solution is heated from inside itself, energy can be delivered more rapidly and the temperature can be rapidly ramped up. Of course an alternative exists if you don’t want to use the technology. The solvent could be heated to a high temperature before mixing with the substrate, which could be added as a slurry.

Aficianados of the technology may tell you that because the energy is being directed into specific molecules (the ones with the dipolar bonds) special reactive effects may be at work but other experienced people quietly say not to believe it. It reminds me of the efforts years ago trying to get special activation by irradiating particular IR frequencies.

What we know is that the technique is being used a lot in discovery chemistry because it works well on a small scale and it is fast. Where microwave synthesis could save process chemists time by using the larger scale continuous flow microwave devices to make kilogram quantities of lead compounds without changing the discovery chemistry. This coud save experimentation time that can be redirected to improving the real process without dividing our attention. Microwave synthesis can keep those urgent requests for a few kilograms at bay, while we work out the synthesis as it ought to be done.

A pharmaceutical process that has been scaled-up is monitored using the results of in-process controls. These are tests that either conform or do not conform to a preset standard. If the test conforms, the operators proceed to the next instruction of the batch process, but if the result is nonconforming, the result is reported to the manager who decides what action to take next. For an in-process test, the actions to be taken are characteristically thought out in advance. If there is no possible corrective action for an out of specification result, the test is not a proper in-process test but rather just a datum that may be part of the analysis of the result when the final outcome is known.

When a process has been optimized it is taken for granted that it will operate within its control limits and no more testing than the in process ones will be required to guide the operators to a successful result.

Pilot Plant Experiments and Forensic Testing.

Although the chemical plant or kilo lab process can be modelled using a laboratory scale procedure, it cannot be optimized without results from representative samples from the scaled up process taken at critical decision points in the process.

The pilot plant runs are still experiments even if the equipment is handled by personnel who are not research chemists. Although the chemist may think that (s)he understands completely the experimental reaction and subsequent purifications steps being scaled up, at least for all practical purposes, this isat least immodest and usually foolish. The experimenter is wisest who anticipates the most potential problems and collects useful samples at every convenient sampling point every time the process is executed on scale. Taking many more samples than simply those, which are mandatory for in-process control. These extra samples we will call forensic samples because they are very often only analyzed when a result is unsatisfactory. When the result is unexpectedly disappointing in any respect. these samples can provide the evidence useful to determine what went wrong and how to correct it.

Forensic samples are carefully stored so they will not deteriorate. They are in addition to the process control samples Forensic samples are not analyzed during the time the process is running, but are for retrospective testing by the process chemists.

There is only one downside to the collection of forensic. If the process runs perfectly and gives a product of the exact same quality as the laboratory samples but with a lower yield, the question may arises whether taking samples might be predominantly responsible for the reduced yield. Most often the size of the samples or the mechanical losses that can occur when taking forensic samples cannot explain a noticeable reduced yield on scale. The samples are typically just not large enough compared to the size of the process.

Recrystallization can efficiently purify organic solids. The weakness of the methodology from the perspective of devising optimal synthetic processes is that a good recrystallization cannot be predict based on molecular structures of starting materials, co-products, by-products and product to the same extent one can predict, for example, the results of acid-base extractions or methyl alcohol/heptane solvent partitioning.

It is for this reason that Kilomentor in synthesis planning for chemical process development gives preference to intermediates that are acids, bases or salts.

Nevertheless, many process intermediates will be compounds that offer no practical alternative to purification by recrystallization and so it is useful to consider simple ways to increase the recovery from recrystallization steps.

Recrystallization separates impurities in two ways during the operations. Typically, the solid is first dissolved in the minimum amount of a hot solvent. The temperature for dissolution is typically the boiling point of that solvent although for high boiling solvents a lower temperature, such as steam bath temperature, may be used. These temperatures are convenient because there is no problem holding a solution at these points. The hot solution then is filtered to remove insoluble substances. This filtration is the first phase separation; solution from insoluble solid. Very often this purification opportunity is not properly recognized because a good solvent usually dissolves essentially everything when warmed or, in instances where it does not, some kind of filter aid is added, obscuring the presence of insolubles. Then, in the second stage, the clear solution (i) may be cooled to a lower temperature (ii) an anti-solvent may be added to reduce the solubility or (iii) both may be combined in use. The crystalline solid phase appears, is separated by filtration and the impurities are retained in the mother liquors.

In the most frequently used techniques, recrystallization is conducted from a single solvent or a mixture of two solvents by dissolving the solid hot, filtering hot, and then cooling to recover a crop of crystals.

When more of the recrystallizing solvent mixture is needed to completely dissolve the crude solid prior to filtering than is needed to effectively hold impurities in solution after cooling good product is likely being lost using this simple process.

It is easy to discover whether good product is being unnecessarily lost in any particular recrystallization situation by the following simple test.

Instead of recrystallizing the solid in a single charge, divide it into two equal homogeneous portions. Recrystallize the first portion as usual with the only difference that if the crystals are washed on the filter, keep the wash liquid separate from the regular filtrate. Dry, and weigh this first portion. Now recrystallized the second portion of crude only using as solvent the mother liquors from the first portion. Again dry and weigh the product and analyze both for purity.

If both the recovery from the second portion is greater than from the first and the purities of the two portions are not significantly different, changing your processing methodology will save you product.

At scale, recrystallization in two portions rather than one will save product but double processing costs. The same result, however, can usually be obtained by dissolving and filtering the entire crude amount in a single charge and then reducing the volume by half before cooling and recovering the solid. When the two conditions are met, the two stage laboratory experiment provides the evidence that you only need half the solvent to efficiently dissolve away the impurities. The second half of the solvent was more than anything else just dissolving away your product.

Note that in order to practice this method without problems the hot solution of crude solid must be stable to any extended boiling during the concentration stage. Of course, if there is a stability problem, the concentrating can be done under reduced pressure to lower the heat requirement.

It is the opinion of Kilomentor that the most significant presentation at the Scientific Update Process Development Conference held in Montreal from June 24-26^th of this year was that of Alex Tao, Vice President and Chief Scientific Officer of Bioverdant. Dr. Tao was a recipient of the 2006 IChemE-AstraZeneca award for Excellence in Green Chemistry and Engineering for his process for Pregabalin. What I hear Dr. Tao saying is that the state of scientific knowledge now calls for a paradigm shift in our perspective on organic chemical process development most particularly for pharmaceuticals.

According to the presentation, because of the availability now of so much genomic data, the number of enzymes available for conducting the equivalent of common API process steps has increased to the point that now such a broad substrate spectrum can be handled that a screen for potential enzymes to catalyze a reaction step is more likely than not to provide a usable hit. This means that for the first time in history, chemists can be optimistic that they will be able to identify an enzyme, available in commercial quantities, that will catalyze any one of a dozen very common chemical conversions.

Furthermore, even if the best wild-type enzyme discovered has only a poor enantiomeric selectivity for the substrate of interest, the science of site-directed mutagenesis has developed so quickly that a wild-type enzyme that only provides say 61.4% of the correct enantiomer can be used to create a new mutant enzyme with 99.5% ee in something like 3-6 months more work and this can be scaled up to provide production quantities.

This Dr. Tao confirmed to me would make it very likely that, if the innovating company has not already done so, a generic pharmaceutical company can expect to improve the route available to make drugs coming off patent using these biocatalytic methods. Moreover, this opportunity is more likely because the technology was not available in its present robust state when the innovator was developing its chemistry.

Using one biotransformation in a process usually removes the need for any resolution because only one enantiomer reacts. This also opens up the possibility of racemizing the wrong enantiomer and so recycling the 50% of the racemic intermediate that is usually not useful. Also prochiral intermediates give chiral products with enzymes; in one step resolving the intermediate and selecting one of two superficially identical groups.

The reactions that can be confidently replaced now are:

• Regio and enantioselective reduction of ketones to alcohol
• Regio and enatioselective hydrolysis of nitriles to acids
• Regio and enantioselective reduction of ketone to primary amines
• Regio and enantioselective conversion of aldehyde to the corresponding homologated α-hydroxyacid, 2-hydroxy-1-amine; α-hydroxyamide
• Regio and enantioselective reduction of αβ-unsaturated aldehydes/ketones/acids/nitrile/nitro.
• Regio and enantioselective conversion of nitrile to primary amide

In his presentation Dr. Tao provided examples of completed improvements for synthesizing levetiracetam, montelukast, pregabalin, (S)-dimethenamid (an agricultural product), synthetic pyrethroids (insecticides), moxifloxacin, paroxetine and atorvastatin.

