15687-27-1 Usage
Uses
Used in Pharmaceutical Industry:
Ibuprofen is used as an analgesic for the relief of pain, as an antipyretic to reduce fever, and as an anti-inflammatory agent to reduce inflammation. It is particularly effective in treating conditions such as rheumatoid arthritis, primary dysmenorrhea, and other inflammatory conditions.
Used in Over-the-counter Medicines:
Ibuprofen is used as an active ingredient in numerous over-the-counter medications, marketed under various trade names including Advil, Motrin, and Nurofen, for the treatment of general pain, fever, and inflammation.
Used in Research and Development:
Ibuprofen is used as a selective cyclooxygenase inhibitor (IC50=14.9uM) that inhibits PGH synthase-1 and PGH synthase-2 with comparable potency, making it a valuable compound for research and development in the pharmaceutical industry.
Used in Cardiovascular Disease Management:
A recent study indicates that concurrent use of ibuprofen and aspirin may interfere with the cardioprotective effects of aspirin in patients with established cardiovascular disease, as ibuprofen can reversibly bind to the platelet COX-1 isozymes, thereby blocking aspirin's ability to inhibit TXA2 synthesis in platelets.
Indications
Alleviate the acute phase of various kinds of chronic arthritis such as rheumatoid arthritis, osteoarthritis, spondyloarthropathies, gouty arthritis and rheumatoid arthritis as well as persistent symptoms of joint swelling and pain. It can be used for the non-cause treatment and control of disease.
For the treatment of various kinds of non-joint soft tissue rheumatic pain, such as shoulder pain, tenosynovitis, bursitis, myalgia and post-exercise pain.
For the treatment of acute mild to moderate pain such as: post-surgery, post-trauma, post-strain, primary dysmenorrhea, toothache, headache and so on.
It has an antipyretic effect against the fever of adults and children.
Indications
Ibuprofen (Advil, Motrin) is used as an analgesic
and antipyretic as well as a treatment for rheumatoid
arthritis and degenerative joint disease. The most frequently
observed side effects are nausea, heartburn,
epigastric pain, rash, and dizziness. Incidence of GI side
effects is lower than with indomethacin.Visual changes
and cross-sensitivity to aspirin have been reported.
Ibuprofen inhibits COX-1 and COX-2 about equally. It
decreases platelet aggregation, but the duration is
shorter and the effect quantitatively lower than with aspirin.
Ibuprofen prolongs bleeding times toward high
normal value and should be used with caution in patients
who have coagulation deficits or are receiving anticoagulant
therapy.
Used in Particular Diseases
Acute Gouty Arthritis:
Dosage and Frequency:?800 mg four times a day
Increase stroke risk
Ibuprofen is one of the most commonly used non-prescription painkillers, commonly used in the treatment of arthritis, muscle pain, neuralgia, headache, migraine, toothache, dysmenorrhea or low back pain. A recent study published in the British Medical Journal found that people who have taken a large number of antipyretic drugs, ibuprofen, have a 3-fold increase in the risk of getting stroke or heart disease.
Researchers from the University of Berne in Switzerland reviewed 31 clinical trials involving more than 11.6 million patients. Patients were treated with one of seven common analgesics. The results showed that patients subjecting to long-term administration of large doses of ibuprofen not only have a risk of getting stroke increased by 3 times, but also have significantly increased risk of suffering heart attack and heart disease death. However, the study also showed that occasionally taking ibuprofen for the treatment of headache will not be dangerous. The study also found that commonly used analgesic diclofenac sodium also has a similar problem.
The study found a health risk associated with long-term use of ibuprofen, being similar to the anti-arthritis drug rofecoxib (Velcro), which was halted in 2004 due to safety concerns.
Precautions
1.For late pregnancy women, it can prolong the pregnancy, causing dystocia and prolonged pregnancy course. Pregnant women and lactating women should not administrate it.
2. Inhibition of platelet aggregation; it can extent the bleeding time. This effect will disappear at 24 hours after withdrawal of the drug.
3. It can increase the blood urea nitrogen and serum creatinine content, further reducing the creatinine clearance rate. The following circumstances should be used with caution:
Bronchial asthma can be aggravated after treatment.
Heart failure, high blood pressure; medication can cause water retention, edema.
Hemophilia or other hemorrhagic diseases (including coagulation disorders and platelet dysfunction); medication can cause prolonged bleeding time, increase the bleeding tendency.
