• Journal of Pharmaceutical Investigation
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• v.27 no.2
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• pp.125-131
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• 1997

Ethoxycarbonyloxyethyl ester of ceftezole (CFZ-ET) was synthesized as a prodrug by esterification of ceftezole (CFZ) with ethoxycarbonyloxyethyl chloride and was confirmed by spectroscopic analyses. CFZ-ET was more lipophillic than CFZ as assessed by n-octanol and water partition coefficients at various pH. CFZ-ET itself did not show any microbiological activity in vitro, but showed substaintial microbiological activity after oral administration of CFZ-ET, indicating that CFZ-ET is converted to microbiologically active metabolite, probably CFZ, in the body. When CFZ-ET was incubated in blood, liver and intestine homogenates of rabbits, liver homogenate showed the fastest conversion of CFZ-ET. CFZ-ET appears rapidly metabolized in the liver when given orally due to the hydrolysis of the ester to CFZ, the parent drug of CFZ-ET. In vivo metabolism of CFZ-ET to CFZ was confirmed in rabbit by HPLC analysis. CFZ-ET were higher than those in the serum samples taken after oral administration of equivalent amount of CFZ. Oral bioavailability of CFZ-ET was 1.5-fold higher than that of CFZ in rabbits because of enhanced lipophilicity and absorption. Based on these findings, CFZ-ET appears useful as a prodrug of CFZ to improve the oral bioavailability of CFZ.

• Korean Journal of Environmental Agriculture
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• v.12 no.1
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• pp.69-80
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• 1993

Environmental hazards of a chemical could be assessed by two different approaches : toxicity test and assessment of exposure potentials to human and environmental organisms. For the prediction of environmental fate of chemicals three available computer programs were compared each other and were verified. The results obtained by using these computer programs, PCHEM, EXAMS, and E4CHEM were summarized as follows. The estimated octanol/water partition coefficients by PCHEM were similar to the experimental values in the literature. But the other factors, water solubility and vapor pressure were different from the data in the literature. The simulation results of selected compounds by EXAMS showed similar tendency to the literature results of model field environment. Therefore, this computer program could be utilized to predict the environmental fate of chemicals. E4CHEM program is very simple and this program could predict the ultimate environmental fate of stable chemicals by input of two or three parameters. However, the validity should further be verified in the future field study using more compounds. It is suggested that these approaches could be fully utilized by understanding their limitations to predict the environmental fate of new chemicals under development, to screen the potential environmental pollutants among chemicals already-in use, and to devise measures to minimize the hazards to the environment.

• Journal of Pharmaceutical Investigation
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• v.31 no.2
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• pp.95-100
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• 2001

Various alkyl ester prodrugs of diclofenac were synthesized in order to investigate the relationship between their skin permeation characteristics and physicochemical properties. Solubility in various vehicles was measured at room temperature. 1-Octanol/water partition coefficients (Log P) and capacity factors (k') were measured to determine the lipophilicity of the prodrugs. Stability of prodrugs in the skin extract and homogenate was also investigated before conducting the skin permeation studies. Increases in the Log P and capacity factor values were observed when alkyl esters of diclofenac were prepared. Since the aqueous solubility of the prodrugs was not high enough, they were saturated in propylene glycol (PG) for skin permeation studies. Prodrugs were rapidly metabolized to diclofenac, both in skin homogenate and in dermal extract of skin. The skin permeation rate of alkyl ester prodrugs was significantly higher than diclofenac with shorter lag time. Moreover, a parabolic relationship was observed between the permeation rate and the log P values of prodrugs, and the maximum flux was achieved at a log P value of around 4.0.

• Journal of Pharmaceutical Investigation
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• v.31 no.3
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• pp.143-150
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• 2001

Butyrolactone ester of ceftezole (CFZ-BL) was synthesized by esterification of ceftezole (CFZ) with ${\alpha}-bromo-{\gamma}-butyrolactone$. The synthesis was confirmed by spectroscopic analysis. CFZ-BL was more lipophilic than CFZ when the lipophilicity was assessed by partition coefficients between n-octanol and water at various pH. CFZ-BL itself did not show any microbiological activity in vitro, but serums taken after oral administration of CFZ-BL showed substaintial microbiological activity indicating that CFZ-BL is converted to microbiologically active metabolite, probably CFZ, in the body. The conversion was confirmed by in vitro incubation study, in which CFZ-BL was incubated in some body tissues of rabbit. Liver homogenate showed fastest conversion of CFZ-BL among the tissues tested (blood and intestine). Thus, CFZ-BL appeares to be rapidly metabolized in the liver to CFZ following oral administration. The metabolism process appears to be hydrolysis of the ester to CFZ, the parent drug of CFZ-BL. In vivo metabolism of CFZ-BL to CFZ was confirmed by analying CFZ by HPLC. CFZ concentration in the serum samples taken after oral administration of CFZ-BL were higher than those in the serum samples taken after oral administration of equivalent amount of CFZ. Oral bioavailability of CFZ-BL, a prodrug of CFZ, was 1.45-fold higher than that of CFZ in rabbits possibly due to enhanced lipophility and absorption of the prodrug.