In an effort to improve the predictability of retrosynthetic analysis, the simplifying assumption is implied that all functional groups of the same class react for all practical purposes with the same ease. Thus it is assumed that the classes: aldehydes, ketone, nitrile, nitro etc. display similarity in reaction. Sometimes a distinction is drawn between the functionality when attached to aryl as opposed to alkyl, but refinement rarely goes further than this. The combined particular electronic and steric effects in the vicinity of the functional groups is essentially ignored. Usually this simplification is a good one.

The more reactive group must usually be more than 100 times more reactive to obtain a quantitatively selective reaction. This can be seen to be true because to be essentially quantitative, when a reaction is 99% complete, the final 1% of starting material must be more reactive than the 99% of product, which could react further at the second functional group. If it is not that much more reactive, the reaction cannot expect to be quantitative (kinetic control assumed here).

This explains the widespread use of protecting groups to address the situation wherein a substrate contains two functionalities of the same type and the reaction of only a particular one is required.

There are situations however where it is documented that the same functional group in different environments react at usefully different rates. This can be the basis for separation of compound mixtures by reaction where the competition in reactivity is between the same nominal group in different substrates. Alternately, such a marked difference in reactivity can be the basis for a synthetic step which converts only one of two functional groups of the same class in an intramolecular competition.

For example suppose one is presented with a mixture of regioisomers, 4-methylethylbenzonitrile and 2-methylethyl-benzonitrile. Although each isomer contains a nominal nitrile, the nitrile groups are not equal in reactivity. It is reported that ortho substituted aryl nitriles do not readily for imidates by reaction with ethanol and anhydrous hydrogen chloride.

Thus if we were to treat a mixture of these nitriles with anhydrous hydrogen chloride in ethanol, we can expect only the para substituted compound to react and this can be used in a simple separation.

Another application can be found using the Zinn reduction of aryl nitro compounds to perform a selective reduction.

Thomas R. Nickson wrote a research article J. Org. Chem. 1986, 51, 3903-3904. The article taught that in the specific case of 3-trifluoromethyl toluene, when it is nitrated the compound formed in largest amount, the 2-nitro could be isolated in pure form because it was the only isomer than did not undergo the Zenin reduction with sodium sulphide and sulphur. Dr. Nickson however also taught that 3-methyl benzaldehyde and 3-methyl benzoic acid both nitrated preferentially in the 2 position. From my own experience I know that the compound 3,4-dichlorobenzaldehyde nitrates preferentially in the 2-position. It is possible that all 1,3-substituted compounds with one electron withdrawing group and one electron donating group nitrate preferentially in the 2 position AND may be separable by their failure to react in the Zenin reduction! Nickson tells us that one electron withdrawing group is advantageous to achieve a fast reduction but he was able to obtain 2-nitro m-xylene and separate it cleanly although in poor yield by reducing the other isomers but this reduction went slowly.

Also when the two substituents are both ortho-para directing the yield of the 2 isomer is much lower (10%) in the case of m-xylene. It is not clear whether the reaction scheme would work with two deactivating groups meta to each other.

The sulfate salt is the second most common pharmaceutical salt behind the hydrochloride. Bisulfate salts are quite acidic so the base from which one is made needs to be acid stable.

Sulfuric acid is a diprotic acid. It can form two different stoichiometric salt types: the 1:1 bisulfate salt and the 2:1 sulfate salts in which two moles of amine are protonated by each of the two protons of H₂SO₄. The pKas of sulphuric acid are –3 and 1.92 with almost five orders of magnitude difference between the acidity of the first and second hydrogen. Most pharmaceutical salts are of the 1:1 bisulfate type. Sulfates are most often made by the addition of an, at least partially aqueous, solution of acid because neat acid is not soluble in apolar solvents and it has some dehydrating capability which can lead to by-products when sufuric acid is in excess. Typical organic solvents used in making sulfates are methanol, ethanol, 1-propanol, 2-propanol, acetone and mixtures thereof. Acetone however is not recommended because an excess of acid causes the oligomerization of acetone creating color in the solution.

Kilomentor anticipates that by providing some examples of pharmaceutical sulfate salt preparations with some commentary to draw attention to important aspects of the methods a skilled experimentalist should have no difficulty making others.

US7230016 PREPARATION OF PIOGLITAZONE SULFATE

24.g of sulfuric acid was added slowly, at room temperature, to 250 ml of methanol followed by addition of 80 g of pioglitazone base with stirring. The mixture turned into a clear solution. 250 ml of ether was slowly added followed by 500 ml of heptane. A solid precipitated, and the suspension was stirred for 3 hours. The solid (98.4 g, yield was 96.5%) was collected by filtering and washed once with ether. The solid had a mp: 1113.5-116.5° C. (recrystallized from methanol).

This example illustrates the addition of the base to the organic solution of sulphuric acid in methanol. Although a small amount of methyl hydrogen sulphate might form this not a problem because MeOSO2OH is a pharmaceutically acceptable counterion. Note also that in the procedure the chemistry provided three opportunities to obtain crystals. Pioglitazone hydrogen sulfate might have precipitated from the methanol solution itself after partial dissolution. The salt might have crystallized when the methanol was diluted 50:50 with diethyl ether. The final opportunity occurred when the solution was diluted 1:1 with heptane and this was successful. Notice that the methanol could not be diluted with heptane directly. Two phases would have resulted. This is an example of a well designed approach to getting crystalline solid. If crystals still had not formed the solution would have been concentrated.

WO06040728A1: Preparation of 1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea

Example 11-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea

(1 equivalent) is dissolved in ethanol at a concentration of 25% w/w and the mixture is heated at 50°C. Aqueous sulfuric acid (1M, 1.1 equivalents) is added. Optionally, the crystallization is initiated by a wet seed of Example 1 (0.5%). The suspension is cooled to 0°C with a cooling rate of 15 C°/h and maintained at this temperature at least 1 hour before filtration and washing with aqueous ethanol (50 % W/V). The solid is dried at 30°C under a wet stream of nitrogen (50% RH) to provide the title compound with a purity of 97.7% with a yield of approximately 90%.

The example illustrates the addition of the acid to an excess of base. The addition is performed warm. An aqueous sulphuric acid reagent is used and it is added to a water miscible solvent in this case ethanol. Using seeds of the salt product is optional here. The example prescribes a cooling rate that will lower the temperature to the final filtration temperature over somewhat more than 3 hours. This is followed by a hold time to ensure that all the material that can crystallize has come out before the filtration. The wash solution is a mixture of solvents similar to that from which the solid is crystallized. Often a slightly less polar wash solution is used than the mixture from which the crystals are produced. This gives some assurance that the wash will not redissolve the solid. Although it is not reported the wash solvent is usually cooled to the temperature of the slurry that was filtered originally. On scale, this is done simply by loading the wash solvent mixture into the crystallizer. Because the solvent is a mixture with water, there is no danger of condensing damaging moisture into the wash solution. The example illustrates using a moist gas stream to dry the solid without dehydrating it.

Example 2 1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea sulfate trihvdrate.

To a suspension of 1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea (21.36 kg) in CH₃OH (178 L) is added aqueous H2SO4 (6 L, 9.91%) during 10 min. The clear solution is filtered and further aqueous H2SO4 (33.8 L, 1.07 M) is added during 45 min. The solution is cooled to -2°C during 1.5 h and stirred at -5 to -9°C for 1 h. The formed precipitate is filtered, washed with cooled CH30H (- 5°C, 54 L) and dried under a stream of nitrogen provide 1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea sulfate of formula l as a non-defined hydrate. A slurry of the so obtained salt in H2O (16.2% w/w) is stirred for 3 days at 25°C. Filtration and drying at 30°C under a wet stream of nitrogen (50% RH) provides the title compound.

This example replaces the ethanol with methanol and is in most particulars very much the same. Here unhydrated gas was used in the drying ad there apparently was some dehydration. Stirring a slurry in water for an extended period recreates the hydrate illustrating a method of preparing a pseudopolymorph hydrate. Drying to the trihydrate was successful when the relative humidity was controlled at 50%.

