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Somagoni Jagan Mohan et al. : Chirality and Its Importance in Pharmaceutical Field Review - An Article Overview 309 Chirality and its Importance in Pharmaceutical Field- An Overview Somagoni Jagan Mohan1, Eaga Chandra Mohan1, and Madhsudan Rao Yamsani1* 1 Centre for Biopharmaceutics and Pharmacokinetics, University College of Pharmaceutical Sciences, Kakatiya University, Warangal - 506 009 (A.P.) India ABSTRACT: Until recently, the majority of single-isomer drugs available were those derived from natural sources (e.g. morphine, epinephrine, hyoscine), and racemates predominated. There is now clear evidence of a trend in the pharmaceutical industry towards the development of chiral drugs. Several factors have influenced this trend, which has occurred independently and in parallel with a quest in the industry totally to develop more potent, selective and specific drugs. The process is equivalent to developing a new active substance and requires a new application, but data on the racemate may be used as appropriate, together with ‘bridging studies’. There is, however, limited potential in the market for the degree of therapeutic benefit obtained to justify the degree of investment. The real benefit of chiral technology lies in its application in the search for novel chemical entities and its appropriate formulation. This paper gives a brief idea about the importance of chirality, nomenclature, use of chiral excipients in formulations containing chiral drugs, stereoselective dissolution, stereoselective kinetics and dynamics, separation and estimation techniques and some interactions of chiral drugs. This paper also gives a brief overview of work done on chirality from formulation point of view. KEY WORDS: Chirality, chiral excipients, chiral drugs, chiral formulation, chiral interactions. Introduction Over one third of marketed drugs world wide are chiral, and regulators will now only approve new chiral drugs in the single enantiomer form, and even then insist on full profiling of the role of the individual enantiomers in vivo (Collins et al., 1992). Polarized light is rotated when passing through solutions containing chiral molecules (but not when passing the racemic mixtures). Optical isomers rotate the light in an equal degree but in opposite direction. If the enantiomer rotates the light to the right, it will be indicated as dextrorotatory (Latin:dextro), “d” or “(+)”. Optical isomers that rotate light to the left, on the other hand will be indicated as levorotatory (Latin:Laevus), “l” or “(-)”. According to the Fischer convetion the absolute configuration around a chiral center can be noted as D or L (Millership et al., 1993). This notation, which is mainly used for amino acids and carbohydrates, correlates the configuration of a chiral center to the configuration of D or L glyceraldehydes. The R/S notation (from Latin; rectus (right) and sinister (left), which has largely replaced the D/L notation, is related to the Cahn-Ingold-Prelog *Corresponding author: Prof. Y. Madhusudan Rao, Centre for Biopharmaceutics and Pharmacokinetics, University College of Pharmaceutical Sciences, Kakatiya University, Warangal - 506 009 (A.P.), India. Tel.: +91-870-2438844 Fax: +91-870-2570543 E-mail: [email protected] 309 convetion, and can also be used for molecules containing more than one chiral center (Islam et al., 1997). Significance of Chirality Most of the molecules of importance to living systems are chiral, e.g. amino acids, sugars, proteins and nucleic acids. An interesting feature of these biomolecules is that in nature they usually exist in only one of the two possible enantomeric forms (Crossley R, 1995). When a chemist synthesizes a chiral molecule in an achiral environment using achiral starting materials, an equal mixture of the two possible enantiomers (i.e. a racemic mixture) is produced. In order to make just one enantiomer, some enantioriched material, reagent, catalyst, or template must be presenting the reaction medium. Oftentimes, only a single enantiomer of a chiral molecule is desired, as in the case when the target molecule is a chiral drug that will be used in living systems. Drug molecules can be linked to any keys that fit into locks in the body and elicit a particular biological response. Since the ‘locks’ in the living organisms are chiral, and exist only in one of the two possible enantiomeric forms, only one enantiomer of the ‘key’ molecule should be used. In general, the use of both enantiomers in a racemic formulation of a chiral drug may be wasteful, and sometimes even introduces extraneous material that may lead to undesired side effects or adverse reactions (Stinson, 1998). This hypothetical interaction between two enantiomers of a chiral drug can be understood better from the Fig 1. 