ABSTRACT
Solubility of pharmaceuticals is still a challenging subject and solubilization using cosolvents is the most common technique used in the pharmaceutical industry. The purpose of this study was reporting and modeling the experimental molar solubility of pioglitazone hydrochloride [PGZ-HC1] in binary and ternary mixtures of ethanol [EtOH], N-methyl pyrrolidone [NMP], polyethylene glycols [PEGs] 200, 400, 600 and water along with the density of saturated solutions at 298.2 K. To provide a computational method, the Jouyban-Acree model was fitted to the solubilities of the binary solvents, and solubilities of the ternary solvents were back-calculated by employing the solubility data in mono-solvents. In the next step, the ternary interaction terms were added to the model and the prediction overall mean percentage deviation [MPD] of the ternary data was reduced. Also a previously proposed version of the model was used to predict the solubility of PGZ-HC1 in binary and ternary mixtures employing the experimental solubility data in mono-solvents. The overall MPD of the model for fitting the binary data and predicted data of ternary solvents were 2.0% and 50.5%, respectively. The overall MPD of the predicted solubilities in ternary solvents using the ternary interaction terms in the model was 34.2%, and by using the proposed version of the Jouyban-Acree model for binary and ternary data the overall correlation and prediction errors were 18.0 and 15.0%, respectively. The solubility of PGZ-HC1 was increased by addition of EtOH, NMP, PEGs 200, 400 and 600 to aqueous solutions. The reported data extended the available solubility data of pharmaceuticals which are crucial in formulation of liquid dosage forms. The constants of the Jouyban-Acree model using the generated data are also reported which provides the possibility of solubility prediction in other solvent mixtures and temperatures
ABSTRACT
Due to high kinetic variation of antiepileptic medications in children, judgment on the efficacy of intravenous phenytoin and phenobarbital in treatment of refractory status epilepsy, requires measurement of serum levels of the drugs. The aim of this study was determine and compare serum levels of phenytoin and phenobarbital, as the two major and common first- line drugs in treatment of children with status epilepsy and refractory status epilepsy. Serum levels of phenytoin and phenobarbital in 20 children [1 month - 12 years] with refractory status epilepsy [candidates for midazolam infusion] was compared with 20 children with status epilepsy. Age, gender, etiology, type of seizure and previous use of antiepileptic drugs were matched. In patients with status epilepsy and refractory status epilepsy mean serum levels of phenobarbital were 28.03 +/- 12.7 microg/ml, 37.22 +/- 20.78 microg/ml respectively while serum levels of phenytoin were 30.38 +/- 16.80 micro g/ml, 31.42 +/- 14.81 microg/ml respectively. There was no significant difference between phenobarbital [P=0.1] and phenytoin [P=0.8] serum levels in these two groups. There was no significant correlation between phenobarbital serum level with age in the group of status epilepsy [P=0.1] and refractory status epilepsy [P=0.8]. In contrast, increased phenytoin serum level was associated with increased age in status epilepsy group [P=0.004] and refractory status epilepsy group [P=0.01]. In both groups, blood level of the drugs were within the therapeutic range. High pharmacokinetic variation of antiepileptic medications in children does not cause any changes in the serum level of intravenous phenytoin and phenobarbital in the groups of status epilepsy and refractory status epilepsy. Development of refractory status epilepsy is probably due to the nature of disease or other unknown factors which need further studies