Vancouver Island University Department of Chemistry

Chem 231

Experiment 5

The Resolution of Ibuprofen

Name: James Baker-taylor Partners: Jimmy Jimbo, Sally Student Lab Instructor: Peter Diamente Date: October 31, 2011 Lab Section: 42

Abstract:
Many drugs are derived from optically active compounds known as chiral molecules. Chiral molecules have no plane of symmetry and exist in pairs of non-superimposable mirror images; enantiomers. Often only one of the two enantiomers is active or desired. The less desired molecule may be less effective or even have adverse effects. In the case of ibuprofen, a commonly used nonsteroidal anti-inflammatory, only one of the enantiomers, (S)-(+)-ibuprofen, is active. A stereochemical process used to separate racemic compounds and isolate the enantiomers is known as chiral resolution. In this experiment a racemic mixture, one containing equal parts of both enantiomers, of ibuprofen was separated, by the formation of diastereomeric salts, into its two enantiomers. 3.1 grams of dissolved racemic ibuprofen was reacted with (S)-(-)--phenylethylamine to create a mixture of diastereomeric salts. Unlike the enantiomers themselves, the diastereomeric salts have different chemical and physical properties. The diastereomeric salts of (+/-)-Ibuprofen and (S)-(-)--phenylethylamine formed have vastly different solubility. One of the diastereomeric salts, the desired (S)-(+)-ibuprofen, is not soluble in aqueous solution and precipitates out. Using a scheme of recrystallization and liquid-liquid extraction, and subsequent rotary evaporation of the dried organic layers; the two enantiomers of ibuprofen were separated and recovered. The enantiomers were identified and tested for purity by melting point analysis [(S)-(+)-Ibuprofen; experimental: 50-53C; literature: 40-53C], and polarimetry values [[(S)-(+)-Ibuprofen; Specific rotation, experimental: +52, literature: +59]. The optical purity of the (+)-ibuprofen was about 88.14%. These results suggest an inexpensive and efficient method for the separation and isolation of the desired ibuprofen enantiomeric form.

Overall Reaction: Resolution of Racemic Ibuprofen

C12H17COOH + C6H5CH(CH3)NH2
(S)-(-)--phenylethylamine Mass: 1.833g Molar Mass: 121.18g/mol Moles: 0.015126 Density: 0.94g/mL

C12H17COO- + C6H5CH(CH3)NH3+
Diasteromeric Salts: (Both IBU enantiomers)

(+/-) Racemic Ibuprofen Mass: 3.0g Molar Mass: 206.29g/mol Moles: 0.015027 Limiting Reagent

Figure 1: Structural representation of overall reaction:

Flow Chart: See Figure 2 attached: Resolution of Ibuprofen Flow Chart Procedure: Refer to McCullagh, J.V. J. Chem Ed. 2008, 85, 941-943 Refer to Chapters 13 and 15, The Organic Chem Lab Survival Manual by J.W Zubrick, Wiley, 2008 7th Ed. Observations: Table 1: Summary of experimental observations
Procedure Added 1.95 mL (S)-(-)--phenylethylamine to dissolved Ibuprofen After (S)-(-)--phenylethylamine addition (3minutes) Vacuum filtered (Buchner funnel) Recrystallized product from Part A dissolved in H2SO4 Stirred Filtrate from Part A in H2SO4 Observations Solution turned pale yellow White precipitate formed Off-white powdered precipitate Oily Droplets suspended in solution. Solution became cloudy and oily droplets suspended in solution.

Table 2: Mass and MP data table Mass of (+/-)-Ibuprofen (g) Mass of (S)-(-)--phenylethylamine (g) Mass of crude diastereomeric salt (g) Mass of recrystallized diastereomeric salt (g) Mass of (+)-Ibuprofen (g) Mass of (-)-Ibuprofen (g) MP range of crude diastereomeric salt (C) MP range of recrystallized diastereomeric salt (C) MP range of (+)-Ibuprofen (C) MP range of (-)-Ibuprofen (C) Literature MP range (+/-)-Ibuprofen (C) Literature MP range (+)-Ibuprofen (C) Literature MP range (-)-Ibuprofen (C)
[ii] [i] [ii]

3.10 1.833 2.20 1.76 0.623 0.834 135-145 167-170 50-53 52-55 77-78 40-53 40-53

Table 3: Polarimetry Data Table Specific Rotation for (+)-Ibuprofen in ethanol (deg.) Specific Rotation for (-)-Ibuprofen in ethanol (deg.) Literature specific Rotation for (+)-Ibuprofen in ethanol (deg.) Literature specific Rotation for (-)-Ibuprofen in ethanol (deg.) Optical Purity of (+)-Ibuprofen (%) Optical Purity of (-)-Ibuprofen (%) Calculations: Per cent Recovery (+)-Ibuprofen: Starting Mass of (+/-)-Ibuprofen: 3.1g Mass of end product (+)-Ibuprofen (Part C): 0.623g (0.623 / 3.1) x 100% = 20.096% Per cent Recovery (-)-Ibuprofen: Starting Mass of (+/-)-Ibuprofen: 3.1g Mass of end product (-)-Ibuprofen (Part C): 0.834g (0.834 / 3.1) x 100% = 26.90% Optical Purity of (S)-(+)-Ibuprofen: : +52 []D20 (ethanol): +59 Optical Purity = ([obs]/[]) x 100% (+52/+59) x 100% = 88.14% Optical Purity of (R)-(-)-Ibuprofen: : -38 []D20 (ethanol): -38 Optical Purity = ([obs]/[]) x 100% (-38/-59) x 100% = 64.41%
[ii] [ii]