Example 4 1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea sulfate dihvdrate

1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea (15.4 kg, 1 equivalent) is dissolved in ethanol (78 L) and the mixture is heated at 50°C. Aqueous sulfuric acid (1M, 1.1 equivalents) is added during minutes. The crystallization is initiated by a wet seed of Example 1 (1%) as described below. The suspension is cooled to 1°C with a cooling rate of 14C°/h and maintained at this temperature at least 11 hours before filtration and washing with aqueous ethanol (50 % W/W, 50 L). The solid is dried at 30°C under a wet stream of nitrogen (33-40% RH) to provide the title compound with a purity of 99.4% with a yield of approximately 79%.
The wet seed used in the above procedure is prepared by mixing - 1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea sulfate dihvdrate (Example 1,) with a saturated solution (421 9) of 1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea sulfate dihvdrate (Example 1, 73.9 9) in aqueous ethanol (50 % W/W, 810 9).

Example 5

1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea sulphate dihvdrate

1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea (1.01 kg, 1 equivalent) is dissolved in ethanol (3.05 kg) under stirring (200±20 rpm) and the mixture is heated at 50°C. Aqueous sulfuric acid (1 M, 1.1 equivalents) is added during 20 minutes. The crystallization is initiated by a wet seed of Example 1 (1 %) as described below. The obtained mixture is maintained at 50°C for about 15 minutes, then it is cooled to 0°C with a cooling rate of 15°C/h and maintained at this temperature for least 1 hour before filtration and washing with aqueous ethanol (50 % W/W, 3 kg). The solid is dried in a conductive agitated dryer at a temperature of 35± 3°C under a wet stream of nitrogen (45±5% RH), optionally under stirring (max. rpm) in case the cake humidity is below 25%, to provide the title compound with a purity of 99.8% with a yield of approximately 94%.

The wet seed used in the above procedure is added in two shots and is prepared by mixing 1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea sulfate dihvdrate (Example 1, 6.5 9) with a saturated solution (13.9 9 for the first shot, plus 15.6 9 for subsequent rinsing and second shot) of 1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea sulfate dihvdrate (Example 1, 7.0 9) in aqueous ethanol (50 % W/W, 50.0 9) for about 2 minutes. The first shot of wet seed is prepared at least 5 minutes before use to ensure that the seed is correctly wetted.

Example 5 illustrates that in a process description of crystallization the mixing times, cooling rates and stirring need to be precisely controlled. The need to properly moisten the seed crystals with the solvent is also illustrated. If the seeds’ surface does not wet properly they cannot catalyze crystal growth properly.

US20060194833A1: Crystalline 1H-imidazo[4,5-b]pyridin-5-amine, 7-[5-[(cyclohexylmethylamino)-methyl]-1H-indol-2-yl]-2-methyl, sulfate (1:1), trihydrate and its pharmaceutical uses

According to the method, ER807447 is first suspended in water to form an aqueous suspension. Sulfuric acid is added to the aqueous suspension to form a solution while keeping the internal temperature of the solution below 25° C. The solution typically has a yellow color. The solution may optionally be filtered to remove particulates from the solution. Other techniques for removing particulates known in the art, centrifuging, etc. may be used as the filtering step. The solution is then slowly warmed until E6070 crystallizes from solution. The solution may be warmed to about 100° C. Typically crystal formation occurs at temperatures of about 70° C. Preferred rates of warming typically range from about 30 minutes to 5 hours. Longer or shorter times may be used, particularly depending upon the batch size. E6070 may not crystallize as readily from highly dilute solutions.

To enhance crystallization, an anti-solvent may be used in the method of making the crystalline E6070 or to recrystallize crystalline E6070. The recrystallization procedure is described in Example 5. In the above method, the anti-solvent may be added to the aqueous suspension before sulfuric acid addition or to the solution after sulfuric acid addition and the optional filtration step. Useable anti-solvents and their use are known in the art. Typical anti-solvents include water-miscible anti-solvents such as, for example, methanol, ethanol, 1-propanol, 2-propanol, acetone and mixtures thereof. When an anti-solvent is used, the solution may become cloudy. It is generally not necessary to warm the solution to as high of temperatures as when just using an aqueous solution.

The procedure above illustrates forming a bisulfate from water. Filtration or other clarification of the formed solution is illustrated. Removing insolubles removes nuclei that can catalyze improper nucleation. The example illustrates that a bisulfate salt in water may actually be supersaturated but the rate of nucleation may be impracically slow. Heating the solution increases the rate of nucleation and causes the insoluble salt to come out. If the sulphate is a high molecular weight molecule that should give an insoluble sulphate in water, perhaps heating will enhance the rate of seed formation as here.

The use of an antisolvent is also illustrated. Note that water miscible organics are often antisolvents for sulphate salts because sulphate salts are so hydrophilic.

Tizanidine Monosulfate (5-chloro-4-f2-imidazolin-2-ylamino')-2,l,3-benzothiadiazole monosulfate )

In a second preparation, tizanidine monosulfate was prepared by the following method: to solid tizanidine (9.957 g; 39.24 mol) was added a solution of sulfuric acid (5.438 g; 55.45 mol) in acetonitrile (175 mL). The yellow solid rapidly converted to a white crystalline solid. The mixture was heated to 60°C and stirred for 90 minutes. The mixture was cooled to room temperature and the solid was subsequently filtered and washed with additional acetonitrile (50 mL). The solid was collected via filtration and air-dried.

Tizanidine monosulfate comprises a 1:1 ratio of ionized tizanidine to sulfate counterion. In this example sulfuric acid in acetonitrile is used

Rosiglitazone Sulfate

Example 1:

5-[4-[2-(N-methyl-N-(2-pyridyl)amino) ethoxy]benzyl] thiazolidine-2,4-dione sulfate

5-[4-[2- (N-Methyl-N-(2-pyridyl)amino) ethoxy]benzyl]thiazolidine-2,4- dione (20.0 g) in glacial acetic acid (50 ml) was stirred and heated to 75°C until a clear solution 5 was observed. Concentrated sulfuric acid (1. 5 ml) was added and the stirred solution cooled to 21 °C. After evaporation of solvent under reduced pressure, methanol (100 ml) was added and the mixture stirred at 21°C for 48 hours. The solid was collected by filtration, washed with methanol (50 ml) and dried under vacuum to give 5-[4-[2-(N-
methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4- dione sulfate (10.7 g) as a crystalline solid.

Melting point: 184 - 189°C.

DSC: Tosser = 184.4°C, Tpeak = 189.1 °C Elemental Analysis: 15 Found: C; 52.96 H; 4.94 N; 10.23 S; 11.78 Theory: (C36H40N6O,oS3) C; 53. 19 H; 4.96 N; 10.34 S; 11.83<>

Pamoates are one of the pharmaceutically acceptable salts; however, they should only be considered for testing in an extended release formulation since the salts are almost always poorly soluble in water or stomach acid. The salts are prepared for retarding the dissolution of basic drugs. Stahl and Wermuth in Handbook of Pharmaceutical Salts Properties, Selection, and Use mention the pamoate salts of amitriptiline, benzphetamine, chlorpromazine, cyclguanyl, difenidol, dothiepin, imipramine, levomepromazine, metformine, noscapine, pamaquine, phendimetrazine, promazine, pyrantel, pyrvinium, and rhodoquine as being used in this way.

The acid was first described by Hosaeus in 1892 and a use was suggested for it in a patent to I.G. Farbenindustrie A.G. in 1992 where it was claimed as a method for manufacturing sparingly soluble, tasteless salts of nitrogenous basic compounds in particular salts of alkaloids such as strychnine and of bases of the ‘plasmochin’ type.

Kilomentor proposes that if one is faced with the problem of isolating an organic nitrogenous base by precipitation from any mixture, a reaction mixture say, the pamoate is probably the best first choice. A good second choice would be 2,2’-dihydroxy1,1’-dinaphthyl-3,3’-dicarboxylic acid, which is the compound similar to embonic acid but with the single difference that the methylene connecting the two naphthalene rings is gone. Both these compounds are either commercially available or easily synthesized. Syntheses are provided below from the paper by Barber and Gaimster, J. Appl. Chem., 2 October, 1952p. 565.

