CHAPTER TWO
KETOPROFEN MONOGRAPH
2.1.3 Stereochemistry
The presence of at least one asymmetric carbon atom in a chemical entity results in the existence of stereoisomers. Ketoprofen has one asymmetric carbon, also referred to as a chiral centre, which gives rise to two enantiomers (140). Both enantiomers possess different biological activities (142). The (S)-enantiomer reduces inflammation and relieves pain, whereas the (R)-enantiomer can be used as a toothpaste additive to prevent periodontal disease. The majority of synthetic chiral drugs are now marketed as racemates, but this situation is rapidly changing due to Food and Drug Administration (FDA) regulations and recent advances in biocatalytic methods (143, 144).
CH3 CO2H
O H
HO2C H
O H3C
(R) - enantiomer (S) - enantiomer Figure 2.2 Stereochemistry of ketoprofen
2.1.4 Melting point
Ketoprofen has been reported to melt in the range of 94°C to 97°C (132, 140), 93°C to 95°C, 94°C, 96°C, 92°C, 91°C (135) and 93°C to 96°C (134).
2.1.5 Solubility
Ketoprofen is practically insoluble in water, freely soluble in acetone, ethanol and methylene chloride (132). It is also soluble in chloroform, ether and benzene (134). In ethanol,
ketoprofen has a solubility of about 1 in 5 and in water < 1 in 10 000 (131). Adjusting the pH to a higher value can solubilize ketoprofen, as solubility increases at pH values above its pKa
(141).
2.1.6 Dissociation constant
Ketoprofen is a weak monocarboxylic acid (141, 145) and has reported dissociation constant values, pKa, of 4.23 (147), 4.55 (131), 4.45 (134, 146), 4.60 (141, 145, 149) in water and 5.02 in aqueous solutions of pH 1.5 (148). The pKa will be an important determinant in ionisation and hence permeation (150).
2.1.7 Maximum flux (Jmax)
The maximum flux through the skin is obtained by taking the permeability co-efficient and multiplying it by the aqueous solubility. The Jmax is reported as 0.75 µg/cm2/h (147, 150).
2.1.8 Partition co-efficient and permeability co-efficient
There is a linear free energy relationship between lipophilicity and biological activity. As a suitable measure of lipophilicity, the partition co-efficient, P, between 1-octanol and water was determined. The value of P varies slightly with temperature and concentration of solute (151). The octanol-water partition co-efficient (log ) has been reported as 3.12 (147, 150). P Previous work by Hadgraft et al. (147) showed that there was maximum percutaneous
absorption for a series of NSAIDs and salicylates where the log was between 2 and 3. At P low log , the permeability co-efficient is low but the aqueous solubility is high and at high P
P
log , the permeability co-efficient is high but the aqueous solubility is low. The reported permeability co-efficient is 5.01 x 10-3 (cm/h)2 (147, 150). NSAIDs tend to have low solubilities and high permeabilities at low pH, but high solubilities and reduced effective permeabilities at higher pH (149).
2.1.9 Optical rotation
Ketoprofen is a racemic mixture of (±) α-(3-benzoylphenyl) propionic acid. Both
enantiomers show Cotton Effects at 223 nm. The (+)-enantiomer shows a positive Cotton Effect indicating an S-absolute configuration and interacts more strongly with human serum albumin as well as with biotransformation enzymes than the (-)-enantiomer (135).
(+)-enantiomer [ α ]D 2 3 + 57.1 o(C = 0.76 in CH2Cl2 ) (-)-enantiomer [ α ]D 2 3 - 57.4 o (C = 0.88 in CH2Cl2 )
2.1.10 Synthesis
Ketoprofen was synthesised by Rhône-Poulenc Research Laboratories, Paris in 1967 and was first approved for clinical use in France and the United Kingdom in 1973 (136, 137). Several methods for the synthesis of ketoprofen have been reported in the literature. Figures 2.3 - 2.5 show the synthesis starting from (3-carboxyl-phenyl)-2-propionitrile,
2-(4-aminophenyl)-propionic acid and (3-benzoylphenyl)-acetonitrile respectively.
