Calculating osmotic pressure of glucose solutions according to ASOG model and measuring it with air humidity osmometry.

The osmotic pressure of glucose solution at a wide concentration range was calculated using ASOG model and experimentally determined by our newly reported air humidity osmometry. The measurements from air humidity osmometry were compared with the well-established freezing point osmometry and ASOG model calculations at low concentrations and with only ASOG model calculations at high concentrations where no standard experimental method could serve as a reference for comparison. Results indicate that air humidity osmometry measurements are comparable to ASOG model calculations at a wide concentration range, while at low concentrations freezing point osmometry measurements provide better comparability with ASOG model calculations.

[Air humidity solubility assay].

Measurement of drug solubility is one of the key elements of compound characterization during the drug discovery and development process. A broad variety of solubility assay methods have been developed, including equilibrium method which requires analysis of the equilibrium composition and kinetic method which monitors the concentration of a compound dynamically at the time when a precipitate first appears or disappears in the solution. Despite the numerous experimental methods, precise drug solubility values are hard to obtain for time-consuming, sample size and manual work. In this article, we reported a new method, namely air humidity solubility assay, which measures the relative humidity of the air in equilibrium with the solution at a given temperature, and then calculates solubility from the relative humidity according to extended-non random two liquid (NRTL) model. NaCl was used as a model drug, and the solubility was measured at the temperature of 20-50 ℃. The results indicate that the solubility of NaCl determined with the new method is generally comparable to that determined by gravimetry that is reported in literature. The new method has a relative error of less than 2%. Although the accuracy is lower than that of gravimetry, air humidity solubility assay is more convenient, practical, operational and universal. This method provides a supplement to the existing methods.

Cross-validation of the osmotic pressure based on Pitzer model with air humidity osmometry at high concentration of ammonium sulfate solutions.

The osmotic pressure of ammonium sulfate solutions has been measured by the well-established freezing point osmometry in dilute solutions and we recently reported air humidity osmometry in a much wider range of concentration. Air humidity osmometry cross-validated the theoretical calculations of osmotic pressure based on the Pitzer model at high concentrations by two one-sided test (TOST) of equivalence with multiple testing corrections, where no other experimental method could serve as a reference for comparison. Although more strict equivalence criteria were established between the measurements of freezing point osmometry and the calculations based on the Pitzer model at low concentration, air humidity osmometry is the only currently available osmometry applicable to high concentration, serves as an economic addition to standard osmometry.

Determining osmotic pressure of drug solutions by air humidity in equilibrium method.

OBJECTIVE: To establish a new osmotic pressure measuring method with a wide measuring range. METHOD: The osmotic pressure of drug solutions is determined by measuring the relative air humidity in equilibrium with the solution. The freezing point osmometry is used as a control. RESULTS: The data obtained by the proposed method are comparable to those by the control method, and the measuring range of the proposed method is significantly wider than that of the control method. CONCLUSION: The proposed method is performed in an isothermal and equilibrium state, so it overcomes the defects of the freezing point and dew point osmometries which result from the heterothermal process in the measurement, and therefore is not limited to diluted solutions.

Calculating osmotic pressure according to nonelectrolyte Wilson nonrandom factor model.

Abstract The osmotic pressure of NaCl solutions was determined by the air humidity in equilibrium (AHE) method. The relationship between the osmotic pressure and the concentration was explored theoretically, and the osmotic pressure was calculated according to the nonelectrolyte Wilson nonrandom factor (N-Wilson-NRF) model from the concentration. The results indicate that the calculated osmotic pressure is comparable to the measured one.

Calculating osmotic pressure of xylitol solutions from molality according to UNIFAC model and measuring it with air humidity osmometry.

The osmotic pressure of xylitol solution at a wide concentration range was calculated according to the UNIFAC model and experimentally determined by our newly reported air humidity osmometry. The measurements from air humidity osmometry were compared with UNIFAC model calculations from dilute to saturated solution. Results indicate that air humidity osmometry measurements are comparable to UNIFAC model calculations at a wide concentration range by two one-sided test and multiple testing corrections. The air humidity osmometry is applicable to measure the osmotic pressure and the osmotic pressure can be calculated from the concentration.

Calculating critical relative humidity from solubility according to nonelectrolyte Wilson nonrandom factor model.

The critical relative humidity (H(cr)) of 25 drugs and chemicals was determined by the air humidity in equilibrium (AHE) method. The relationship between the H(cr) and the solubility was explored theoretically, and the H(cr) was calculated according to the nonelectrolyte Wilson nonrandom factor (N-Wilson-NRF) model or Raoult's law from their solubility. The results indicate that the calculated H(cr) is comparable to the measured one.

Relationship between critical relative humidity and solubility of drugs.