310 International Journal of Pharmaceutical Sciences and Nanotechnology Active Enantiomer Volume 1 • Issue 4 • January-March 2009 Formulation: Inactive Enantiomer Mirror plane Fig. 1 Hypothetical interaction between the two enantiomers of a chiral drug and its binding site. The active enantiomer has a three dimentional structure that allows the drug domain A to interact with binding site domain a, B to interact with b, C to interact with c. In contrast, the inactive enantiomer cannot be aligned to bind the same three sites simultaneously. The difference in three dimentional structure allows the active enantiomer to bind and have a biological effect, where as the inactive enantiomer can not. Different drugs showing different activities with different enantiomers are given in Table 1. Table 1. Examples of drugs showing different activities with different enantiomers (Indra , 2004). Chirality influences drug delivery because a single enantiomer or a non- racemic blend may have improved solubility, dissolution, and stability. In addition, many available pharmaceutical excipients (e.g., cellulose and its derivatives) either naturally occur as single enantiomers or are derivatives of the latter chiral molecules. These stereochemically pure molecules may interact with other chiral molecules (i.e., the active ingredient) and form stereoisomers. The latter will have physicochemical properties different from the original chiral molecule. For example, the presence of heptakis (2,6-di-O-ethy l)-betacyclodextrin results in stereoselective dissolution of tiaprofenic acid. While this stereoselective release did not result in stereoselective bioavailability, it highlights the potential implication of the effect of chirality on physicochemical properties of drugs. Similar to the solid dosage forms containing chiral excipients, biological membranes may provide chiral environments. Most drugs cross the gastrointestinal membrane through simple passive diffusion; thus, no stereoselectivity in the process is expected (Eichelbaum, 1996). Chiral excipients: With the advent of stereospecific analytical methods in recent years, more attention has been drawn to the influence of chiral excipients on the modification of in vitro release and in vivo disposition of chiral drugs. Chiral excipients have been widely used in pharmaceutical dosage forms. Different chiral excipients and their pharmaceutical applications are given in the Table 2. Few drugs that show the importance of chiral switch: Cinchona Alkaloids While (-)-Quinine and (+)-Quinidine are diastereomers, they are not enantiomers, as is also the case with (-)cinchonidine and (+)-cinchonine. Of these four alkaloids, (-)-Quinine, (-)-cinchonidine and (+)-cinchonine are all antimalarials. While (+) Quinidine also possesses antimalarial properties, but it is normally prescribed as antiarrhythmic to regulate heartbeat (Balkovec et al., 2001). Table 2. Selected chiral excipients and their pharmaceutical applications (Indra, 2004). Excipient Celluloses Carboxymethylcellulose calcium Ethylcellulose Hydroxyethyl cellulose Hydroxypropyl cellulose Hydroxypropylmethyl cellulose Phthalate Microcrystalline cellulose Cellulose acetate Cellulose acetate butyrate Cellulose acetate phthalate Major Applications Suspending agent, stabilizer, coating agent Binder, coating material, viscosity builder Viscosity builder, binder, film former, dissolution modifier Viscosity builder, binder, stabilizer Enteric coating agent, taste masking Binder, diluent, stabilizer, disintegrant, Dissolution modifier, film coating agent Dissolution modifier, film former Dissolution modifier, film former Table 2. Contd… Somagoni Jagan Mohan et al. : Chirality and Its