Automated system for release studies of salicylic acid based on a SIA method

The aim of this work was to describe a fully automated system for the in vitro release testing of semisolid dosage forms based on SIA technique. The system was tested for monitoring release profiles of different ointments containing 3% of salicylic acid (Belosalic, Diprosalic, Triamcinolone S). The native fluorescence of salicylic acid was used for fluorimetric detection. Phosphate buffer pH 7.4 was the receptor medium; samples were taken at 10 min intervals during 6 h of the release test; and each test was followed by calibration with five standard solutions. The linear calibration range was 0.05–10 μg ml⁻¹ (r = 0.9996, six standards); the maximal SIA sample throughput for this system was 120 h⁻¹, sample volume being 50 μl and flow rate 50 μl s⁻¹. The detection limit for salicylic acid was 0.01 μg ml⁻¹.     

Human adult and foetal liver sulphotransferases: inhibition by mefenamic acid and salicylic acid

1. The aim was to see whether mefenamic acid and salicylic acid had different inhibition profiles for SULT1A1 (substrate: 4-nitrophenol) and SULT1A3 (dopamine) activities and on (?)-salbutamol and minoxidil sulphation rates in the human adult and mid-gestational foetal livers. 2. The activity (pmol min^?1 mg^?1) of SULT1A1 was 662 ± 78 (adult) and 246 ± 159 (foetus; p = 0.0003) and that of SULT1A3 was 24 ± 4 (adult) and 121 ± 90 (foetus; p = 0.030). The rate (pmol min^?1 mg^?1) of (?)-salbutamol sulphation was 109 ± 27 (adult) and 117 ± 34 (foetus; p = 0.144) and that of minoxidil sulphation was 202 ± 38 (adult) and 108 ± 44 (foetus; p = 0.001). 3. With mefenamic acid as an inhibitor, the IC₅₀ (μM) for SULT1A1 was 0.02 ± 0.004 (adult) and 0.01 ± 0.002 (foetus; p = 0.001); for SULT1A3 it was 76 ± 6 (adult) and 77 ± 13 (foetus; p = 0.889); for the rate of (?)-salbutamol sulphation it was 0.07 ± 0.005 (adult) and not determinable (foetus) and for minoxidil sulphation it was 1.6 ± 0.7 (adult) and 0.15 ± 0.04 (foetus; p = 0.076). 4. With salicylic acid as an inhibitor, the IC₅₀ (μM) for SULT1A1 was 30 ± 2 (adult) and 25 ± 1 (foetus; p = 0.011); for SULT1A3 it was 690 ± 36 (adult) and 570 ± 16 (foetus; p = 0.229); for the rate of (?)-salbutamol sulphation it was 93 ± 11 (adult) and 344 ± 42 (foetus; p = 0.010); with minoxidil as substrate, the IC₅₀ was not determinable. 5. In summary, SULT1A1, SULT1A3 and the sulphotransferases towards (?)- salbutamol and minoxidil had measurable activities in the mid-gestational human foetal liver. Mefenamic acid was a more potent inhibitor than salicylic acid of both human adult and foetal liver SULT1A1 and SULT1A3 activities. Foetal liver SULT1A1 was more susceptible than adult liver SULT1A1 to inhibition by mefenamic acid and salicylic acid. These results are consistent with the view that sulphotransferases develop early in the human foetal liver and drugs may inhibit their activities.     