Both the critical relative humidity (H(cr)) and the solubility are important physicochemical properties that affect the quality of drugs. However, the relationship between them is not noticed yet. By an analysis of interaction between molecules of drug and water, the conclusion logically obtained is: the higher the solubility is, the lower the H(cr) will be. To validate this idea, the H(cr) and the solubility of 33 drugs and chemicals were determined and a negative linear correlation was found between the two factors when the solubility was expressed as the mole fraction of water. This negative linear correlation was further confirmed by a computer simulation according to modified Debye-Hückel equation.

Using extended Wilson model to study the relationship between critical relative humidity and solubility of electrolytes.

Based on thermodynamic principle, the critical relative humidity of electrolytes is closely related to their solubility. The authors explored the relationship theoretically and calculated critical relative humidity of 21 electrolytes from their solubility in the light of Raoult's law and extended Wilson model. The results indicate that the critical relative humidity values calculated by Raoult's law can not accord with the reported ones and there is a systematic error in the high concentration range; while these calculated by extended Wilson model are comparable to the reported ones.

Calculating critical relative humidity from solubility according to Pitzer ion interaction model.

The solubility and the critical relative humidity (H(cr)) of 14 drugs and inorganic salts were determined, the relationship between the H(cr) and the solubility was explored theoretically, and the H(cr) was calculated in the light of Raoult's law and Pitzer ion interaction model from their solubility. The results indicate that the H(cr) values calculated by Raoult's law in high humidity (H(cr)>80%) and by Pitzer ion interaction model in low humidity (H(cr)<80%) are comparable to the measured ones.

Determining critical relative humidity by measuring air humidity in equilibrium directly.

A method that simply, accurately and directly determines the critical relative humidity (H(cr)) of drugs by the measurement of the relative air humidity in equilibrium with saturated solution of drugs is presented. A new pocket humidity meter with a calibrated humidity sensor has been devised. The work of the humidity meter including the sensor is described. The principle for the proposed method is more rational and much simpler than that for both conventional methods and dynamic vapour sorption (DVS) methods. Compared with conventional methods, the proposed method is simple, prompt and can save sample; compared with the DVS system, the pocket humidity meter is significantly simpler and cheaper. The H(cr) of eleven salts and drugs measured by the proposed method and conventional methods serves as a model. The results of two-tailed two samples t-test indicate that there is no significant difference between the new method and the conventional ones.

Calculating the critical relative humidity from the solubility of electrolyte according to extended non-random two liquid model.

According to thermodynamic principle, the critical relative humidity of electrolytes is closely related to their solubility. The authors explored the relationship theoretically and calculated the critical relative humidity of 21 electrolytes in the light of Raoult's law, modified Debye-Hückel model and extended non-random two liquid (NRTL) model from their solubility. The results indicate that the critical relative humidity values calculated by Raoult's law can not accord with the reported ones and there is a systematic error in high concentration range; the values calculated by modified Debye-Hückel model still can not accord with the reported ones well although without systematic error; and the values calculated by extended NRTL are comparable to the reported ones.

Single time point isothermal drug stability experiments at constant humidity.

A single time point isothermal drug stability experiments at constant humidity is introduced. In the new method, kinetic parameters related to both moisture and temperature were obtained by a single pair of experiments: these related to moisture by one with a group of testing humidities and a fixed temperature, those related to temperature by the other with a group of testing temperatures and a constant humidity. By a simulation, the estimates for the kinetic parameters (E(a), m, A) obtained by the proposed method and the reported programmed humidifying and heating method were statistically evaluated and were compared with those obtained by the isothermal measurements at constant humidity. Results indicated that under the same experimental conditions, the estimates obtained by the proposed method were significantly more precise than those obtained by the reported programmed humidifying and heating method. The estimates obtained by the isothermal method at constant humidity were somewhat more precise than those obtained by the proposed method. However, the experimental period needed by the isothermal method at constant humidity was greatly longer than that needed by the proposed method. The stability of dicloxacillin sodium, as a solid state model, was investigated by the single time point isothermal drug stability experiments at constant humidity. The results indicated that the kinetic parameters obtained by the proposed method were comparable to those from the reported.

Step nonisothermal method to study stability of drugs.

A step nonisothermal experiment under high oxygen pressure and a new computation with optimization for step nonisothermal experiment on stability study of drugs was introduced. The kinetics parameters of captopril oxidation in aqueous solution were determined by this method. It is reported that the reaction of captopril solution occurs under either aerobic or anaerobic condition, giving different products. Then the total rate constant k(total) can be expressed as [image omitted] where k(anaerobic) and k(aerobic) are the rate constants of anaerobic and aerobic degradations, respectively. The results indicated that the parameters obtained in the step nonisothermal experiment were comparable with those obtained in the isothermal-isobaric experiments. By a computer simulation, the estimates for the kinetic parameters (E(a) and k(0)) obtained with step nonisothermal method were statistically evaluated. Results indicated that the estimates obtained with isothermal-isobaric method were somewhat more precise than those obtained with step nonisothermal method. However, the experimental period needed by isothermal-isobaric method was much longer than that needed by step nonisothermal method.