Patients with a history of gastrointestinal ulcers are prone to get gastrointestinal side effects, including generating new ulcers.
Patients of renal dysfunction, after administration, can get increased renal adverse reactions, and even get renal failure.
During long-term medication, it should be regularly checked of blood phase and liver, kidney function.
Drug Interactions
Drinking or combination with other non-steroidal anti-inflammatory drugs can increase the gastrointestinal side effects, and have the risk of ulcers. Long-term combination with acetaminophen can increase the toxic side effects on the kidney.
Combination with aspirin or other salicylic acid drugs causes no increase in the efficacy, but cam cause gastrointestinal adverse reactions and increase of the bleeding tendency.
Combination with heparin, dicoumarol and other anticoagulants as well as platelet aggregation inhibitors has the risk for increasing bleeding.
Combination with furosemide can weaken the sodium excretion effect and antihypertensive effect.
Combination with verapamil and nifedipine can increase the plasma concentration of the product.
Ibuprofen can increase the plasma concentration of digoxin; pay attention to adjusting the dose of digoxin upon co-administration.
Ibuprofen can enhance the role of anti-diabetic drugs (including oral hypoglycemic agents).
The goods, when used in combination with antihypertensive drugs can affect the antihypertensive effect of the latter one.
Probenecid can reduce the excretion of the goods, increase the concentration of blood, thereby increasing the toxicity, so it is proper to reduce the dosage upon co-administration.
The goods can reduce the excretion of methotrexate, increase the blood concentration which can reach up to the level of poisoning, so the goods should not be used with medium or large doses of methotrexate.
Side Effects
Gastrointestinal symptoms include indigestion, stomach burning sensation, stomach pain and nausea as well as vomiting. This usually appears in 16% long-term administrators. These symptoms will disappear upon drug withdraw. In most cases, the patients can tolerate even without withdrawal. A small number (<1%) of patients can get gastric ulcer and gastrointestinal bleeding. This are also cases of perforation due to ulcer.
Neurological symptoms such as headache, lethargy and dizziness; Tinnitus (rare) appears in 1% to 3% of patients.
Renal insufficiency is rare, mostly occur in patients of potential kidney disease; but a small number of patients may obtain lower extremity edema.
Other rare symptoms also include rash, bronchial asthma attack, elevated liver enzymes and leukopenia.
During medication, there might be emergence of gastrointestinal bleeding, liver and kidney dysfunction, visual impairment, abnormal blood and allergic reactions, etc., that should be discontinued.
Originator
Brufen,Boots,UK,1969
History
Ibuprofen
was developed while searching for an alternative pain reliever to aspirin in the 1950s. It and
related compounds were synthesized in 1961 by Stewart Adams, John Nicholson, and Colin
Burrows who were working for the Boots Pure Drug Company in Great Britain. Adams and
Nicholson filed for a British patent on ibuprofen in 1962 and obtained the patent in 1964;
subsequent patents were obtained in the United States. The patent of Adams and Nicholson
was for the invention of phenylalkane derivatives of the form shown in Figure 49.1, where
R1 could be various alkyl groups, R2 was hydrogen or methyl, and X was COOH or COOR,
with R being alkyl or aminoalkyl groups. The first clinical trials for ibuprofen were started in
1966. Ibuprofen was introduced under the trade name Brufen in 1969 in Great Britain. It was
introduced in the United States in 1974. Ibuprofen was initially off ered by prescription, but
it became available in over-the-counter medications in the 1980s.