Human adult and foetal liver sulphotransferases: inhibition by mefenamic acid and salicylic acid

1. The aim was to see whether mefenamic acid and salicylic acid had different inhibition profiles for SULT1A1 (substrate: 4-nitrophenol) and SULT1A3 (dopamine) activities and on (-)-salbutamol and minoxidil sulphation rates in the human adult and mid-gestational foetal livers. 2. The activity (pmolmin(-1) mg(-1) of SULT1A1 was 662 +/- 78 (adult) and 246 +/- 159 (foetus; p = 0.003) and that of SULT1A3 was 24 +/- 4 (adult) and 121 +/- 90 (foetus; p = 0.030). The rate (pmol min(-1) mg(-1)) of (-)-salbutamol sulphation was 109 +/- 27 (adult) and 117 +/- 34 (foetus; p = (0.144) and that of minoxidil sulphation was 202 +/- 38 (adult) and 108 +/- 44 (foetus; p = 0.001). 3. With mefenamic acid as an inhibitor, the IC50 (microM) for SULT1A1 was 0.2 +/- 0.004 (adult) and 0.01 +/- 0.002 (foetus; p = 0.001); for SULT1A3 it was 76 +/- 6 (adult) and 77 +/- 13 (foetus; p = 0.889); for the rate of ( )-salbutamol sulphation it was 0.07 +/- 0.005 (adult) and not determinable (foetus) and for minoxidil sulphation it was 1.6 +/- 0.7 (adult) and 0.15 +/- 0.04 (foetus; p = 0.076). 4. With salicylic acid as an inhibitor, the IC50 (microM) for SULT1A1 was 30 +/- 2 (adult) and 25 +/- 1 (foetus; p = 0.011); for SULT1A3 it was 690 +/- 36 (adult) and 570 +/- 16 (foetus; p = 0.229); for the rate of ( )-salbutamol sulphation it was 93 +/- 11 (adult) and 344 +/- 42 (foetus; p = 0.010); with minoxidil as substrate, the IC50 was not determinable. 5. In summary, SULT1A1, SULT1A3 and the sulphotransferases towards (-)-salbutamol and minoxidil had measurable activities in the mid-gestational human foetal liver. Mefenamic acid was a more potent inhibitor than salicylic acid of both human adult and foetal liver SULT1A1 and SULT1A3 activities. Foetal liver SULT1A1 was more susceptible than adult liver SULT1A1 to inhibition by mefenamic acid and salicylic acid. These results are consistent with the view that sulphotransferases develop early in the human foetal liver and drugs may inhibit their activities.     

Kinetic study on dissociation of amylose/salicylic acid compound using non-isothermal method

The inclusion compound of amylose and salicylic acid (SA) was prepared by a sealed temperature control method, and the formation of the inclusion compound was confirmed by IR spectrum and powder X-ray diffraction. The kinetic parameters of dissociation of amylose/SA compound were studied by the nonisothermal method which was defined as a relationship between the dissociation ratio and time. The values of activation energy (Ea) and frequency factors (InA) were calculated by a nonlinear least-square method. In this study, the formation of the inclusion compound of amylose/SA was confirmed by IR spectrum powder X-ray diffraction. SA existed in a molecule form in the spiral stouction of amylose. The dissociation of amylose/SA compound was attributed to first order reaction. The values of Ea calculated by the nor-isothermal method were 21.71 and 22.41 kJ x mol(-1) at heating rate 5 and 10 degrees C x h(-1), respectively. The corresponding isothermal method value of Ea was 22.17 kJ x mol(-1); the calculated InA values were 9.32 and 10.08 at heating rate 5 and 10 degrees C x h(-1), respectively. The corresponding isothermal method lnA value was 9.26. The results were in good agreement with Ea values and lnA values by isothermal method. These results indicated that the non-isothermal method described in this study could be adequately used for the stability study of inclusion compound and was a rapid and accurate method for the determination of kinetic parameters.     

Kinetic analysis of the transport of salicylic acid, a nonsteroidal anti-inflammatory drug, across human placenta.