Embonic Acid

Method I- 2-hydroxy-3-naphthoic acid (750 g.) was suspended in glacial acetic acid (7.5 L.) and stirred at 5-100 C until dissolved. A mixture of glacial acetic acid (750 g.), 40% formaldehyde solution (450 g.) and concentrated sulfuric acid (71 g.) was added over20 minutes, the reaction being sufficiently exothermic to maintain the temperature between 95 and 100 C The suspension of embonic acid was stirred at 95-100 Cfor 30 minutes, allowed to cool to 70, filtered and washed first with ht glacial acetic acid (4.5 l.) and then distilled water until the washings were no longer ed to Congo red. The material was dried at 100 C to give embonic acid (700 g,)

Method II- 2-Hydroxy-3-naphthoic acid (500 g.) and 10% NaOH(1500 ml) were heated to 90 C with stirring; about 2/3of the solid dissolved. 40% formaldehyde solution (63 g.) was added, the temperature rising to 92 C, then a further 83 g. of 40% formaldehyde solution which caused a further rise in temperature to 95 C. No solid remained at this stage. After heating at 95 for a further 5 minutes, the solution crystallized spontaneously. The mixture was maintained at 95 C for 1 hour, cooled to 20 C and the sodium embonate filtered and washed with saturated brine (125 ml.) The damp sodium embonate (about 1.2 kg.) could be used as such or converted to the acid by dissolving in a mixture of water (3 l.) ad acetone (700 ml.), by heating to 50 C and adding glacial acetic acid (225 ml.)and then concentrated hydrochloric acid (bout 200 ml.) until the mixture was acid to Congo red. The precipitated embonic acid (480 g.) was filtered, washed with hot water until free of chloride, and dried at 100 C.

2,2’-Dihydroxy1,1’-dinaphthyl-3,3’-dicarboxylic acid

2,-Hydroxy-3-naphthoic acid (18.8 g.) was dissolved in a solution of sodium hydroxide (8.0 g.) in water (580 ml) and the solution was refluxed while a solution of ferric chloride (23 g.) of the hexahydrate) and conc. Hydrochloride acid (26 ml.) in water (29 ml.) was added drop-wise with stirring during a 20 minute period./the dark coloured reaction mixture was stirred at the boil for a further 30 minutes, then cooled, filtered and the filtrate rejected. After washing with a little water, the residue was dissolved in a slight excess of N-sodium hydroxide solution (200 ml.) The solution was treated with charcoal, filtered, acidified with concentrated hydrochloric acid and filtered. The yellow residue, after washing with water, was recrystallized from aqueous ethanol to give 2,2’-dihydroxy-1,1’-dinaphtrhyl-3,3’dicarboxylic acid (2.8 g.) as a pale-yellow hemi-hydrate m.p. 330-333 C.

US2397903 describes the poorly soluble salts with thiamine and dipyridoxine. US2641610 claims the use of the insoluble embonate salts of bis quartenary ammonium substances as a means of purifying and making the double salts with other anions by exchange.

Experimental details for making embonates either from relatively free bases or from mixtures of natural products are provided below for inspiration with your own problems.

WO9425460A1

Risperidone

Example I
A solution of 3- [2- [4-(6-fluoro- 1,2-benzisoxazol-3-yl)- I-piperidinyl) ethyl] -6,7,8,9-tetrahydro-2-methyl-4H-Pyrido[1,2-ajpyrimidin-4-one,19.70 g (0. 048mol) in ethanol (600ml) was added to a solution 18.64 g of pamoic acid (0. 048mol) in N,N-dimethylformamide (400ml). (1g/22 ml )
The mixture was stirred for 3 hours. The resulting precipitate was filtered off by suction, washed with ethanol and dried, yielding 3 1 g (8.1 %) of 3-[2-[4-(6-fluoro- 1,2benzisoxazol-3-yl)- I -piperidinyl)ethyl) -6,7,8,9-tetrahydro-2-methyl-4H-pyfido[ 1, 2ajpyrimidin-4-one 4,4'-methylenebis[3-hydroxy-2-naphthalenecarboxylate) (1: 1); mp. 269.2'C.

This is a very poor yield of salt; just 8.1%. Pamoic acid apparently is soluble in dimethyl formamide. This is useful information. The risperidone was dissolved in the usual ethanol. Perhaps the experimentalist did not wait long enough for the solid to all precipitate. They filtered after 3 hours.

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Example 1:
The pamoate salt of haloperidol can be prepared by treatment of haloperidol with pamoic acid or pamoate salt in solvent. Haloperidol pamoate can be prepared by adding a solution of haloperidol in an appropriate solvent, ea. ethanol with acetic acid, to a solution of disodium pamoate, pamoic acid or other pamoate salt and leaving undisturbed for 1-3 or more days until precipitation. Alternatively, other methods such as evaporation, slow or fast cooling or stirring solutions can also be used to precipitate salt.
Specifically, 2.5 ml of a O.1M solution of haloperidol in an acidified ethanol (5% acetic acid) was added to 2.5 ml of a O.1M solution of disodium pamoate (2.5ml) in ethanol/water (50/50). The mixture was allowed to sit at room temperature for 1-3 days. The resulting precipitate was filtered off by suction, washed with ethanol and dried in a vacuum oven at 60°C, yielding 240mg of 1:1 haloperidol pamoate salt.

Example 2:
2.5 ml of a 0.25M solution of haloperidol in an acidified ethanol (5% acetic acid) was added to 12.5 ml of a 0.05M solution of disodium pamoate in ethanol/water (75/25). The mixture was allowed to sit at room temperature for 1-3 days. The resulting precipitate was filtered off by suction, washed with ethanol and dried in a vacuum oven at 60°C, yielding 206mg of 2:1 haloperidol pamoate salt.

Example 3:
2.5 ml of a 0.25M solution of haloperidol in an acidified ethanol (5% acetic acid) was added to 6.25 ml of a O.1M solution of disodium pamoate in ethanol/water (50/50). The mixture was allowed to sit at room temperature for 1-3 days. The resulting precipitate was filtered off by suction, washed with ethanol and dried in a vacuum oven at 60°C, yielding 264mg of 2:1 haloperidol pamoate salt. - 1 1

Example 4:
ml of a 0.05M solution of haloperidol in an acidified ethanol (5% acetic acid) was added to 1 ml of a 0.25M solution of disodium pamoate in ethanol/water (50/50). The mixture was allowed to sit at room temperature for 1-3 days. The resulting precipitate was filtered off by suction, washed with ethanol and dried in a vacuum oven at 60°C, yielding 107 mg of 1:1 haloperidol pamoate salt.

Example 5:
5.ml of a 0.05M solution of haloperidol in an acidified ethanol (5% acetic acid) was added to 2.5 ml of a O.1M solution of disodium pamoate in ethanol/water (50/50). The mixture was allowed to sit at room temperature for 1-3 days. The resulting precipitate was filtered off by suction, washed with ethanol and dried in a vacuum oven at 60°C, yielding 119 mg of 1:1 haloperidol pamoate salt.

Example 6:
A (0.05 - 0.5M) solution of aripiprazole in an acidified ethanol is added to a (0.05 - 0.5M) disodium pamoate solution in a mixture of water/ethanol (100/0 0/100). The mixture is allowed to sit at room temperature for 1-3 days. The resulting precipitate is filtered off by suction, washed with solvent and dried in a vacuum oven at 60°C.

These methods teach the method of adding the base acidifuied with 5% acetic acid in ethanol to the disodium pamoate in ethanol/water. The disodium salt is more soluble and so this method depends upon the acidification of sodium pamoate with acetic acid to create the pamoic acid in situ where it can interact with the amine in the presence of acetic acid. The more insoluble amine pamoate crystallizes. These examples illustrate the fact that pamoates often must be allowed to change form from a gel like form to crystalline over some time. Heating sometimes accelerates this change.

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(C) Preparation of 3-(3-methoxyphenyl)-3-(3- dimethylaminopropyl]-4,4-dimethyl-piperidine-2,6-dione pamoate salt (anhydrous)

A solution of AGN-2979 bisulphate salt obtained in Step B (1 mmole, 430 mg) in 10 ml of water was mixed with methylene chloride (20 ml) and basified with aqueous ammonium hydroxide (29% w/w). After separation of the layers, the aqueous phase was extracted twice with methylene chloride. The combined organic phases were dried over anhydrous magnesium sulphate and the solvent was evaporated under reduced pressure. The residue was dissolved in ethanol (10 ml) and mixed with a hot solution of pamoic acid (embonic acid, 390 mg,1 mmole) in hot ethanol (30 ml) and the mixture was heated to reflux. After cooling, the pamoate salt crystallised and the salt was recrystallised in hot ethanol to give a pale yellow powder (melting point = 146°-150°C.