+52 -38 +59 -59 88.14% 64.41%

Specific Rotation From Observed rotation: []T = /lc []= obs /lc // l = 2dm and c is in g/mL

(+)-Ibuprofen: 12.9/[(0.62g/5mL)(2)] = +52.0161 +52 (-)-Ibuprofen: 12.6/[(0.832g/5mL)(2)] = -37.8606 -38

Discussion: In the pharmaceutical industry many drugs are made of chiral molecules. Many of these molecules have non-superimposable mirror images called enantiomers. Enantiomers have similar physical and chemical properties, but tend to react differently with other chiral compounds [iii]. The biological effects of enantiomers can be vastly different [iv]. In the past, drugs were often sold commercially as racemic mixtures. Due to costs of processing and access to necessary supplies it was not always economical to resolve drug molecules to enantiomerically-pure compounds. However advancements in chemistry have made the processing of optically pure substances more economical and the production of single-enantiomer drugs is becoming more common [iv]. In some cases the results of racemic drug mixtures is only a lessened effectiveness or potency; where one of the enantiomers is either less effective or inert compared to the other active enantiomer. Such is the case for ibuprofen, where the (R)-(-)-ibuprofen is inactive, but not harmful, and can in fact be converted to the more desirable (S)-(+)-ibuprofen enantiomer [v]. However, in some drugs one of the enantiomers may have adverse or even harmful effects. A good example is the case of the drug Albuterol, used to treat asthma, where the once thought inert enantiomer has been found to intensify the disease [vi]. Furthermore the optically pure form of the desired enantiomer has also been found to be many times more effective and longer lasting in the body. Originally the resolution of the enantiomers of Albuterol used liquid column chromatography; a less efficient and more expensive method of separating a racemate. But, advancements in resolution technology have allowed methods like the isolation of diastereomeric salts and strongacid treatment of many compounds to separate enantiomers. And, in the case of drugs like ibuprofen and Albuterol, this method provides a less expensive resolution procedure resulting in higher

enantiomeric purity. Enantiomers have opposite configurations at all chiral centers, and are mirror images of each other, leading to the same physical and chemical-reactive properties except in how they polarize light, where the rotations are equal but opposite [vii]. Diastereomers have more than one chiral centre, and differ amongst themselves at one or more of these centres. Diastereomers have different physical properties and different reactivity, unlike enantiomers [viii]. Concerning the resolution of enantiomers, there are different methods to consider. Enzymatic resolutions can be effective, but costly; liquid column chromatography is another option, yet can be more difficult and inefficient comparatively; and others may involve chemicals that are restricted or otherwise controlled [ix]. The procedure in this experiment uses the isolation of diastereomeric salts and strong-acid treatment to resolve the enantiomers of ibuprofen. This procedure utilizes the differences between enantiomers and diastereomers in regards to physical and chemical properties. Both enantiomers of ibuprofen will react with an amine base in much the same way. By using a single form of a chiral amine base and reacting it with a racemate carboxylic acid like ibuprofen, the result is a mixture of diastereomeric salts; similar, but structurally different and possessing different physical properties. In this procedure the difference in solubility is used to separate the salts, and then subsequent strong-acid acidification allows the isolation and recovery of the pure enantiomers [x]. First in this experiment; racemic ibuprofen was dissolved and heated in 0.24M KOH. The electrons from the oxygen attack the hydrogen on the carboxylic acid and deprotonate the (+/-)ibuprofen. Potassium is a good leaving group and separates from the hydroxide ion, that will form H2O. The deprotonated (+/-)-ibuprofen will ionically attract the free K+ ions. The addition of the (S)-(-)--phenylethylamine, having a amine group with a lone pair of electrons, will attack protons in the solution (provided from the water and H3O+), the positively charged (S)-(-)-phenylethylamine, having gained a proton, will ionically react with the deprotonated ibuprofen enantiomers, replacing the K+ and creating the diastereomeric salts (Figure 2, Part A). The (S,S) salt is insoluble in aqueous solution and precipitates out, while the (R,S) salt is soluble and remains in