The aim of this study was to develop a pharmacokinetic model to describe the transplacental transfer of drugs, based on the human placental perfusion study. The maternal and fetal sides of human placentas were perfused with salicylic acid together with antipyrine, a passive diffusion marker. The drug concentration in the placental tissue was determined at the end of perfusion. A compartment model consisting of maternal space, fetal intravascular space, and placental tissue was fitted to the observed concentration profiles of salicylic acid in the maternal and fetal effluents. The developed model could adequately explain the concentration profiles of salicylic acid in the effluents with influx clearances from maternal and fetal perfusates to placental tissue of 0.0407 and 0.0813 ml/min/g cotyledon and efflux rate constants from placental tissue to maternal and fetal perfusates (k2 and k3) of 0.0238 and 0.176 min(-1), respectively. The kinetics of antipyrine was adequately described by assuming rapid equilibrium between fetal perfusate and placental tissue compartments. The influx plasma clearance from the maternal side (K'1) in humans was estimated by taking into account the protein binding. The K'1/k2 value of salicylic acid was 1.07 ml/g cotyledon and was larger than that of antipyrine (0.642 ml/g cotyledon). We evaluated the transplacental transfer kinetics of salicylic acid by human placental perfusion study with various perfusion protocols. Based on the data obtained, we developed a pharmacokinetic model, which should enable us to estimate the influx profile of drugs into umbilical arterial blood from the maternal plasma concentration profile.     

FT-IR and NMR spectroscopic studies of salicylic acid derivatives. I. Gentisamide -- a metabolite of salicylamide

Gentisamide (GAM, 2,5-dihydroxybenzamide), a minor first-pass metabolite of salicylamide (SAM, 2-hydroxybenzamide), was studied using FT-IR, 1D and 2D homo- and heteronuclear 1H and 13C NMR spectroscopy. GAM was isolated from human urine eight hours after oral administration of SAM. FT-IR, 1H and 13C NMR spectra unequivocally confirmed the chemical structure of GAM through chemical and substituent shifts, coupling constants and connectivities in COSY, NOESY, HETCOR and HBMC spectra. From NOESY spectra of GAM in DMSO-d6, it was concluded that the amide protons are oriented toward the ortho-proton at C-6. Obtained results indicate that the presence of the additional phenol group at C-5 in GAM favours the formation of intramolecular hydrogen bonding of the O...HO type between C2-OH proton and oxygen atom of the amide group.     

The inhibition of cyclo-oxygenase of rabbit platelets by aspirin is prevented by salicylic acid and by phenanthrolines.

Salicylic acid, 1,10- and 1,7-phenanthroline prevented inhibition by aspirin of platelet aggregation and of generation of thromboxane A2 due to arachidonic acid, to the ionophore A21387, to thrombin and to collagen. Dithiothreitol, another drug which prevents aggregation and formation of thromboxane A2, but only reversibly, failed to interfere with the inhibition by aspirin. Irreversible inhibition by indomethacin and by the substrate analogue 5,8,11,14-tetraynoic acid was also unaffected by salicylic acid or by 1,10-phenanthroline, which thus probably exert a specific interaction with the aspirin-binding site. Inactivation of platelet cyclo-oxygenase with arachidonic acid led to inhibition of the formation of thromboxane A2 and of aggregation due to arachidonic acid itself and to collagen, but barely affected aggregation by thrombin, even though generation of thromboxane A2 was blocked. Use of salicylic acid and of reversible inhibitors of cyclo-oxygenase may help to unravel the mechanism of inhibition due to other agents.     

反相高效液相色谱法同时测定复方水杨酸洗剂中水杨酸和间苯二酚的含量

目的　建立测定复方水杨酸洗剂中水杨酸和间苯二酚含量的高效液相色谱法。方法　采用反相C18色谱柱,以乙腈 甲醇 水(10∶5∶85 )为流动相,流速: 1. 0mL·min-1,检测波长为 278nm。结果　水杨酸与间苯二酚的线性范围均为 300 ~900μg·mL-1,水杨酸r=0. 999 6,平均回收率为 100. 24%,RSD为 0. 83%;间苯二酚r=0. 9995,平均回收率为 99. 97%,RSD为 1. 02%.结论　该方法简便准确,可同时测定复方水杨酸洗剂中水杨酸及间苯二酚的含量。     