The procedure separates free base, evaporates to an oil and dissolves it in ethanol. It is mixed with a hot solution of pamoic acid dissolved in hot ethanol. The embonate came out in crystalline form on cooling.

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FORMS OF 4-(4-METHYLPIPERAZIN-1-YLMETHYL)-n-[4-METHYL-3-(4-PYRIDIN-3-YL)PYRIMIDIN-2-YLAMINO)PHENYL]-BENZAMIDE - IMATINIB

Example 10
4.l(4-Methyl-1 -piperazinyl)methyl]-N-[4-methyl-3-[ [4-(3-pyridinyl)-2- pyrimidinyl]amino]phenyl]- benzamide, pamoate

A mixture of 4-[(4-methyl-1- piperazinyl) methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2- pyrimidinyl]amino] phenyl]-benzamide (4.94 g, 10 mmol) and 4,4'-methylenebis[3-hydroxy-2- naphthoic acid (Fluke, Buchs, Switzerland; 3.88 g, 10 mmol) in ethanol (50 mL) is heated.
Water (25 mL) is then added. Upon cooling, the product crystallizes and is filtered-off and dried to afford 4-[(4-methyl-1- piperazinyl)methyl]-N- [4-methyl-3-[[4-(3-pyridinyl)- 2- pyrimidinyl]amino]phenyl]-benzemide, pamoate as a pale- yellow solid, having the following analytical properties: Analysis found: C, 69.12; H. 5.62; N. 10.88%; H2O, 2.50%. Calculated for C52H47N7O7- 1.26 H2O: C, 69.04; H. 5.52; N. 10.84%; H2O, 2. 51%.

Heating pamoic acid in ethanol will create some solubility. The solids must have dissolved since the addition of water is usually done to the point of turbidity and then the crystals allowed to come out as the solution cools.

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MELDONIUM SALTS, METHOD OF THEIR PREPARATION AND PHARMACEUTICAL COMPOSITION ON THEIR BASIS

EXAMPLE 10
Meldonium pamoate (1:1; x H20). Meldonium (5.46 g, 30 mmol) and pamoic acid (5.82 g, 15 mmol) are mixed with water and acetone (15 ml), the formed suspension is evaporated, 30-40 ml toluene is added to the residual viscous mass, it is grated, and evaporation is repeated. If the residue is insufficiently dry, treatment with toluene is repeated. Mp. 128-133°C (decomp.). H NMR spectrum (DMSO-d6), 6, ppm: 2.41 (2H, t, CH2COO-); 3.14 (2H, t, CH2N); 3.25 (9H, s, Me3N+); 4.75 (2H, s, -CH=(pam)) , 7.12 (2H, t, Harom); 7.26 (2H, td, Harom); 7.77 (2H, d, Harom); 8.18 (2H, d, Harom); 8.35 (2H, s, Harom). Found, %: C 62,90; H 5,83; N 4,98. Calculated, %: C 63,07; H S,84; N 5,07. Initially H:O content in the sample was 1.71%; after 24 hours maintenance at 100% humidity sample mass increased by 9% due to absorbed water.

Pamoic acid is not particularly soluble in either water or acetone. Evaporation would readily remove the acetone. The water would only be grudgingly removed as an azeotrope with toluene.

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PAROXETINE SALTS

Example 32 : Preparation of paroxetine pamoate 1: 1 salt.
A solution of paroxetine base in toluene (5 ml, 2. 10 g) was added to a solution of pamoic acid (2.48 g) in pyridine (40 ml), and the mixture was stirred at ambient temperature for 30 minutes. The solvent was then removed by distillation at reduced pressure, the residual oil diluted with toluene (30 ml) and the solvent again removed by distillation at reduced pressure. This procedure was repeated two more times. The solid product was washed with hot diethyl ether (c. 100 ml x 3) , and filtered under nitrogen to give a pale yellow solid. The product was washed twice more with diethyl ether (2 x 100 n- A), and then with methanol (30 ml), and finally dried under vacuum.
Yield = 3.27 g,
IR nujol mull:
Bands at 1636, 1558, 1508, 1459, 1377, 1183, 1036, 830, 722 CM-1.

Example 33 : Preparation of paroxetine pamoate 2:1 salt.
A solution of paroxetine base in toluene (10 ml, 4.2 g) was added to a solution of pamoic acid (2.48 g) in pyridine (40 ml). The mixture was stirred at ambient temperature for 30 minutes. The solvent was then removed by distillation at reduced pressure, the residual oil diluted with toluene (30 ml) and the solvent again removed by distillation at reduced pressure. This procedure was repeated two more times. The solid product was washed with diethyl ether (c. 50 ml), and filtered under nitrogen to give a white solid. This solid was washed twice more with diethyl ether (2 x 10 ml), and then dried under vacuum.
Yield 6.7 g.
IR nujol mull:
Bands at 1641, 1461, 13 77, 1181, 1035, 829, 757 cm- 1.

Pamoic acid is soluble in pyridine presumably as a pyridinium salt. It can be recrystallized from dilute aqueous pyridine. It is also soluble in nitrobenzene.

Molecules 2007, 12 1313

Extraction and precipitation of alkaloid-embonates

Homogenous dried leaves of a registered Finnish variety of C. roseus (1.0 g) were extracted for 30 minutes with 0.1 M hydrochloric acid solution (100 mL) in an ultrasonic bath (USF Finnsonic W 181,Ultra Sonic Finland). The mixture was then centrifuged at 2000 rpm for 10 min and the sediment was re-extracted with additional HCl (100 mL) for another 30 minutes. The combined supernatant from two repeated extractions was filtered and extracted with petroleum ether (200 mL) to eliminate chlorophyll and other lipophilic compounds. The acidic fraction was separated and an alkaline solution(pH 10.5) of 10 % embonic acid was slowly added for the precipitation of alkaloids as their embonate complexes. The pH of the resultant solution was increased to 5.0. The precipitate was separated simply by decantation and it was used as starting material for the semi-synthesis.

If you have a compound that is even quite a poor electron pair donor and that compound will not crystallize or will not crystallize to produce good quality crystals, what substance would be the best choice to test as a hydrogen bond donor? If you have a troublesome impurity in your product that can be predicted to be a better Lewis acid than your desired product, what would you propose as a good candidate to form a separable co-crystal with it?

An answer may be extracted a paper by the late Margaret C. Etter, Acct. Chem. Res. 1990, 23, 120-126. This is not a paper that synthetic organic chemists or process development chemists are likely to read. The lead author was a crystallographer and solid-state chemist. What makes the question interesting for us is that solid stoichiometric compositions can be made from substances with as poor a Lewis basicity as aliphatic ethers. The compound that forms these complexes is symmetrical bis-N,N-(3-nitrophenyl)urea. The compound can be easily synthesized from 3-nitroaniline and any phosgene equivalent giving a solid with melting point 256-258 C. It can be crystallized from any of acetic acid, benzene, chloroform, dichloromethane, ethanol, 95% ethanol or ethylene glycol. Heating the complex will drive off the Lewis base if it is volatile under high vacuum. One of two polymorphs will form but the form is not important for making co-crystals.

The complexes with a donor can be formed in a suitable solvent that is evaporated or if the donor is a solid, such as triphenyl phosphine oxide, simply by grinding two solids together. Making complexes with a component that is only present as an impurity in a product mixture has not yet been tried. The trick could perhaps be used to remove a difficult impurity such as triphenylphosphine oxide, dicyclohexylurea, dimethyl sulfoxide, polyethylene glycol. Even if a slight excess of the dinitro-urea was needed to completely remove the impurity of concern from a crude product mixture. Subsequent removal of this urea in second treatment might be much simpler than getting rid of the original troublesome impurity.

From the list of solvents from which symmetrical bis N,N-(3-nitrophenyl)urea can be crystallized, it would appear that the compound is insoluble in hydrocarbons and these might be useful as anti-solvents to increase the yield of adducts.

In Stahl and Wermuths book, Pharmaceutical Salts: Properties, Selection and Use there is a further piece of advice beyond what Kilomentor has already written about concerning salt selection. Unlike the other advice it is provided by implication only and needs to be simply stated.