Manufacturing Process
Isobutylbenzene is first acetylated to give isobutylacetophenone. 4-ibutylacetophenone (40 g), sulfur (11 g) and morpholine (30 ml) were refluxed
for 16 hours, cooled, acetic acid (170 ml) and concentrated hydrochloric acid
(280 ml) were added and the mixture was refluxed for a further 7 hours. The mixture was concentrated in vacuo to remove acetic acid and the concentrate
was diluted with water.The oil which separated was isolated with ether, the ethereal solution was
extracted with aqueous sodium carbonate and this extract was acidified with
hydrochloric acid. The oil was isolated with ether, evaporated to dryness and
the residue was esterified by refluxing with ethanol (100 ml) and concentrated
sulfuric acid (3 ml) for 5 hours. The excess alcohol was distilled off, the
residue was diluted with water, and the oil which separated was isolated with
ether. The ethereal solution was washed with sodium carbonate solution; then
with water and was dried. The ether was evaporated off and the oil was
distilled to give ethyl 4-i-butylphenylacetate.Sodium ethoxide from sodium (3.67 g) in absolute alcohol (64 ml) was added
over 20 minutes with stirring to a mixture of ethyl 4-i-butylphenylacetate
(28.14 g) and ethyl carbonate (102 ml) at 100°C. The reaction flask was
fitted with a Fenske column through which alcohol and then ethyl carbonate
distilled. After 1 hour when the still head reached 124°C heating was
discontinued. Glacial acetic acid (12 ml) and water (50 ml) was added to the
stirred ice-cooled mixture and the ester isolated in ether, washed with sodium
carbonate solution, water and distilled to give ethyl 4-i-butylphenylmalonate.Ethyl 4-i-butylphenylmalonate (27.53 g) in absolute alcohol (25 ml) was
added with stirring to a solution of sodium ethoxide From sodium (2.17 g) in
absolute alcohol (75 ml). Ethyl iodide (15 ml) was added and the mixture
refluxed for 2% hours, the alcohol distilled and the residue diluted with water,
extracted with ether, washed with sodium bisulfite, water, and evaporated to
dryness.The residual oil was stirred and refluxed with sodium hydroxide (75 ml of 5
N), water (45 ml) and 95% ethanol (120 ml). Within a few minutes a sodium
salt separated and after 1 hour the solid was collected, washed with ethanol,
dissolved in hot water and acidified with dilute hydrochloric acid to give the
methyl malonic acid which was collected and dried in vacuo MP 177° to 180°C
(dec.).The malonic acid (9 g) was heated to 210° to 220°C in an oil bath for 20
minutes until decarboxylation had ceased. The propionic acid was cooled and
recrystallized from light petroleum (BP 60° to 80°C). Two further
recrystallizations from the same solvent gave colorless prisms of 2-(4-
isobutylphenyl)propionicacid MP 75° to 77.5°C. (The procedure was reported
in US Patent 3,228,831.)
Therapeutic Function
Antiinflammatory
World Health Organization (WHO)
Ibuprofen, a non-steroidal anti-inflammatory agent, was
introduced in 1969. It was approved for sale without prescription in packages
containing no more than 400 mg, in the United Kingdom in 1983. This action was
followed by the USA, Canada and several European countries. Since this time
reports of suspected adverse effects have increased. Most of these relate to gastrointestinal
disturbances, hypersensitivity reactions but aseptic meningitis, skin
rashes and renal damage have been recorded.
Synthesis Reference(s)
Chemical and Pharmaceutical Bulletin, 31, p. 3139, 1983 DOI: 10.1248/cpb.31.3139The Journal of Organic Chemistry, 52, p. 287, 1987 DOI: 10.1021/jo00378a027
Flammability and Explosibility
Nonflammable
Biochem/physiol Actions
Primary TargetCOX-1
Pharmacokinetics
Ibuprofen is rapidly absorbed on oral administration, with peak plasma levels being generally attained within 2 hours
and a duration of action of less than 6 hours. As with most of these acidic NSAIDs, ibuprofen (pKa = 4.4) is
extensively bound to plasma proteins (99%) and will interact with other acidic drugs that are protein bound.
Clinical Use
Ibuprofen is indicated for the relief of the signs and symptoms of rheumatoid arthritis and osteoarthritis, the relief of
mild to moderate pain, the reduction of fever, and the treatment of dysmenorrhea.
Synthesis
Ibuprofen, 2-(4-iso-butylphenyl)propionic acid (3.2.23), can be synthesized
by various methods [88–98]. The simplest way to synthesize ibuprofen is by the acylation
of iso-butylbenzol by acetyl chloride. The resulting iso-butylbenzophenone (3.2.21) is
reacted with sodium cyanide, giving oxynitrile (3.2.22), which upon reaction with
hydroiodic acid in the presence of phosphorus is converted into 2-(4-iso-butylphenyl)propionic acid (3.2.23), which subsequently undergoes phases of dehydration, reduction, and
hydrolysis.Another way to synthesize ibuprofen consists of the chloromethylation of iso-butylbenzene, giving 4-iso-butylbenzylchloride (3.2.24). This product is reacted with sodium
cyanide, making 4-iso-butylbenzyl cyanide (3.2.25), which is alkylated in the presence of
sodium amide by methyl iodide into 2-(4-iso-butylbenzyl)propionitrile (3.2.26).