Hippuric acid as a major excretion product associated with black tea consumption

1. Nine habitual tea-drinking volunteers were recruited and asked to follow a low-polyphenol and low-caffeine diet for 6 days and to provide daily 24-h urine samples. On day 4 of the experiment strong black tea brewed under standardized conditions was re-introduced to the volunteers' diet. 2. 1H-NMR and HPLC profiling of the urine samples indicated that consumption of black tea (6-10 mugs per day) was associated with a significant (p = 0.00017) increase in hippuric acid excretion relative to control, increasing from 153-512 to 742-1374 mg day(-1). The excretion of substantial amounts of hippuric acid has not previously been associated with black tea consumption. 3. For some volunteers, the quantity of benzoic acid processed exceeded the acceptable daily intake (ADI), but this is not considered to constitute any hazard. 4. A mass-balance analysis indicated that the necessary quantity of benzoic acid could not be obtained from the contents of gallic acid, flavanols, flavonol glycosides and theaflavins in black tea even if 100% transformation was obtained, suggesting that the thearubigins (the major and chemically ill-defined polyphenols of black tea) may be an important source.     

Hippuric acid as a major excretion product associated with black tea consumption

1. Nine habitual tea-drinking volunteers were recruited and asked to follow a low-polyphenol and low-caffeine diet for 6 days and to provide daily 24-h urine samples. On day 4 of the experiment strong black tea brewed under standardized conditions was reintroduced to the volunteers' diet. 2. ¹H-NMR and HPLC profiling of the urine samples indicated that consumption of black tea (6-10 mugs per day) was associated with a significant (p=0.00017) increase in hippuric acid excretion relative to control, increasing from 153-512 to 742-1374?mg day^-1. The excretion of substantial amounts of hippuric acid has not previously been associated with black tea consumption. 3. For some volunteers, the quantity of benzoic acid processed exceeded the acceptable daily intake (ADI), but this is not considered to constitute any hazard. 4. A mass-balance analysis indicated that the necessary quantity of benzoic acid could not be obtained from the contents of gallic acid, flavanols, flavonol glycosides and theaflavins in black tea even if 100% transformation was obtained, suggesting that the thearubigins (the major and chemically ill-defined polyphenols of black tea) may be an important source.     

Modification of polyacryloyl chloride with salicylic acid

Translated from Khimiko-farmatsevticheskii Zhurnal, Vol. 28, No. 12, pp. 40–41, December, 1994.     

HPLC法测定水杨酸苯酚洗剂中苯酚和水杨酸的含量

目的:建立HPLC法分离测定水杨酸苯酚洗剂中水杨酸和苯酚的含量.方法:色谱柱为Shim-packCLC-CN柱,柱温:40℃,流动相为甲醇-水(28:72),以冰醋酸调节pH至5.0;检测波长为277nm.结果:水杨酸和苯酚的线性范围分别为10.0～500.0μg/mL(r=0.999 9)和10.0～200.0μg/mL(r=0.999 9),平均回收率分别为100.9%和100.8%.结论:本方法简便、准确,可用于水杨酸苯酚洗剂的质量控制.     

Direct preparation of spherically agglomerated salicylic acid crystals during crystallization

Needle-like salicylic acid crystals were transformed into a spherically shaped dense form during crystallization by the spherical crystallization technique. Agitation of a mixture of ethanol-water-chloroform containing salicylic acid yielded spherically agglomerated salicylic acid crystals. The crystallinity of the agglomerated salicylic acid the amount of ethanol in the solvent mixture was decreased. The wettability of the agglomerated crystals increased when the amount of ethanol in the solvent mixture was decreased, and this enhanced the dissolution rate of the crystals. The remarkable improvements in the flow and packing of the agglomerated crystals enabled the direct compression of the crystals.