Importance in Pharmaceutical Field - An Overview B. Starch, Sugars and Derivatives Alginic acid Carrageenan Dextrose Fructose Guar gum or Galactomannan Lactose Mannitol Maltose Pectin Scleroglucan Sorbitol Starch Sucrose Xanthan gum C. Cyclodextrins Beta-cyclodextrin Hydroxypropyl β- cyclodextrin Heptakis (2,6-di-O-ethyl)- β- cyclodextrin D. Acids Ascorbic acid Lactic acid Malic acid Tartaric acid E. Amino Acids, Peptides, and Derivatives Arginine Aspartame Bovine serum albumin Human serum albumin Lysine Protamine F. Fats, Oils, Essential oils Medium chain triglycerides Carvacrol Carvone 1,8, cineole ± linalool D-limonene Menthone L-menthol α-tocopherol Binder, disintegrant, viscosity builder Sustained release matrix, suspending agent Diluent, sweetener Diluent, sweetener, dissolution enhancer Binder, disintegrant, viscosity builder, Diluent, sweetener Diluent, sweetener, bulking agent for lyophilized product Diluent, sweetener Dissolution modifier, dispersant Dissolution modifier Diluent, sweetener, humectant Diluent, binder Sweetener Viscosity builder, suspension stabilizer Complexing agent, dissolution enhancer, Stabilizer Complexing agent, dissolution enhancer, Stabilizer Anti-oxidant Acidifying agent. Acidulant, Acidulant, buffering agent, antioxidant, flavouring agent Effervescent agent, diluent Stabilizer Sweetener Solubility enhancer ( for biomolecules) Solubility enhancer ( for biomolecules) Stabilizer Stabilizer Emulsifying agent, suspending agent in emulsion systems, absorption enhancer, dissolution modifier Flavor, Permeation enhancer Flavor, Permeation enhancer Flavor, Permeation enhancer Flavor, Permeation enhancer Flavor, Permeation enhancer Flavor, Permeation enhancer Flavor, Permeation enhancer Antioxidant Ascorbic acid: As (+)-Ascorbic acid and (-)-Erythorbic acid (Fig. 1a) are often labeled as L-ascorbic acid and D-erythorbic acid, respectively, there is often a misconception that these two items are enantiomers. These are not enantiomers, but are diastereomers as the structures are not mirror images. (-)Erythorbic acid exhibits only 5% of the anti-ascorbutic activity compared to (+)-Ascorbic acid (Friedman et al., 1999). Fig. 1a Ascorbic acid. 311 312 International Journal of Pharmaceutical Sciences and Nanotechnology Thalidomide: The use of thalidomide (Fig. 2) led to a tragedy in the 1960s in Europe. The drug was prescribed to pregnant women to counter morning sickness. Studies later suggested that these effects were caused by the Senantiomer and that the R-enantiomer contained the desired therapeutic activity. More recently, studies have concluded that both enantiomers of thalidomide are unstable and spontaneously epimerize to form the racemate in-vivo in humans. The in-vitro studies demonstrated the hydrolysis products 5-hydroxy-thalidomide and 5’hydroxy-thalidomide while in-vivo only the 5'-hydroxy metabolite was found, in low concentrations, in plasma samples from eight healthy male volunteers who had received thalidomide orally (Meyring et al., 2002). Volume 1 • Issue 4 • January-March 2009 pharmacokinetic differences between the enantiomers with (S)- albuterol being cleared more slowly. The (S)enantiomer tends to accumulate in preference to the therapeutically effective (R)-enantiomer. These pharmacokinetic and pharmacodynamic differences provided the basis for the chiral switch patent of albuterol to levalbuterol, (R)-albuterol, which has the same bronchodilator activity as racemic albuterol, but has a superior side-effect profile (Nowak, 2003). Fig. 3 Albuterol. (S)-Ibruprofen and (S)-Ketoprofen: R-Thalidomide Sedative-hypnotic S-Thalidomide Mutagenic Fig. 2 Thalidomide. The chiral center of the thalidomide enatiomers is unaffected by the stereoselective biotransformation process. (3'R,5'R)-trans-5'-hydroxythalidomide is the main metabolite of (R)-thalidomide, which epimerizes spontaneously to give the more stable (3'S,5'R)-cis isomer. On the contrary, (S)-thalidomide is preferentially metabolized by hydroxylation in the phthalimide moiety, resulting in the formation of (S)-5-hydroxythalidomide. Although Thalidomide is tainted from its past history, it (and analogs) have recently been a subject of numerous studies. In 1998 the U.S. Food and Drug Administration approved thalidomide