Hydrolysis of the resulting product in the presence of a base produces ibuprofen (3.2.23).
Drug interactions
Potentially hazardous interactions with other drugs
ACE inhibitors and angiotensin-II antagonists:
antagonism of hypotensive effect; increased risk of
nephrotoxicity and hyperkalaemia. Analgesics: avoid concomitant use of 2 or more
NSAIDs, including aspirin (increased side effects);
avoid with ketorolac (increased risk of side effects
and haemorrhage); possibly reduced antiplatelet
effect with aspirin.
Antibacterials: possibly increased risk of convulsions
with quinolones.
Anticoagulants: effects of coumarins and
phenindione enhanced; possibly increased risk of
bleeding with heparins, dabigatran and edoxaban -
avoid long term use with edoxaban.
Antidepressants: increased risk of bleeding with
SSRIs and venlaflaxine.
Antidiabetic agents: effects of sulphonylureas
enhanced.
Antiepileptics: possibly increased phenytoin
concentration.
Antivirals: increased risk of haematological toxicity
with zidovudine; concentration possibly increased by
ritonavir.
Ciclosporin: may potentiate nephrotoxicity.
Cytotoxics: reduced excretion of methotrexate;
increased risk of bleeding with erlotinib.
Diuretics: increased risk of nephrotoxicity;
antagonism of diuretic effect; hyperkalaemia with
potassium-sparing diuretics.
Lithium: excretion decreased.
Pentoxifylline: increased risk of bleeding.
Tacrolimus: increased risk of nephrotoxicity.
Environmental Fate
Ibuprofen has a high water solubility and low volatility, which
suggest a high mobility in the aquatic environment. This makes
it a commonly detected chemical of the pharmaceutical and
personal care products (PPCPs) in the environment. It is not as
persistent, however, as many other chemicals. Ibuprofen
undergoes photodegradation with exposure to direct and
indirect sunlight, although degradation products can have
effects on aquatic environments.
Metabolism
Metabolism occurs rapidly, and the drug is nearly completely excreted in the urine as unchanged drug and oxidative
metabolites within 24 hours following administration. Metabolism by CYP2C9 (90%) and CYP2C19 (10%)
involves primarily ω-, and ω1-, and ω2-oxidation of the p-isobutyl side chain, followed by alcohol oxidation of the primary alcohol resulting from ω–oxidation to the corresponding carboxylic acid. All metabolites are inactive. When
ibuprofen is administered as the individual enantiomers, the major metabolite isolated is the S-(+)-enantiomer
whatever the configuration of the starting enantiomer. Interestingly, the R-(–)-enantiomer is inverted to the
S-(+)-enantiomer in vivo via an acetyl–coenzyme A intermediate, accounting for the observation that the two
enantiomers are bioequivalent in vivo. This is a metabolic phenomenon that also has been observed for other
arylpropionic acids, such as ketoprofen, benoxaprofen, fenoprofen, and naproxen.
Toxicity evaluation
The mechanisms of ibuprofen-induced toxicity have not been
clearly defined. Acute renal failure is postulated to result from
decreased production of intrarenal prostaglandins via inhibition
of the cyclooxygenase pathway. In turn, this will decrease
the renal blood flow and glomerular filtration rate. Ibuprofen
also interferes with prostaglandin synthesis in the gastrointestinal
system, which can contribute to its irritating effect on the
mucosa of the gastrointestinal tract. Anion gap metabolic
acidosis is likely caused by elevated lactate due to hypotension
and hypoperfusion and also due to ibuprofen and its metabolites,
which are all weak acids. Seizures have been reported in
large ibuprofen overdoses, but the mechanism of toxicity
remains unknown. In massive overdoses, ibuprofen is thought
to have cellular toxicity disrupting mitochondrial energy
processes causing the formation of lactic acid.
references
[1]. kato m, nishida s, kitasato h, et al. cyclooxygenase-1 and cyclooxygenase-2 selectivity of non-steroidal anti-inflammatory drugs: investigation using human peripheral monocytes. j pharm pharmacol, 2001, 53(12): 1679-1685.[2]. janssen a, schiffmann s, birod k, et al. p53 is important for the anti-proliferative effect of ibuprofen in colon carcinoma cells. biochem biophys res commun, 2008, 365(4): 698-703.[3]. dabhi jk, solanki jk, mehta a. antiatherosclerotic activity of ibuprofen, a non-selective cox inhibitor--an animal study. indian j exp biol, 2008, 46(6): 476-481.[4]. redondo-castro e, navarro x. chronic ibuprofen administration reduces neuropathic pain but does not exert neuroprotection after spinal cord injury in adult rats. exp neurol, 2014, 252: 95-103.