solution [vii]. The precipitate is vacuum filtered and the salts are effectively separated. The solid from the first step is recrystallized in 2-propanol (Figure2, Part B). Recrystallization is used to increase the optical purity of the solid. The crystals are then dissolved in 2M H2SO4, a strong acid, for five minutes. This is done to re-protonate the ibuprofen. This separates the ibuprofen from the (S)-(-)--phenylethylamine. The (S)-(+)-ibuprofen enantiomer is not soluble in aqueous solution and is extracted with t-butyl ether (Figure 2, Part C). The organic layer is washed with H2O and NaCl, to remove impurities from the organic layer. The layers are separated, isolating the (S)-(+)-ibuprofen. The filtrate from the beginning of the experiment is mixed with H2SO4 to re-protonate the (R)-(-)-enantiomer of ibuprofen, separating it from the phenylethylamine. Once separated the (R)-()-enantiomer of ibuprofen is not soluble in aqueous solution (like the (+)-enantiomer). The substance is extracted and washed as stated above (Figure 2, Part D). The extracted products were collected weighed and dried and tested for purity. The immediate precipitation upon adding the (S)-(-)--phenylethylamine supports the formation of a diastereomeric salt. The (S,S)-diastereomer of the salt is not soluble in aqueous solution [v]. Before recrystallization the melting point of the formed solid was taken (135-145C), after recrystallization the melting point was taken again (167-170C); indicating an increase in purity. After acidification of each of the salts the following melting point analyses and polarimetry tests supported the recovery and isolation of each of the ibuprofen enantiomers. The polarimetry tests for specific rotation showed that the solid from part C was the (+)-enantiomer, and the solid from part D was the (-)-enantiomer. The calculated specific rotation of the (+)-enantiomer (+52) was closer to the literature value (+/-59), than the (-)-enantiomer (-38). The optical purity of the (S)-(+)-enantiomer was 88.14%, while that of the (R)-(-)-enantiomer was only 64.41%. This difference can be easily explained via the process of recrystallization. The recrystallization of the (S,S)-salt increased the purity of the recovered product, and thus the optical purity. This indicates

that this is an effective process for the recovery of the desired, active, enantiomer of ibuprofen. Melting Point comparison of (S)-(+)-Ibuprofen: Range of pure sample (C): 50-53 (Average: 51.5) Literature Value (C): 49-53 (Average: 51) Calculation for purity: 51.5/51 x 100 = 100.98% About 100% pure The calculation for purity with respect to melting point of the purified sample indicates a relatively pure sample. It this case the percentage is above 100%. Melting point is not an accurate way to determine purity. Reasons being that melting points for many substances are ranges, and observed melting point ranges for obtained products are subject to error. The % recovery for the (+)-enantiomer was 20.096%; and the % recovery for the (-)enantiomer was 26.90%. Theoretically the % recovery for each of the enantiomers from racemic ibuprofen would be 50% each. However, certain steps promote losses in product. Namely he processes that involve dissolving the solutes and then recovering the precipitates. In order for the precipitate to form the product must be in solution. In the first step before the addition of the 1phenylethylamine, both enantiomers were dissolved in solution. After the addition of the phenylethylamine the (S,S)-salt precipitated out. However, some of the (S)-(+)-ibuprofen (being soluble) would remain in solution and not precipitate out. This is similar for the recrystallizations step and during the extraction steps for both enantiomers. Conclusion: This experiment shows the successful resolution of the ibuprofen enantiomers. The % recovery of each of the enantiomers was lower than it could be, but this could be refined. More importantly, the purity of the enantiomers was moderate to high. The optical purity of the desired, active (S)-(+)-ibuprofen, enantiomer was higher. This supports this method of resolution as efficient; being that the solubility properties of the associated diastereomeric salt when reacted with (S)-(-)--phenylethylamine facilitate this process and allow for easy recovery and recrystallization of the desired product.

ENDNOTES
i

Sigma-Adrich, Ibuprofen, 4883, Material Safety Data Sheet, Version 4.1, Revision Date 10/22/2010 Sigma-Aldrich. (2011). (s)-( )-ibuprofen . Retrieved from http://www.sigmaaldrich.com/catalog/ProductDetail.do?lang=en&N4=375160|ALDRICH&N5=SEARCH_CONCA T_PNO|BRAND_KEY&F=SPEC iii Organic Chemistry 8th Ed, John McMurry, Brooks/Cole, 2012, p150-154 iv Enantiopure drug. (2011, August 2). In Wikipedia, The Free Encyclopedia. Retrieved 05:34, November 25, 2011, from http://en.wikipedia.org/w/index.php?title=Enantiopure_drug&oldid=442729239 v McCullagh, J.V. J. Chem Ed. 2008, 85, 941-943 vi Bill T. Ameredes, Ph.D. and William J. Calhoun, M.D. American Journal of Respiratory and Critical Care Medicine Vol 174. pp. 965-969 vii Organic Chemistry 8th Ed, John McMurry, Brooks/Cole, 2012, p147-153 viii Organic Chemistry 8th Ed, John McMurry, Brooks/Cole, 2012, p156-160 ix McCullagh, J.V. J. Chem Ed. 2008, 85, 941-943 x Organic Chemistry 8th Ed, John McMurry, Brooks/Cole, 2012, p161-163
ii