On pg. 181 of the book, the selection of an appropriate pharmaceutical salt for the candidate drug called RPR200765 is presented. The following details of that problem are provided. RPR200765 was a candidate drug substance to be used to treat rheumatoid arthritis. The drug would have had to be taken regularly for the rest of patients lives. It is a crystalline, weak base with a substituted pyridine ring system, a pKa of 5.3 and log P of 2.5. The anticipated pharmaceutically effective dose was expected to fall between 100-125 mg. One can calculate that the molecular weight of RPR200765 by itself was 488.48. The actual API material is identified in Bioorganic & Medicinal Chemistry Letters (200), 11(5) 693-696.

Four potential salts were identified in the example: mesylate, camphorsulfonate, hydrochloride and hydrobromide. What was particularly instructive is the comment concerning the camphorsulfonate. The authors wrote that the only disadvantage of the camphorsulfonate when compared to the mesylate (the first choice) was the increased molecular weight due to the larger counter ion. It was considered that this could create problems with experimental capsule or tablet later in development.

Camphorsulfonic acid has a molecular weight of 232. The molecular weight of the monocamphorsulfonate salt of RPR200765 would have been 720.48. Giving a dose of 100-125 mg on the free base basis (0.256 mmoles), as camphorsulfonate salt, would amount to giving a dose 184 mg of this pharmaceutical salt. Delivering a dose of 184 mg of API, it is said, was anticipated to be problematic. From this it is possible to generalize that the practical limit to the weight of API that can be confidently handled is about 184 milligrams in the highest strength. This seriously restricts the choices of pharmaceutical salts for medicines particularly where the neutral active has a low molecular weight because this means there will be more moles in the dose and so more moles of salt former.

To take a current example, the highest prescribed dose of the cancer drug imatinib is 400 mg as free base. The molecular weight of the free base is 493. If we imagine the salt with an acid of molecular weight 232(camphorsulfonate) the weight of active API would be 588 mg. This is already more than 3 times what this teaching advises one can be comfortable with for achieving a successful formulation. It is obvious that the acid used to form the pharmaceutical salt for imatinib is going to have to have a low molecular weight. Pharmaceutically acceptable acids with molecular weight below 100 are only: acetic, carbonic, formic, glycolic, hydrobromic, hydrochloric, isobutyric, lactic, methanesulfonic, nitric, oxalic, phosphoric, sulphuric and thiocyanic. Of these the only ones without other concerns are hydrochloric, methanesulfonic, phosphoric and sulphuric. Suddenly salt selection becomes a lot easier! In the case of imatinib, the methanesulfonate was chosen as the drug substance!

Put as the converse it means that besides camphorsulfonic acid also galactaric, glucoheptanoic, lactobionic, 2-naphthalene sulfonic, 1,5-naphthalenesulfonic, oleic, palmitic, pamoic, sebacic, stearic and tannic acids need not be initially considered for salt formation with candidate bases. Five of these are from the group of 30 called Class 1 acids, the most preferred acids based on safety considerations.

Similarly benethamine, benzathine and hydrabamine are distinctly less preferred for salt formation with acid candidates based on their molecular weights.

The objective of the Kilomentor Blog is education. One can learn the basis for chemical process development and organic synthesis in schools, either technical or university undergraduate. One can build upon these with chemistry or engineering postgraduate training, but there is no path onward from there, which is widely accessible. This may be because of a person’s location on the planet or financial means. The careers that spring up from these roots are fun and useful to society. They should be open to the best minds on the planet; to whoever is intrigued to practice these arts. I write what has been useful to me and what I have learned slowly and painstakingly over 40 years. Wherever you are, all you need is access to the internet and you can share for free my experience, my insights, and yes, my errors. My goal is to provide a level playing field world-wide for organic process scientists.

A month ago my fiftieth blog article was published. The number of viewings for Kilomentor has passed 27,000. Several months ago the Kilomentor Blog was for several weeks the first ranked article on Google when the search terms: chemical process development’ organic synthesis, were entered.

Writing for Kilomentor has encouraged me to read more widely and try to put in perspective what I read. It has driven me to ask myself what the core knowledge in this profession is. It has enabled me to work together with some of you, solving problems together.

Thanks for reading.

Clarke Slemon PhD

The Kilomentor

A powerful idea for pharmaceutical product development is contained in an article titled, Consider a new approach to pharmaceutical development, authored by Pradir Ki Basu, Ronald A Mack, ,and Jonathan M. Vinson available at

http://findarticles.com/p/articles/mi_qa5350/is_199908/ai_n21444525

Hereunder, Kilomentor discusses aspects of their core idea, but these comments can only be followed after reading the original article.

Much of the article presents arguments supporting the importance of cost efficiently discovering a synthetic method, scaling it up and putting into production a process for manufacturing a new pharmaceutical. This is the pharmaceutical business with the actual marketing and selling stripped away. Its importance to profitability does not need to be debated.

The present authors are concerned about the efficient execution of the plan that starts after the identification of a biologically active target that is a candidate to be a commercial drug and proceeds to the validation of manufacture that molecule at commercial scale.

The new approach that they propose positions ‘process vision’ as the core concept. It is the definition and exemplification of ‘process vision’ which is the article’s most significant accomplishment. The authors identify the defining characteristics of the process vision at different places in the article but for me, I cannot say I adequately understood it until I drew particular phrases together in my notes.

· “The process vision satisfies all essential requirements, including those for safety, quality, waste minimization, cost, time, and operability.”

· “The process vision is neither the process with maximum yield nor the one that gives maximum product purity…..it is neither a chemist’s vision, nor an engineer’s vision; it is not even the vision of the chemists and engineers together.”

· “It is a vision a vision that all stakeholders in development, manufacturing and marketing can share…..”

Reading between the lines and amplifying certain aspects, the process vision might be a policy statement that provides as a starting point, desirable standards by which team members of each stage of the plan (laboratory process, kilo lab, pilot plant, and manufacturing facility) strive to meet their downstream colleagues’ concerns from the outsell of their work.

The authors make this clearer with specific examples of the unique orientation and emphasis that players at the different stages have and which they want to bring into early assessment, early inevitable cross purposes, and early compromise or conflict resolution. They write, “Chemists think in terms of steps, reactions, yield, purity, and so on; engineers in terms of unit operations, physical properties, heat load, and the like; manufacturing personnel in terms of unit operations, in terms of throughput, waste, control issues and plant modifications that may be required to run a process; and marketing people in terms of net present value of the product, how much it can sell for etc.”

For me, what the authors are somewhat ambiguous about is the mechanism they recommend for achieving this ‘process vision’ even though over and over again in the article they return to this same theme:

“It is important ….to get stakeholders to develop….agreed-upon objectives of process development.”

“communication among….personnel is critical during process development.”

“We need to…. provid[e] development team members with systems or tools to facilitate communications among different disciplines.”

“Unless the manufacturing team is involved in the process development, they will not have confidence in the scale-up”.

“…manufacturing and commercial input at this stage [late stage discovery] is essential for choosing the optimum processing route”.

“Team members need to be involved setting targets for cost, manufacturability, waste and emission loads, development time….”

“These alternatives must be evaluated based on….criteria agreed upon by all stakeholders….”

“If stakeholders are involved in planning experiments, it’s likely that more useful data could be collected from fewer experiments.”

For me these snippets hint at or outright propose two different strategies.

One can try to bring a diverse project team, with participation beginning with late stage R&D and including representatives all the way up to marketing, together frequently enough to work out priorities and make decisions even at the experimental program level.

Alternatively, one can establish some sort of median or normal or starting-point performance criteria addressing the main, recurring concerns of process development, manufacturing, and marketing which will serve as a process vision statement that will act as a proxy for the multiform interests of the entire downstream project team and continuously represent their standard concerns to upstream collaborators.

According to this meaning, a process vision statement would be a tool commanding corporate authority that would continuously challenging upstream groups with the standard core concerns of the downstream members.

The authors marvelously illustrate this challenging throughout their article. What I interpret them to be saying is that the problem is not that different elements of the project team have concerns which inevitably seem to operate at cross purposes; but that the team members will reach solutions that satisfy all parties, so long as the area of tension is discovered early enough.