Check Digit Verification of cas no
The CAS Registry Mumber 15687-27-1 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 1,5,6,8 and 7 respectively; the second part has 2 digits, 2 and 7 respectively.
Calculate Digit Verification of CAS Registry Number 15687-27:
(7*1)+(6*5)+(5*6)+(4*8)+(3*7)+(2*2)+(1*7)=131
131 % 10 = 1
So 15687-27-1 is a valid CAS Registry Number.
InChI:InChI=1/C13H18O2/c1-9(2)8-11-4-6-12(7-5-11)10(3)13(14)15/h4-7,9-10H,8H2,1-3H3,(H,14,15)/p-1/t10-/m1/s1
15687-27-1Relevant articles and documents
A NOVEL SYNTHESIS OF α,β-UNSATURATED NITRILES FROM AROMATIC KETONES VIA CYANOPHOSPHATES
Harusawa, Shinya,Yoneda, Ryuji,Kurihara, Takushi,Hamada, Yasumasa,Shioiri, Takayuki
, p. 427 - 428 (1984)
Reaction of aromatic ketones with diethyl phosphorocyanidate in the presence of lithium cyanide gave cyanophosphates, which were converted into α,β-unsaturated nitriles by treatment with boron trifluoride etherate in high yields.
Synthesis, pharmacological activity and hydrolytic behavior of glyceride prodrugs of ibuprofen
Khan,Akhter, Mymoona
, p. 371 - 376 (2005)
For reducing the gastrointestinal toxicity associated with ibuprofen its carboxylic group was condensed with the hydroxyl group of 1,2,3-trihydroxy propane 1,3-dipalmitate/stearate to give the ester prodrugs 3a and 3b. The release of ibuprofen from these prodrugs has been studied at pH 3, 4, 5 and 7.4 by HPLC using methanol and 0.05% phosphoric acid (80%) (70:30) as mobile phase. The prodrugs showed insignificant hydrolysis at pH 5 compared to pH 7.4 indicating that the prodrugs do not break in stomach but release ibuprofen at pH 7.4 in adequate amounts. In vivo hydrolysis studies in rats, the peak plasma concentration of ibuprofen was attained in 1.5:h in case of ibuprofen and in 2:h in prodrugs treated animals. The plasma concentration was found to be less at all times in animals treated with ibuprofen compared to the prodrugs treated animals. The maximum anti-inflammatory activity of ibuprofen was observed at 2 h whereas prodrugs showed maximum activity at 3 h and remained practically constant upto 8:h whereas a decrease in activity was observed with free ibuprofen. Further the prodrugs showed less gastric ulcers compared to ibuprofen. An average score of 0.16, 0.45, 0.97 and 0.20, 0.76, 1.02 of ulcers was observed with 3a and 3b compared to an average score of 0.75, 1.10, and 2.97 with ibuprofen. These prodrugs also showed significant protection against acetic acid induced writhings in rats. These finding suggested that both the prodrugs are better in action as compared to the parent drug and are advantageous in having less gastrointestinal side effects.
The continuous-flow synthesis of ibuprofen
Bogdan, Andrew R.,Poe, Sarah L.,Kubis, Daniel C.,Broadwater, Steven J.,McQuade, D. Tyler
, p. 8547 - 8550 (2009)
Let relief flow forth I A three-step, continuous-flow synthesis of ibuprofen was accomplished using a simplified microreactor. By designing a synthesis in which excess reagents and byproducts are compatible with downstream reactions, no intermediate purification or isolation steps are required.
