[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.

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.

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.

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.

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.

[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.

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.

Determination of phenytoin sodium injection and tablets by highly accurate nephelometric titration.

A highly accurate nephelometric titration method was developed for the quantitative analysis of phenytoin sodium injection and tablets. The titration operating conditions and the validation of the method were studied. Five batches of phenytoin sodium injection and tablets were determined by the proposed method and the control experiment methods, respectively. The results of the titration are comparable to those of control experiments. The proposed method is accurate and reproducible, which is considered suitable for the quantitative analysis of a large number of samples.

[Kinetic study on the degradation of penicillin potassium at different temperature and relative humidity].

OBJECTIVE: To perform a kinetic analysis and formulation of the degradation of penicillin potassium in the solid phase at different temperature and relative humidity. METHODS: Penicillin potassium was incubated in a temperature-and-humidity-controlled oven at different temperature and relative humidity, and was determined by HPLC at suitable time intervals during the incubation. RESULTS: The reaction rate was expressed as -dc/dt=k(c0-c+B), where c is the residual concentration, k degradation rate constant, c0 original concentration and B a constant related to original concentration of degradant. Degradation curves were fitted with c=c0-Bexp (kt)+B. The k was expressed as k=Aexp(-Ea/RT)exp(mHr), where active energy E. is 77.26 kJ/mol and constant m 0.1159. CONCLUSION: The degradation of penicillin potassium could be expressed with c=c0-Bexp [Aexp (-Ea/RT)exp (mHr)t]+B.

Influence of light and temperature on the stability of procaine hydrochloride injection.

AIM: To study the influence of light and heat on the stability of procaine hydrochloride injection. METHODS: Accelerated tests upon exposure to light at high temperatures were employed. RESULTS: In experiments with either isothermal heating or exposure to light at high temperatures, the drug degradation rate obeys first-order kinetics. The total rate constant, ktotal, caused by both light and heat can be divided into two parts: ktotal = kdark + klight, where kdark and klight are the rate constants caused by heat and light, respectively. The klight can be expressed as klight = Alight x E x exp(-Ea,light/RT). Where E is the illuminance of light, Alight is an experimental constant related to light sources, and Ea,light is an experimental constant. CONCLUSION: Because the form of klight is similar to the Arrhenius equation, it is suggested that Ea,light might be the observed activation energy of the rate-determining step of the subsequent processes of the photochemical reaction. This viewpoint is supported by the fact that the Ea,light is independent of light sources.

[Influence of illuminance on the photo-reaction rate order of nitrofurazone solution].

OBJECTIVE: To explore the relationship between the illuminance and the observed order of reaction of photodegradation of nitrofurazone solution. METHODS: Studying the observed order of reaction of photodegradation of nitrofurazone solution exposed to light with three illuminance values at three concentration values respectively. RESULTS: The observed order of reaction of photodegradation increased with the decrease of concentration when the illuminance kept constant and, on the other hand, the observed order increased with the increase of illuminance when the concentration kept constant. CONCLUSION: The observed order of reaction of photodegradation of nitrofurazone solution depends on both the concentration of the drug and the illuminance of the incident light.

[Effect of programmed humidification and temperature on drug stability].

AIM: To simplify the study on the effect of relative humidity and temperature on drug stability. METHODS: The stability of penicillin potassium as a model was studied with programmed humidifying and heating. RESULTS: Results of our programmed humidifying and heating experiments are comparable to those of traditional experiment at constant humidity and temperature. CONCLUSION: Programmed humidifying and heating experiments are applicable to drug stability study.

[Highly-accurate nephelometric titrimetry].

AIM: To indicate the titration end-point of precipitation reaction by measuring the relative intensity of the scattered light in the titrate for use in pharmaceutical analysis. METHODS: A visible light-emitting diode (LED) was used as a light source and a photodiode was used as the optical detector. Light on the detector creates an electric current through the diode. With the addition of the titrant, the titrate became turbid and the intensity of the scattered light in the solution increased gradually. If the precipitation reaction proceeded the completion and the solubility of the precipitate was small enough, the intensity of the scattered light will reach maximum at the stoichiometric point; thus, the titration end-point can be indicated. The accuracy of nephelometric titrimetry was discussed theoretically and the titration of NaCl with AgNO3 was used as a model. To demonstrate the applicability of the new titrimetry in pharmaceutical analysis, phenytoin sodium and procaine hydrochloride were titrated with AgNO3 and NaOH solutions, respectively. RESULTS: With our new titrator and nephelometric sensor, the accuracy and precision of our new titrimetry can be better than 0.2% under suitable conditions. CONCLUSION: This new titrimetry can be used for pharmaceutical analysis.

[Effect of light and heat on the stability of furacilin aqueous solution].

AIM: To study the effect of both light and heat on the stability of furacilin aqueous solution and the probability of substituting for isothermal accelerated tests by nonisothermal accelerated tests upon exposure to light at high temperatures. METHODS: The isothermal and nonisothermal accelerated tests were employed. The accelerated tests were proceeded in the dark and exposed to light at high temperature. Tungsten, ultraviolet and fluorescent lamps were employed in exposure tests. RESULTS: The degradation of furacilin aqueous solution in isothermal heating experiments or the exposure experiments to light at high temperatures obeys zero-order kinetics. The total degradation rate constant k caused by both light and heat can be divided into two parts: k = kdark + klight, where kdark and klight are the degradation rate constant caused by heat and light, respectively. The klight can be expressed as klight = Alight.exp(-Ea,light/RT).E, where E is the illuminance of light; Alight and Ea,light are both experimental constants. The parameters obtained in nonisothermal accelerated tests were comparable to those obtained in classic isothermal accelerated tests. CONCLUSION: Nonisothermal accelerated tests may substitute for isothermal accelerated tests during the study of the effects of both light and heat on the stability of drugs, in order to save time, labor and drugs.