for use in treating leprosy symptoms and studies indicate some promising results for use in treating symptoms associated with AIDS, behchet disease, lupus, sjogren syndrome, rheumatoid arthritis, inflammatory bowel disease, macular degeneration, and some cancers (Eriksson et al., 2001). Both (S)-Ibruprofen and (S)-Ketoprofen (Fig. 4 & 5) are the chiral switch drugs of the popular racemates. The activities of the two enantiomers of Ibuprofen and ketoprofen are essentially indistinguishable in vivo, owing to a unidirectional metabolic bioconversion of the (R)enantiomers to the (S)-enantiomers. The combination of the stereospecificity of action, together with the configurational inversion reaction provided drug companies a rationale for the use of the (S)-enantiomers of these drugs in therapy, as this reduces the total dose and reduces the toxicity that is associated with the (R)enantiomer by removing the rate (and extent) of inversion as a source of variation in metabolism and pharmacological effects. In the ketoprofen case, (S)-(+)-ketoprofen (dexketoprofen) is several times more potent than the racemate. The presentation of dexketoprofen as the tromethamine salt provides three advantages: effective analgesia at lower doses, rapid onset, and reduced gastric irritation and improved tolerability (due to the novel salt form) (Agranat et al., 2002). Albuterol: Albuterol is the racemate of 4-[2-(tert-butylamino)-1hydroxyethyl]-2 (hydroxymethyl) phenol (Fig. 3) and is the leading bronchodilator, an adrenoceptor agonist that can increase bronchial airway diameter without increasing heart rate. The bronchodilator activity resides in (R)albuterol. (S)-albuterol, however, is not inert, as it indirectly antagonizes the benefits of (R)-albuterol and may have proinflammatory effects. There are Fig. 4 (S)-Ibruprofen Fig. 5 (S)-Ketoprofen. Somagoni Jagan Mohan et al. : Chirality and Its Importance in Pharmaceutical Field - An Overview Bupivacaine: Racemic Bupivacaine (Fig. 6) currently is the most widely used long-acting local anaesthetic. (S)-(-)-Bupivacaine (Levobupivacaine), The S- enantiomer of bupivacaine, has recently been introduced by Purdue Pharma LP under the tradename Chirocaine® as a new long-acting local anaesthetic with a potentially reduced toxicity compared with bupivacaine (Gristwood et al, 1999). Numerous studies have compared levobupivacaine with bupivacaine and in most (but not all) studies there is evidence that levobupivacaine is less toxic. Studies have also shown that, following i.v. administration, levobupivacaine produces significantly less effects on cardiovascular function than racemic bupivacaine (Gristwood et al., 2002). 313 receptors. Metabolically, the formation of morphine glucuronides is enantio- and regioselective in rats and humans. In rat liver microsomes, natural (-)-morphine formed only the 3-O-glucuronide, whereas the unnatural (+)-morphine formed glucuronides at both the 3-OH and 6OH positions, with the 6-O-glucuronide being the principal product. In human liver microsomes, both the 3-OH-and 6OH positions were glucuronidated with each of the enantiomers, with the 3-O-glucuronide being the major product with (-)-morphine, and the 6-OH position being preferred with the (+)-enantiomer (Coughtrie et al., 1989). Fig. 8 Morphine Methadone: Fig. 6 Bupivacaine. Omeprazole: Methadone (Fig. 9) has been used to assist heroin users in withdrawal since the 1960’s. The opioid agonist properties of racemic-methadone are ascribed almost entirely to only one enantiomer, (R)-(-)-Methadone (Olsen et al., 1977). Omeprazole (Fig. 7) is a gastric anti-secretory proton pump inhibitor marketed under the tradenames Losec® and Prilosec® by AstraZeneca and it developed the chiral switch drug esomeprazole (which is the (S)-(-)-enantiomer of omeprazole) based on the premise that therapeutic benefit would be achieved by less inter-individual variation, (slow versus rapid metabolizers), and that average higher plasma levels would provide higher dose efficiency in patients (Chong et al., 2003). Fig. 9 Methadone. Cocaine: Fig. 7 Omeprazole. Morphine: The opiate receptors are stereospecific and pharmacological activity is dramatically dependent on absolute configuration. For example, unnatural (+)morphine (Fig. 8) has