The digital code driven autonomous synthesis of ibuprofen automated in a 3D-printer-based robot
Kitson, Philip J.,Glatzel, Stefan,Cronin, Leroy
, p. 2776 - 2783 (2016)
An automated synthesis robot was constructed by modifying an open source 3D printing platform. The resulting automated system was used to 3D print reaction vessels (reactionware) of differing internal volumes using polypropylene feedstock via a fused deposition modeling 3D printing approach and subsequently make use of these fabricated vessels to synthesize the nonsteroidal antiinflammatory drug ibuprofen via a consecutive one-pot three-step approach. The synthesis of ibuprofen could be achieved on different scales simply by adjusting the parameters in the robot control software. The software for controlling the synthesis robot was written in the python programming language and hard-coded for the synthesis of ibuprofen by the method described, opening possibilities for the sharing of validated synthetic 'programs' which can run on similar low cost, user-constructed robotic platforms towards an 'open-source' regime in the area of chemical synthesis.
Highly active supported palladium catalyst for the regioselective synthesis of 2-arylpropionic acids by carbonylation
Jayasree,Seayad,Chaudhari
, p. 1067 - 1068 (1999)
A catalyst system consisting of supported palladium in the presence of phosphine ligands, TsOH and LiCl catalyses the carbonylation of 1-arylethanols to 2-arylpropionic acids with significantly improved activity and regioselectivity; the catalyst can be recycled with no loss in activity and selectivity.
Synthesis and hydrolytic behaviour of glycerol-1,2-diibuprofenate-3-nitrate, a putative pro-drug of ibuprofen and glycerol-1-nitrate
Ingram,Moynihan,Powell,Rostron
, p. 345 - 350 (2001)
Nitroxylated derivatives of non-steroidal anti-inflammatory drugs appear to offer protection against the gastrotoxicity normally associated with non-steroidal anti-inflammatory drugs, ostensibly via local production of nitric oxide. A diester of ibuprofen and glycerol-1-mononitrate has been prepared via the condensation of ibuprofen with 3-bromopropan-1,2-diol, followed by silver-(I)-nitrate-mediated nitroxylation. The release of ibuprofen from this diester has been studied in a simulated gastric fluid model with direct analysis by reverse-phase HPLC, using an acetonitrile-water (80 % :20 %) mobile phase containing trifluoroacetic acid (0.005%). n-Propyl ibuprofen was found to undergo pH-dependent hydrolysis, ranging from negligible hydrolysis at pH 5 to 52 % hydrolysis at pH 3, over a 2-h period in this model. The ibuprofen-glycerol mononitrate diester was subjected to the most vigorous model hydrolytic conditions and was found to undergo 50 % hydrolysis during the study period. This study shows that pro-drugs of ibuprofen and glycerol mononitrate can be obtained, and can undergo degradation to the parent drugs under conditions simulating those likely to be encountered in the stomach.
Carbonylation of vinyl aromatics: Convenient regioselective synthesis of 2-arylpropanoic acids
Seayad,Jayasree,Chaudhari
, p. 459 - 461 (1999)
(equation presented) Various substituted and nonsubstituted 2-arylpropanoic acids have been synthesized in high turnovers with high regioselectivity by palladium-catalyzed carbonylation of vinyl aromatics. Both terminal and internal olefins are carbonylated, though hindered olefins are less reactive. In all the cases high yields and high selectivity are observed. Olefins with electron-withdrawing para substituents gave the highest regioselectivity in the formation of the corresponding 2-arylpropanoic acids.
Separate mechanisms of ion oligomerization tune the physicochemical properties of n-butylammonium acetate: Cation-base clusters vs. Anion-acid dimers
Berton, Paula,Kelley, Steven P.,Wang, Hui,Myerson, Allan S.,Rogers, Robin D.
, p. 25544 - 25554 (2017)
We investigated the ability of the ions comprising protic ionic liquids to strongly interact with their neutral acid and base forms through the characterization of n-butylammonium acetate ([C4NH3][OAc]) in the presence of excess n-butylamine (C4NH2) or excess acetic acid (HOAc). The conjugate and parent acid or base form new nonstoichiometric, noncovalently bound species (i.e., oligomeric ions) which change the physical and chemical properties of the resulting liquids, thus offering tunability. The effects of adding C4NH2 or HOAc to [C4NH3][OAc] on the resulting thermal and spectroscopic properties differ and suggest that C4NH2 interacts primarily with [C4NH3]+ to form 3-dimensional polymeric networks likely similar to those in H2O/[H3O]+, while HOAc interacts primarily with [OAc]- to form oligomeric ions (e.g., [H(OAc)2]-). The densities of the systems increased with the increase of acid content and reached a maximum when the acid molar fraction was 0.90, but decreased with increasing amine concentration. The viscosities decreased significantly with increasing acid or base concentration. The solvent properties of the mixtures were assessed by measuring the solubilities of benzene, ethyl acetate, diethyl ether, heptane, ibuprofen free acid, and lidocaine free base. The solubilities of the organic solutes and active pharmaceutical ingredients can be tuned with the concentration of acid or amine in the mixtures. In addition, crystallization of the active pharmaceutical ingredients can be induced with the modification of the composition of the mixtures. These observations support the usage of these mixtures for the synthesis and purification of acid or basic active pharmaceutical ingredients in the pharmaceutical industry.