HO C O
CH CN CH3
SOCl2
Cl C O
CH CN CH3
C O
CH CN CH3
C O
CH COOH CH3
Friedel-Craft
Hydrolysis
S COH O
CH COOH CH3
CH COOH CH3
O C S
CH COOH CH3
O C
+ HNO2 COOH
CH CH3
CH COOH CH3
HS
Potassium ethylxanthate
2-iodobenzoic acid
Polyphosphoric acid
Raney nickel
H2N
Figure 2.4 Synthesis of ketoprofen starting from 2-(4-aminophenyl)-propionic acid (135)
C O
CH2 CN
(C2H5)2CO3 NaOC2H5
C O
C O
C CH3 CN
COOC2H5 CH3I
C O
CH COOH CH3
H2SO4
C CN Na
COOC2H5
Figure 2.5 Synthesis of ketoprofen starting from (3-benzoylphenyl)-acetonitrile (135)
2.1.11 Stability
Ketoprofen must be protected from light and moisture (135). Exposure of aqueous solutions of ketoprofen (as the sodium salt) to ultraviolet radiation at 254 nm or daylight, for one hour at room temperature, was reported (134) to yield (3-benzoylphenyl) ethane which was subsequently converted to (3-benzoylphenyl) ethanol and (3-benzoylphenyl) ethanone (analysis by thin layer chromatography and high-performance liquid chromatography).
Samples that were protected from light showed negligible decomposition over 24 months.
Figure 2.6 Ketoprofen impurities and photodegradation products (132) O
O CH3
H
CO2H R
R1 O
O H
R
R1
CH3
and enantiomer
and enantiomer
1-(3-benzoylphenyl) ethanone
R = H, R1 = C6H5:
(3-benzoylphenyl) acetic acid R = CH3, R1 = OH:
(2RS)-2-(3-carboxyphenyl) propanoic acid R = CO2H, R1 = CH3:
(2RS)-2-[3-(4-methylbenzoyl) phenyl]
propanoic acid
R = CO-NH2, R1 = H:
(2RS)-2-(3-benzoylphenyl) propanamide R = CN, R1 = H:
(2RS)-2-(3-benzoylphenyl) propanenitrile
2.1.12 Ultraviolet absorption
The ultraviolet (uv) spectrum of ketoprofen in 0.2 M phosphate buffer at pH 6.8 is depicted in Figure 2.7. The λmax is 260 nm. The spectrum was obtained using a double beam GBC UV/Vis 916 Spectrophotometer from GBC Scientific Equipment Pty Ltd (Victoria,
Australia). The solvent also affects the λmax. In acetonitrile the λmax is 254 nm. The λmax reported in alcohol is 255 nm (132, 135).
2.1.13 Infrared spectrum
The major band assignments of ketoprofen are given in Table 2.1.
Table 2.1 Major infrared band assignments of ketoprofen (135) Band position (cm-1) Assignment 3200 - 2500 O - H stretching
3020 C - H stretching of aromatic groups
2970, 2930 C - H stretching of CH3 group (asymmetric) 2880 C - H stretching of CH3 group (symmetrical) 1695 C = O stretching of the acid
1655 C = O stretching of the ketone 1595, 1580, 1455 C = C stretching of the aromatic ring 1440 C – H deformation of CH3 (asymmetrical) 1370 C – H deformation of CH3 (symmetrical) 860 - 690 C – H deformation of aromatic rings
2.1.14 Nuclear magnetic resonance spectrum
The H1-NMR spectrum of ketoprofen in CDCl3 on an EM-360 6 MHz NMR
spectrophotometer is shown in Figure 2.9. Table 2.2 compares published values for ketoprofen.
Table 2.2 Published ketoprofen H1-NMR spectrum values (135) Instrument used Values
Varian EM-360 1.53 (d, 3 H, J = 7 Hz), 3.80 (q, 1 H, J = 7 Hz), 7.20 – 7.90 (m, 9 H), 11.50 (s, 1 H)
Varian T60 & A60 1.52 (d, 3 H, J = 7 Hz), 3.76 (q, 1 H, J = 7 Hz), 7.2 – 7.8 (m, 9 H), 11.8 (s, 1 H)
Figure 2.7 Ultraviolet spectrum of ketoprofen standard in aqueous solution
Figure 2.8 Infrared spectrum of ketoprofen (135)
Figure 2.9 Nuclear magnetic resonance spectrum of ketoprofen (135)