extremely weak affinity for opiate Similarly, the naturally occurring (1R,2R,3S,5S)-(-)cocaine (Fig. 10) is psychoactive whereas its enantiomer is inactive. Metabolically, the behaviorally inactive (+)cocaine was found to hydrolyze at least 1,000 times faster in baboon plasma than (–)-cocaine. Positron emission tomography shows that (-)-cocaine is rapidly taken up in the striata of both the human and baboon brain. No brain uptake was seen for (+)-cocaine, although transport of cocaine into the brain was not expected to be stereoselective. The explanation for the lack of uptake was determined to be very rapid metabolism of (+)-cocaine in the blood 30 seconds after administration of labeled (+)cocaine, it was undetectable in plasma (Gatley et al., 1990). 314 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 1 • Issue 4 • January-March 2009 The quantitative determination of verapamil enantiomers released by these systems was carried out by using a stereospecific HPLC method. Hydroxypropylmethylcelluose, beta-cyclodextrin, Hydroxypropyl-beta-cyclodextrin, and cross linked amylose did not show any stereoselective dissolution properties while pectin, galactmannan and scleroglucan seemed to give a slightly higher dissolution rate of the R, compared with the S-enantiomer (Conte et al., 1996). Selective separation and estimation of chiral drugs: Fig. 10 Cocaine. Amlodipine: Amlodipine (Fig. 11) exhibits chirality, i.e., it exists as two isomers. Moreover, the receptor binding studies have shown that it the S (-) isomer of amlodipine that has L-type calcium channel blocking activity. The R (-) isomer exhibits a 1000-fold weaker calcium channel blocking activity. Thus, the antihypertensive and antianginal activity of amlodipine can be attributed only to S (-) amlodipine, whereas the R (-) isomer can be regarded as inactive. Since racemic amlodipine contains R (+) and S (+) isomer in 1:1 ratio, purifying the pharmacologically active S (-) isomer can reduce the dose of racemic amlodipine to half (Lorfen et al., 1994). Fig. 11 Amlodipine. 1. Natural products Isolation of natural products can be achieved in several ways. Glutamic acid has been crystallized from gluten hydrolysate. The very important carbohydrate sucrose (table sugar) is collected from sugar cane and beets. Glucose another key carbohydrate member of the chiral pool is obtained from the hydrolysis of starch. Many terpenes are extracted from the various plants in which they are produced. Few monoterpenes and their plant sources are given in Table 3. Table 3. Monoterpenes and their plant sources (Liu, 1999). Terpene Source α-Pinene various pine trees d-Limonene orange, caraway, l-Limonene turpentine oils dl-Limonene turpentine oils l- Carvone spearmint oil d-Carvone caraway oil dl-Carvone ginger grass oils l-Menthone pinus palustrismell Stereoselective Dissolution: In most cases the modulation of the drug delivery rate from modified-release formulations is achieved with polymers also used as chiral stationary phases in liquid chromatography. It is therefore hypothesized that the interaction of the enantiomers with the excipient may lead to differential delivery rates from the devices for each enantiomers. Preferential crystallization: Stereoselective dissolution of verapamil hydrochloride from the matrix tablets press coated with chiral excipients evaluates the excipient stereoselective dissolution of (±)verapamil, a model racemic drug and, for this purpose, different matrix compositions, a commercial product and a particular device have been considered. The delivery device, recently proposed for the delayed release of drugs, consists of an active core containing the drug, coated by compression with different types of polymeric materials. Classical Resolution Preferential crystallization of conglomerates is one of the most attractive methods for separating optically inactive isomers. However, only a few percent of racemic mixtures exist as conglomerates, therefore this option has limited availability. Classical resolution remains the most widely used technique for obtaining optically pure compounds for synthesis of pharmaceuticals, agro chemicals and other biologically active products a chiral acid or base resolving is reacted with a racemic mixture and