Kilomentor has a strong preference for the second alternative. Use of a process vision statement as a proxy for the perspectives and concerns of downstream project groups seems preferable to using meetings of a large group with the frequency needed to actually direct even the collection of particular data. For a company’s drug product projects to be successful and on-time, any process’s strategy must not conflict too greatly with the psychological needs and private professional goals of the individual team members. The people downstream in the project, whether they be in process development, manufacturing, or marketing, simply will not give a project the attention it needs until it arrives at the phase where they are being held singly and personally responsible. They are too busy concentrating their attention on what is on their plate already and extinguishing the fat that is already in the fire. This is human nature! Besides, pharmaceutical product projects can go on so long that some participants can realistically expect to no longer be involved when a late-stage discovery project limps into manufacturing or marketing. People may hope or plan to outrun the difficulties.

Equally problematically, the up stream professionals, working at a particular phase of the work on their own turf, would require an uncommon personal modestly to accept without rancor face-to-face demands that particular questions be answered on a priority basis.

A corporate ‘process vision’ statement takes the personalities and egos out. At the same time, the standards proposed by a process vision statement would command authority and yet not be carved in stone. They would exist to bring a persistent awareness of particular concerns. They would bring those different needs, which may be pulling at cross purposes to early attention, and they can be expected to bring the affected team members together to create or negotiate a solution.

This excellent thought provoking article by Basu, Mack and Vinson contains other important ideas which I hope to look at in later blogs.

Kilomentor continues with his review of the properties and procedures for the manufacture of pharmaceutical salts. The procedures are among the most import in chemical process development and organic synthesis.

It would seem from looking at the names of pharmaceutical products that phosphate anion is a fairly frequently used pharmaceutical salt former, but closer examination reveals that there are actually very few ionic pharmaceutical phosphate salts. Among drug substances called phosphates, the majority are covalent phosphate esters of an alcohol functional group.

Nevertheless, there is a place for the phosphate salts because the monophosphate is probably the most hydrophilic anion used to make pharmaceutical salts. Dihydrogen phosphate anion contains two very polarized hydrogen-oxygen bonds that energetically prefer to exist in a hydrogen bonding, high dielectric medium. When this hydrophilic anion is combined with a large hydrophobic cation, the result is almost always an insoluble salt. To balance this advantage the following disadvantages must be weighed:

· These salts have a high propensity to give several different hydrate pseudopolymorphs.

· phosphoric acid as a viscous oil or very low melting solid that is difficult to manipulate quantitatively.

· phosphoric acid is not miscible with the non-polar organic solvents which are the preferred media for the hydrophobic base partner

· the acid’s hygroscopicity makes weighing more difficult.

Evidence of the hydrophilicity of phosphate is provided by its selection for use in a standard procedure for making those acid addition salts of acids, which are themselves in the neutral form poorly stable, such as nitrates, thiocyanates, perchlorates and fluoroborates.

The procedure is taken from Brandstrom and Gustavii, Acta Chemica Scandinavica 23 (1969) 1215-1218.

To a two phase mixture of 1M aqueous phosphoric acid and methylene chloride or chloroform, add the free base which thereupon dissolves in the aqueous acid. Add sodium nitrate, sodium thiocyanate, sodium perchlorate or sodium terafluoroborate; mix the phases and extract the salt, anion and protonated base, into the organic layer quantitatively. Because the phosphoric acid monoanion is so hydrophilic it does not compete with these anions for extraction into the lipophilic organic layer even though it is present in enormous excess. That phosphoric acid is the bulk acidifying agent used testifies to its preference for the aqueous phase. The pKas of phosphoric acid are K₁ =7.107 x 10^{-3 ;} K₂ =7.99 x 10^-8; K₃= 4.8 x 10^-13.

The literature provides another piece of evidence that ionic phosphates may be good choices for giving solid crystalline salts for a wide range of bases. Helene Perrier and Marc Labelle found the phosphates the second most preferred salts for isolating as salts a wide range of intermediates containing the 3-acylquinoline moiety [J. Org. Chem. (1999), 64, 2110-2113.

Some corroborative information about crystalline phosphate salts comes from an article analyzing salts found in the Cambridge structural Database. http://www.msm.cam.ac.uk/pfizer/pdf/Publications/P03%20(02)%20-%20Occurrence%20of%20Pharmaceutically%20Acceptable%20Anions%20and%20Cations%20in%20the%20Cambridge%20Structural%20Database.pdf

The phosphate dianion was found to have the highest percentage of its salts as hydrates of all the salts examined. According to the authors’ interpretation this suggests that increasing charge on a single ion leads to increasing hydrate formation. They reference another paper that suggests that hydrate formation is a result of an imbalance between the number of hydrogen bond donors and acceptors in a crystal. [Infantes l., Chisholm J. Motherwell S. Cryst. Eng. Comm. 2003, 5: 480-486.]

Some specific examples of procedures are given in the extended text below.

By far the most frequently successful pharmaceutical salt is the hydrochloride. In fact the hydrochloride salt is selected 50% of the time when chemists look for an acceptable salt. Typically, there must be a very good reason for not adopting this salt. If a hydrochloride crystallizes, one typically needs a n excellent reason not to use the hydrochloride.

The hydrochloride is a preferred choice because chloride does not have any activity of its own, unlike bromide, nitrate and others. Hydrochloric acid is a very significant acid in the stomach. By salt exchange hydrochlorides are formed to some extent no matter what the counter ion of an API is in the pharmaceutical product.

Hydrochloric acid is a strong mineral acid strong enough to quantitatively protonate even weak bases.

Hydrochlorides characteristically are substantially more soluble than the free bases used to make them, so the hydrochloride typically improves the bioavailability.

Hydrochlorides can be prepared in aqueous solution, in protic organic solvents, in aprotic organic solvents, and in non-polar solvents because hydrogen chloride can exist in both a covalent form in apolar solvents or as ionized protons and chloride ions in more polar solvents. The actual acidity varies being equal to the acidity of the conjugate acid of the solvent molecule. That is to say hydronium ions exist in water, protonated alcohol ions in alcohol, protonated acetic acid in glacial acetic acid or protonated ethyl acetate molecules in ethyl acetate. The multiple forms of HCl result in multiple techniques for the addition of the hydrogen and chloride ions to the pharmaceutical base we need to make into a salt.

Hydrogen chloride gas can be passed into neat organic solvents to prepare titratable molar solutions that are quite stable. Hydrogen chloride in lower alcohols is not stable for a long time and must e used soon after it is formed. More often the gas is added to the base dissolved in the lower alcohol. HCl forms quite stable solutions in IPA which can be sotred at ambient temperatures for several days. Hydrochloric acid solutions in non aqueous solution can be made by adding acetyl chloride into ethanol wher a quantitative reaction occurs to give hydrogen chloride and an equamolar amount of ethyl acetate.

A recent PCTpatent teaches the creation of hydrogen chloride in situ from trimethylsilyl chloride and any solvent with a silylated functionality or any inert solvent containing a slight excess over the silyl chloride of a silylable group.

Hydrochlorides can be made by reaction of the organic base with an equivalent of ammonium chloride. The stronger organic base preferentially takes the hydrogen chloride and the ammonia gas is liberated and may exit the reaction mixture.

If the free base of concern has some solubility in water, the hydrochloride can be made from aqueous hydrochloric acid and the base in water. Often heating is required to get the free base dissolved and the hydrochloride salt separates on cooling. In aqueous solution the solubility of the amine hydrochloride can be decreased by the addition of additional inorganic water soluble chloride to increase the common chloride ion. The addition of inorganic salts also increases the precipitation by the salting out effect.Excess hydrochloric acid can be used to decrease the solubility of the desired salt so long as the pharmaceutical chloride is stable in strong aqueous acid.

Standard aqueous solutions of hydrochloric acid can be added directly into the base dissolved in a water miscible polar solvent such as methanol, ethanol, propanols, butanols, acetone, 2-butanone, acetonitrile,

The most powerful and widely practiced method of making a hydrochloride salt in the laboratory is to add gaseous hydrogen chloride into a diethyl ether solution of the free base. If you think a hydrochloride salt might not be crystalline, this technique is likely to provide evidence one way or the other. It is not a practical process method to make the slat but it will give evidence that the solid salt is possible and will provide some seed crystals for other preparative methods.