NMR spectroscopic studies on the in vitro acyl glucuronide migration kinetics of ibuprofen ((±)-(R,S)-2-(4-isobutylphenyl) propanoic acid), its metabolites, and analogues
Johnson, Caroline H.,Wilson, Ian D.,Harding, John R.,Stachulski, Andrew V.,Iddon, Lisa,Nicholson, Jeremy K.,Lindon, John C.
, p. 8720 - 8727 (2007)
Carboxylic acid-containing drugs are often metabolized to 1-β-O-acyl glucuronides (AGs). These can undergo an internal chemical rearrangement, and the resulting reactive positional isomers can bind to endogenous proteins, with clear potential for adverse effects. Additionally any 1-β-O-acyl- glucuronidated phase I metabolite of the drug can also show this propensity, and investigation of the adverse effect potential of a drug also needs to consider such metabolites. Here the transacylation of the common drug ibuprofen and two of its metabolites is investigated in vitro. 1-β-O-Acyl (S)-ibuprofen glucuronide was isolated from human urine and also synthesized by selective acylation. Urine was also used as a source of the (R)-ibuprofen, (S)-2-hydroxyibuprofen, and (S,S)-carboxy-ibuprofen AGs. The degradation rates (a combination of transacylation and hydrolysis) were measured using 1H NMR spectroscopy, and the measured decrease in the 1-β anomer over time was used to derive half-lives for the glucuronides. The biosynthetic and chemically synthesized (S)-ibuprofen AGs had half-lives of 3.68 and 3.76 h, respectively. (R)-Ibuprofen AG had a half-life of 1.79 h, a value approximately half that of the (S)-diastereoisomer, consistent with results from other 2-aryl propionic acid drug AGs. The 2-hydroxyibuprofen and carboxyibuprofen AGs gave half-lives of 5.03 and 4.80 h, considerably longer than that of either of the parent drug glucuronides. In addition, two (S)-ibuprofen glucuronides were synthesized with the glucuronide carboxyl function esterified with either ethyl or allyl groups. The (S)-ibuprofen AG ethyl ester and (S)-ibuprofen AG allyl esters were determined to have half-lives of 7.24 and 9.35 h, respectively. In order to construct useful structure-reactivity relationships, it is necessary to evaluate transacylation and hydrolysis separately, and here it is shown that the (R)- and (S)-ibuprofen AGs have different transacylation properties. The implications of these findings are discussed in terms of structure-activity relationships.
Expanding the substrate scope of enzymes: Combining mutations obtained by CASTing
Reetz, Manfred T.,Carballeira, Jose Daniel,Peyralans, Jerome,Hoebenreich, Horst,Maichele, Andrea,Vogel, Andreas
, p. 6031 - 6038 (2006)
In a previous paper, the combinatorial active-site saturation test (CAST) was introduced as an effective strategy for the directed evolution of enzymes toward broader substrate acceptance. CASTing comprises the systematic design and screening of focused libraries around the complete binding pocket, but it is only the first step of an evolutionary process because only the initial libraries of mutants are considered. In the present study, a simple method is presented for further optimization of initial hits by combining the mutational changes obtained from two different libraries. Combined lipase mutants were screened for hydrolytic activity against six notoriously difficult substrates (bulky carboxylic acid esters) and improved mutants showing significantly higher activity were identified. The enantioselectivity of the mutants in the hydrolytic kinetic resolution of two substrates was also studied, with the best mutant-substrate combination resulting in a selectivity factor of E=49. Finally, the catalytic profile of the evolved mutants in the hydrolysis of simple nonbranched carboxylic acid esters, ranging from acetate to palmitate, was studied for theoretical reasons.