two diastereomeric salts are formed. Different resolving agents used for the classical resolution and drugs prepared with this technique are given in Tables 4 & 5, respectively. Somagoni Jagan Mohan et al. : Chirality and Its Importance in Pharmaceutical Field - An Overview 315 Table 4. Selected Common Resolving Agents (Sheldon, 1993) Table 5. Drugs Prepared via Classical Resolution (Sheldon, 1999) Kinetic Resolution Kinetic resolution offers a means of obtaining optically pure chemicals when preferential crystallization or classical resolution methodologies are not available for the desired compound. This technology relies on differing activities of enantiomers when placed in a chiral environment. Typically one enantiomer remains unreactive and the other isomer forms a product with a chiral reagent. The two compounds can be then separated with relative ease and often with very high optical purities. Kinetic resolutions can be achieved with chemical and biological catalysts. Interactions The two enantiomers of a racemic drug may interact with each other at different pharmacokinetic or pharmacodynamic levels. In addition to enantiomer-enantiomer interactions, a racemic drug may interact with other drugs stereoselectively (Crossley, 1995). For instance, stereoselective interactions have been reported in man between propranolol and calcium channel blockers, cimetidine, and quinidine. Calcium channel blockers nicardipine and diltiazem, and verapamil all decreased the first pass metabolism of both enantiomers of propranolol. However, this inhibitory effect was stereoselective for the both R(+)-enantiomer in case of verapamil and nifedipine, resulting in a significant increase in the (+) :(-) AUC ratios in plasma. In terms of effects, nicardipine did not increase the blood pressure reduction of propranolol, a phenomenon that can be explained by a more significant pharmacokinetic effect on the less active R(+)-enantiomer. Similarly, cimetidine decreased the oral clearance of R(+)- propranolol to a more significant degree than that of the S(-)-enantiomer. As per quinidine human liver microsomes studies indicated that selective inhibitor of CYPD26 reduced the ring hydroxylation propranolol in a stereoselective manner in favour of R(+)-propranolol. This was in agreement with in vivo studies showing 180% and 100% increases in the plasma AUCs of R(+)- and S(-)propranolol, respectively, because of quinidine coadministration. Interestingly, all these studies have shown that the inhibition of the metabolism propranolol by different drugs is stereoselective for R-(-)-propranolol (Rezamehvar et al., 2001). The pharmacokinetics of R – and S- atenolol after intravenous administration of racemic atenolol were studied in 3-, 12- and 24-month –old rats and 3-month-old rats with renal failure induced by uranyl nitrate. In all age groups, the area under the plasma concentration-time curves is higher for R- than for S-atenolol; volume of distribution, total clearance and renal clearance are lower for R-atenolol than for S-atenolol , but the differences are small. The total amount of both enantiomers excreted in the urine is decreased in the rats with renal failure. Therefore there is no stereoselective effect of treatment of the rats with uranyl nitrate (Bogaert, 1993). With pretreatment of rats with clofibrate, clinically important interaction of clofibrate on the chiral disposition of ibuprofen was observed. With respect to the protein levels of two key enzymes involved in chiral inversion, clofibrate pretreatment significantly induced expression of long chain acyl-coenzyme a synthetase, although the expression of the epimerase was unaltered. It is concluded, that clofibrate may increase the proportion of R-ibuprofen incorporated into long-lived lipid stores (Stefen scheuerer, 1998). 316 International Journal of Pharmaceutical Sciences and Nanotechnology Significant differences in the protein binding and the total systemic plasma clearance of (-) - and (+)-verapamil in humans was observed (Eichelbaum et al., 1984). The difference in clearance presumably was caused by hepatic clearance, because oral administration resulted in significantly higher concentrations of (+)-verapamil. 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