Evaluation of the stability of aspirin in solid state by the programmed humidifying and non-isothermal experiments.

The influence of both moisture and heat on the stability of aspirin was investigated by a single pair of experiments, one with programmed humidity control and the other non-isothermal, rather than many standard isothermal studies, each at constant relative humidity. In experiments, we adopted the acid-base back titration method to measure the content of aspirin in the presence of its degradation products. It was found that the degradation of aspirin could be expressed as ln[(c0-c)/c]=kt+D, where D was a lag time item not related to humidity and temperature. The relationship between the degradation rate constant k and humidity Hr) and temperature T could be described as Arrhenius equation multiplied by an exponential item of relative humidity: k = A . exp(mHr) . exp(-(Ea/RT)), where A, Ea and m were the pre-exponential factor, observed activation energy, and a parameter related to humidity, respectively. The results obtained from the programmed humidifying and non-isothermal experiments, A=(1.09+/-2.04)x10(12) h(-1), Ea=(93.5+/-2.2) kJ . mol(-1) and m=1.18+/-0.19, were comparable to those from isothermal studies at constant humidity, A=(1.71+/-0.35)x10(12) h(-1), Ea=(94.9+/-0.7) kJ . mol(-1) and m=1.20+/-0.02. Since the programmed humidifying and non-isothermal experiments save time, labor and materials, it is suggested that the new experimental method can be used to investigate the stability of drugs unstable to both moisture and heat, instead of many classical isothermal experiments at constant humidity.

Step nonisothermal method in kinetics studies of captopril oxidation under compressed oxygen.

A step nonisothermal experiment under high oxygen pressure and a computation with optimization for a step nonisothermal experiment on a stability study of drugs are introduced. The kinetics parameters of captopril oxidation in aqueous solution were determined with this method. It is reported that the reaction of captopril solution occurs under either aerobic or anaerobic conditions, giving different products. Then the total rate constant k(total) can be expressed as: k(total)=k(anaerobic)+k(aerobic)=A(anaerobic) exp (-E(a, anaerobic)/RT)+A(aerobic) exp (-E(a, aerobic)/RT)p(O(2)), where k(anaerobic) and k(aerobic) are the rate constants of anaerobic and aerobic degradation, respectively. The results indicate that the parameters obtained in the step nonisothermal experiment are comparable to those obtained in isothermal-isobaric experiments.

[Stability of penicillin potassium with linear degradation programmed humidifying experiments].

A linear degradation humidifying model for drug stability experiment is introduced. This new humidifying model is presented as: H(r) = -M1-ln {exp(- MH(r,0)) - [exp(-MH(r,0)) -exp(-MH(r-m)) t(m)-t}. Where H(r) is the relative humidity; t is the time; H(r,m) and t(m) are the final relative humidity and time of the experiment, respectively. M is humidifying constant used in the humidifying program. In the new programmed humidifying model, a linear relationship between the content function of drugs and the relative humidity is obtained, the degradation of drugs can be more uniform within different humidity ranges and the experimental results are more accurate than those in the reported linear humidifying model. The stability of penicillin potassium, as a solid state model, was investigated by the linear degradation programmed humidifying and the exponential heating experiments. The results indicated that the kinetic parameters obtained by the linear degradation programmed humidifying and the exponential heating models were significantly more precise than those obtained by the linear programmed humidifying and the reciprocal heating models.

Compressed oxygen in drug stability experiments.

A drug stability experiment accelerated by compressed oxygen was established. The stability of 10% ascorbic acid solution as a model was studied and the kinetic parameters were obtained with the newly established experimental method. Because ascorbic acid degrades under both anaerobic and aerobic conditions, the total rate constant k(total) can be expressed as: k(total)=k(anaerobic) + k(aerobic), where k(anaerobic) and k(aerobic) are the rate constants of anaerobic and aerobic degradations, respectively. The k(anaerobic) can be expressed as k(anaerobic) = A(anaerobic) x exp(-E(a,anaerobic)/RT) according to Arrhenius equation, and the k(aerobic) was found to be k(aerobic) = A(aerobic) x exp(-E(a,aerobic)/RT) x p(O2) in our study.

Application of highly accurate nephelometric titration in the assaying of phenytoin sodium.

AIM: To determine phenytoin sodium by a highly accurate nephelometric titration. METHODS: The titration operating conditions were optimized and the solubility product constant of phenytoin silver precipitation was determined. RESULTS: The result of the titration is comparable to those of control experiments. CONCLUSION: The proposed method has been found to be accurate, precise, specific, reproducible, and linear.