• Archives of Pharmacal Research
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• v.26 no.7
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• pp.526-531
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• 2003

KR-31378 is a new drug candidate intended for the use in the prevention of ischemia-reperfusion damage. The objective of this preformulation study was to determine the physicochemical properties of KR-31378. The n-octanol to water partition coefficients of KR-31378 were 0.0504 at pH 3 and 0.8874 at pH 10. Accelerated stability of KR-31378 in solution and solid state was studied at 5, 40, $60^{\circ}C$. The stability testing indicated that the t90 for the drug in solid was estimated to be 2 years and 128.6 days at $25^{\circ}C$, while the that in aquesou solution was 68.6 days at $25^{\circ}C$. The KR-31378 was also found to be unstable under the relative humidity of 76%, probably because of the hygroscopic nature of the drug. In order to study compatibility of KR-31378 with typical excipients, potential change in differential scanning calorimetry spectrum was studied in 1:1 binary mixtures of KR-31378 and Aerosil, Avicel, Eudragit, lactose, PEG, talc, CMC, PVP, starch. As a result, CMC, PVP, and starch were found to be incompatible with KR-31378, indicating the addition of these excipients may complicate the manufacturing of the formulation for the drug. Particle size distribution of KR-31378 powder was in the size range of 9-93 $\mu$ m with the mean particle size of 37.9 $\mu$ m. The flowability of KR-31378 was apparently inadequate, indicating the granulation may be necessary for the processing of the drug to solid dosage forms. Crystallization of the drug with a number of organic solvents did not lead a crystalline polymorphism. In addition, dissolution of the drug from the powder was adequately rapid at $37^{\circ}C$ in water.

• Journal of Pharmaceutical Investigation
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• v.31 no.4
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• pp.217-224
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• 2001

To develop a novel transdermal delivery system of loxoprofen (LP), a potent antiinflammatory and analgesic agent, the effects of various vehicles and penetration enhancers on the skin permeation of LP from solution formulations were investigated. The permeation rate of LP through excised guinea pig skin was measured using a side-by-side permeation system at $32^{\circ}C$. The solubilities of LP in various vehicles were determined by the equilibrium solubility method, and partition coefficients $(P_c)$ were determined. The solubility of LP increased in the rank order of water & isopropyl myristate (IPM) & glyceryl dicaprylate/dicaprate & propylene glycol dicaprylate/caprate & propylene glycol laurate (PGL) & polyethylene glycol 400 & diethylene glycol monoethyl ether (DGME) & ethanol. n-Octanol-water $P_c$ value was 15.5. Among pure vehicles tested, IPM and PGL showed highest fluxes of $89.9{\pm}5.0$ and $45.4{\pm}0.3\;{\mu}g/cm^2/hr$ from saturated solutions, respectively. However, it was not possible to demonstrate any correlation between the solubility of LP and its permeation rate, indicating the change in the barrier property of the skin and/or carrier mechanisms by vehicles tested. The addition of DGME to IPM or PGL markedly increased the solubility of LP, but the permeation rate did not decrease when the concentration of DGME in the cosolvent was increased upto 40%. The addition of linoleic acid (3%) in the cosolvent slightly increased the permeation rate, but others such as lauroyl sarcosine, fatty alcohols and fatty acids tested did not show enhancing effect. In conclusion, the DGME-IPM or DGME-PGL cosolvent system proved to be a good vehicle to enhance the skin permeation of LP.

• Archives of Pharmacal Research
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• v.26 no.12
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• pp.1002-1008
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• 2003

Ferulic acid (3-methoxy, 4-hydroxy cinnamic acid) is a flavoid component possessing antioxidant property. The compound is currently under development as a new drug candidate for the treatment of the dementia. The objective of this preformulation study was to determine the physicochemical properties of ferulic acid. The n-octanol to water partition coefficients of ferulic acid were 0.375 and 0.489 at the pHs of 3 and 10, respectively. Accelerated stability study for ferulic acid indicated that the t 90 value for the drug was estimated to be 459 days at $25^{\circ}C$. Ferulic acid was also found to be unstable under the relative humidity of more than 76%, probably because of the hygroscopic nature of the drug. In order to study compatibility of ferulic acid with typical excipients, potential change in differential scanning calorimetry spectrum was studied in 1: 1 binary mixtures of ferulic acid and typical pharmaceutical excipients (e.g., Aerosil, Avicel, CMC, Eudragit, lactose, PEG, PVP, starch and talc). Avicel, CMC, PVP and starch were found to be incompatible with ferulic acid, indicating the addition of these excipients may complicate the manufacturing of the formulation for the drug. Particle size distribution of ferulic acid powder was in the size range of 10-190 $\mu$m with the mean particle size of 61 $\mu$m. The flowability of ferulic acid was apparently inadequate, indicating the granulation may be necessary for the processing of the drug to solid dosage forms. Two polymorphic forms were obtained by recrystallization from various solvents used in formulation. New polymorphic form of ferulic acid, Form II, was obtained by recrystallization from 1,4-dioxane. The equilibrium solubility for Form I was approximately twice of that for Form II. The dissolution rate of Form II was higher than that of Form I in the early phase (<6 min). Therefore, these physicochemical information has to be taken in the consideration for the formulation of ferulic acid.