If a solid pharmaceutical hydrochloride is formed, the next goal is to obtain it in a satisfactory recovery. Pharmaceutical bases are typically expensive moieties and losing material in a low recovery hydrochloride formation is undesirable. When a solution of a hydrochloride and the pharmaceutical base has been formed but only a small amount or no crystals at all precipitate three strategies are possible

1. cool the solvent to decrease the overall solubility in the solvent volume
2. all an antisolvent which changes the quality of the solvent system and lowers the solubility
3. add an antisolvent and then cool

As a rule of thumb if the recovery is 80% or more at ambient temperature, simply cooling the solvent can be expected to give an excellent recovery; if the recovery is 40-80% at ambient cooling should be applied and then an altisolvent judiciously added; but when the starting recovery is less than 40% an antisolvent should be added to just the cloud point and then cooling should be applied.

Treatment is completely reversible. What you cool down you can rewarm so this is usually tried first.

If treatment 2 is used it is useful for the analysis of the results to take a sample of the solid obtained just by cooling in order to measure the purity at that point, then add the antisolvent to give a practical recovery and compare the purity of the product when using an anti-solvent with the purity before that addition.

When the solid formation in the single solvent condition is low or none, an anti-solvent is added to the cloud point either to a hot or ambient solution and then controlled cooling is applied to try for crystallization.

Mixtures of solvents are not preferred in scale up processes because it introduces the nedd for an in process test to guarantee the proper solvent ratio. Second crops are more difficult to obtain from a mixed solvent in a simple procedure. Nevertheless situations where a mixed solvent gives the best purification and recovery do occur. It is advantage if two solvents differ substantially in boiling point. This allows recovery of pure solvents from the filtrate.

Solvents that form an azeotrope with water have the advantage that it is easier to be sure that the crystallization is under anhydrous conditions.

An article entitled “Pharmaceutical Manufacturing Goes Green” appeared in the recent March 1 2008 issue of Genetic Engineering & biotechnology News (GEN). It was stated that “advances in enzymatic catalysis of synthetic reactions, solvent substitutions, and recycling of by-products and waste may not only reduce the environmental impact of pharmaceutical processes but, with the potential to have a positive effect upon synthetic efficiency and overall productivity, can also decrease waste streams, lessen energy input, and minimize the need for hazardous reagents”.

It is only human nature that academic scientists who have hitched their career aspirations to green chemistry will advocate the greenness of a process as the essential basis for process evaluation; but realistically all that can be hoped for is that industrial process chemists will increasingly include green technology and its potential advantages to the corporation among all the basis upon which a preferred process is selected. There is, however, good reason to expect that this will happen.

As the GEN article notes realistically, ‘This may be a particular challenge in organic chemistry, in which many of the classical chemical reactions have been in use for decades to produce small molecule drugs”.

The industry does have an advantage in this re-education program since at this time there is a particularly rapid turnover of chemists because so many of them are reaching retirement age. The ranks must necessarily be quickly filled up with younger more environmental conscious and hopefully trained in universities very aware of the need for green chemistry.

Because of the patent laws and health regulations in the main, world pharmaceutical markets, the emphasis in the pharmaceutical industry must be on the synthetic route which is overall the most rapid, inexpensive, scaleable and rugged. The high risk of failure and the cost of even a successful development necessitate that pharmaceutical companies maximize the number of years that they have a monopoly in the marketplace before patent expiry. This forces these organizations towards using the first dependable, economic and scaleable process that will deliver a product that can satisfy the health regulatory authorities. Once product from this early process has been used in successful clinical trials, there are bureaucratic hurdles created that make it very expensive to “green up” steps of the process or to replace whole portions of the process with ecologically more friendly alternatives. Pharmaceutical companies will never introduce process retrofits that require the repeating of clinical trials because these human tests are the most expensive part of drug development.

Green chemistry will typically be unsuccessful as a retrofit strategy for old products but they can be immediately introduced into all new processes. All that is required is awareness that it is wanted. When a process step is optimized, the entire reaction space is not explored. Decisions are made at the beginning of the project concerning the values of discrete variables (variables that cannot change continuously like time or temperature) that will be included in the optimization study. An example is useful to understand this. Suppose in a process step an alcohol is converted to an acetate ester. Only a few acetylating agents will be chosen to examine: say acetic anhydride and acetyl chloride. If transesterification with ethyl acetate or isopropenyl acetate is not included at this stage, no transesterification process has any chance of becoming the optimized method. To exemplify again, an auxiliary base may be include in the optimization study and the candidates will be preselected: say pyridine, and triethylamine. If a recyclable base such as polyvinylpyridine is not included among these discrete variables in the study, it has no chance of becoming part of the optimized process step. If chloroform or methylene chloride are included among the discrete solvents selected for the optimization, they have a good chance of becoming part of the optimized process step. If the choices at the outset for building the process step are greener, the resulting optimized step must be greener. It is only when this ‘greener’ study cannot come up with an adequate process step that chemists may need to fall back on the traditional ungreen methodologies.

In the GEN report, David Constable of GlaxoSmithKline teaches that the cost of new solvent, combined with the cost of disposal of both the used solvent and the water contaminated with organic solvent constitute about 75-80% of the environmental impact and energy use in the life cycle of a pharmaceutical compound. If Kilomentor translates this into actionable terms, it means: learn the effect the solvent/substrate ratio upon yield and purity during process optimization.

The selection of the reagents, catalysts and solvents to be tested in the optimization of new process steps is going to be done within industry. The work is being performed on drug intermediates that are secret at the time the work is going on. Where academia can contribute to the green revolution is to provide a literature, which suggests green alternatives that industrial project manager can use in their optimization studies. Publish a more atom economic acetylation. Publish and popularize a readily recyclable trap for hydrogen chloride gas to replace triethylamine. Put it in your text books. Teach it in your lectures. Make it top of mind.

The GEN article reported that David Constable of GlaxoSmithKline iinformed a conference that in the past five years his company had achieved a 50% per kg API reduction in use of methylene chloride for final processing, where it had been replaced with either methyl isobutyl ketone or ethyl acetate. He also reported a 95% decline in DMF use.

The GEN article also mentions the solvent tetrahydrofuran as a solvent of concern to EPA for emission of toxins to air and water. Tetrahydrofuran is an important solvent for organometallic reagents and 2-methyltetrahydrofuran appears to be a good replacement. This needs to be made more widely known. 2-methyltetrahydrofuran is not completely miscible with water and so can be recovered more easily.

Atom economy is being popularized as an important aspect of green chemistry. Atom economy measures the amount of a reagent that gets incorporated into the final product versus the portion that goes into waste. For example in making an acetate product from an alcohol using Ac-OAc, the Ac goes to make the acetate product and the OAc goes into waste. Using AcCl, the Ac goes into product, the Cl goes into waste. The goal of atom economy is to reduce the percentage weight that goes into waste for any reagent.

It is important for process chemists to understand the concept of atom economy but Kilomentor’s assessment is that the idea is overhyped. Reagents typically contribute very little to the waste burden compared to solvents, and reagents are very much more likely to be critical to the particular reactivity of a substrate because the reagent is a very important part of the activated complex for the reaction transition state. The result is likely to be that a small positive influence of reagent structure is going to be difficult to counterbalance by arguments about relative atom economy. If a less atom efficient reagent gives a more cost effective process, the latter will win out.

Neal Anderson of Anderson’s Process Solutions identifies oxidation/reduction reactions as among the least atom economic which is rather automatic given that most oxidations or reductions only add or remove a couple of hydrogens. Kilomentor has already provided a blog discussing the more promising oxidation technologies, including a method using only catalytic amounts of chromium. Anderson’s good suggestion to design processes avoiding unnecessary changes in oxidation state is a worthy repetition of what he taught in his superb book, Practical Process Research & Development, Academic Press. , This book is still the best process chemistry book available.

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• Continuous Chemical Flow Reactors that Scale so Well are not New
• Using the Bisulfite Adduct for Purification at Scale: Practical Purity and Purging of Impurities by the Process Steps
• The Potential Use of Acetic Acid and Acetic Anhydride for performing Solvent Switches during Work-Ups
• A Question about Genotoxic Impurities
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• Separating Sulphur-containing from Sulphur-free Compounds both in the Lab and At Scale
• The Relationship between the Risk of Catastrophic Failure and the Size of the Scale Up Steps in Chemical Process Development
• The Advantages of Transfer Hydrogenation for Chemical Process Scale Up
• Distillation with Reduced Pressure using Carbon Dioxide Atmosphere to Create Enhanced Vacuum
• Reactions on Immobilized Enzymes can Telescope Process Steps, Eliminate Isolations and Reduce Costs at All Stages of Pharmaceutical Development

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