Drug Shelf Life Research Articles

An Inventory Model for Deteriorating Drugs with Stochastic Lead Time

Inventory management of deteriorating drugs has attracted considerable attention recently in hospitals. Drugs are a kind of special product. Two characteristics of some drugs are the shorter shelf life and high service level. This causes hospitals a great deal of difficulty in inventory management of perishable drugs. On one hand, hospitals should increase the drug inventory to achieve a higher service level. On the other hand, hospitals should decrease the drug inventory because of the short shelf life of drugs. An effective management of pharmaceuticals is required to ensure 100% product availability at the right time, at the right cost, in good conditions to the right customers. This requires a trade-off between shelf-life and service level. In addition, many uncontrollable factors can lead to random lead time of drugs. This paper focuses on deteriorating drugs with stochastic lead time. We have established a stochastic lead time inventory model for deteriorating drugs with fixed demand. The lead time obeyed a certain distribution function and shortages were allowed. This model also considered constraints on service level, stock space and drug shelf life. Through the analysis of the model, the shelf life of drugs and service level were weighted in different lead time distributions. Empirical analysis and sensitivity analysis were given to get reach important conclusions and enlightenment.

Electrochemical Sensing of Carbachol in Ophthalmic Solutions

This paper presents the design and fabrication of a potentiometric sensor for the determination of carbachol in ophthalmic solutions. Carbachol is the active ingredient in certain ophthalmic solutions and its concentration must be maintained to provide its expected therapeutic result during the treatment of glaucoma. Carbachol is an analytically challenging molecule to measure because it lacks a detectable chromophore and is redox-inactive. This work demonstrates the first use of potentiometry to measure carbachol using an ion-selective electrode (ISE). Incorporating calix[4]resorcinarene as an ionophore resulted in a lower limit-of-detection (0.12 μM), larger linear response range (1 μM–10 mM), and enhanced selectivity when compared to the ionophore-free ISE. The ISE was used for direct detection of carbachol in a commercially available ophthalmic solution (without sample separation and pre-treatment steps), and the results were validated using the official US pharmacopeia benchmark method. To expand the application of this sensor, we performed real-time monitoring of carbachol's degradation, allowing for the calculation of the activation energy of its hydrolysis, an important parameter when estimating a drug's shelf-life.

Facile Synthesis of Tributyrin Catalyzed by Versatile Sulfated Iron Oxide: Reaction Pathway and Kinetic Evaluation

Tributyrin, the triglyceride ester, exhibits strong properties as inhibitor of cancer cell growth in both humans and animals, which can increase the shelf life of drug. In this paper, tributyrin was synthesized by esterification reaction of butanoic acid with glycerol catalyzed by a low cost, ecofriendly green catalyst sulfated iron oxide. Effect of varying catalyst loading, stirring speed, and temperature on initial reaction rate was investigated. Reaction kinetics and adsorption and thermodynamic parameters were determined by evaluating the effect of concentration of butanoic acid, glycerol, and water addition on reaction rate. Eley–Rideal model using activity coefficients was employed to account for nonideality of the system to elucidate the experimental data. A maximal acid conversion of 91.8% was obtained at the temperature of 448.15 K. Activation energy was calculated to be 25.348 kJ/mol. The end product of reaction was characterized by means of thin layer chromatography (TLC), Fourier transform inf...

Responding to drug shortages and rising costs: IV chemotherapy drug use optimization achieved by closed safety devices in hospital pharmacies

The aim of this article was to assess whether the use of closed system drug transfer devices (CSTDs) can successfully extend the shelf-life of intravenous (IV) cytotoxic drugs and thus contribute to financial savings to the pharmacy budget. In two study centres, two 6-month studies of the same design were conducted simultaneously. Three months of withdrawal of IV cytotoxic drugs from vials using conventional needle/syringe methods was compared with 3 months of using a CSTD (Tevadaptor®). During the study, the maximal withdrawable drug quantity from vials and loss due to discarding residuals, mostly in connection with sterility concerns, were measured according to the applied techniques. As the applied CSTD system eliminates microbiological risks, drug shelf-life was extended with CSTD use in the second period. The costs of drugs using conventional dispensing versus CSTD use were also compared. The amount of drug remaining in vials did not significantly differ between needle/syringe and CSTD use. Amount of drugs saved by CSTD use (through the extension of their shelf-life) was significant in all comparisons. For a set of 9 and 20 generic IV chemotherapy drugs, annual drug cost savings of €54,117 (Centre 1) and €16,901 (Centre 2) may be achieved, representing 3.9 and 3.4 % of the pharmacy budgets of the respective centres. When expensive IV biological drugs are considered, budget savings of up to 18.6 % may be achieved with CSTD use. Microbiological stability is the largest obstacle in efficient IV drug utilization. It usually means a 24-h expiry after preparation, although the physicochemical stability of the drug exceeds this period. The use of a CSTD, combined with a standard aseptic environment, provides sterility for the admixture during the preparation process. Taking advantage of the extended drug shelf-lives of drugs provided by the use of a CSTD (Tevadaptor® in this study), a significant amount of drug can be saved, resulting in financial benefits for the pharmacy budget.

Use of Kinetic Methods in Storage Stability Studies on Drugs and Pharmaceuticals

Utility of kinetic methods for predicting shelf life of drugs and pharmaceuticals and its importance in our country with varying conditions of climate ranging from hot and humid to extreme cold and dry have been brought out in this review.

Novel strategy for online monitoring of the degradation kinetics of propantheline bromide via a calixarene-based ion-selective electrode

Propantheline bromide (PB) is a hydrolysable anti-cholinergic drug. A novel strategy for the online monitoring of PB degradation kinetics catalysed by hydroxyl ions is presented. This is achieved by the incorporation of an on-site PB-selective electrode constructed using as an ionophore. This sensor was used to track the hydrolysis of PB by continuous measurement of the decrease in the produced emf over time. The use of this new technique provides real-time observation and yields a continuous profile of the hydrolysis behaviour of PB under various pH conditions as well as the temperature dependency of each reaction. Moreover, a great advantage of this proposed on-line system is its higher accuracy for rate constant estimation relative to other off-line methods. This kinetic data analysis permitted the determination of the hydrolysis activation energy and prediction of the drug shelf life. The estimated activation energy from Arrhenius plot was 20.77kcal mol−1.

Estimating Drug Shelf-life with Unknown Lot-to-lot Variability

This article addresses the problem of estimating the shelf-life of a drug through a standard stability study that is routinely performed in the pharmaceutical industry. Based upon a dataset of the degradation of the drug efficacy over time, the objective is to estimate at what time point the drug efficacy falls below a minimally acceptable level. In this article, attention is directed toward the different roles played by lot-to-lot variability and measurement error in the performances of various estimation methodologies. The standard estimation method, as proposed by the United States Food and Drug Administration, for example, in accordance with current international guidelines, is compared with some new approaches. Simulation results are presented, which illustrate the advantages and disadvantages of the different estimation methodologies, and some recommendations and suggestions are made for shelf-life estimations.

Detection of some volatile degradation products released during photoexposition of ranitidine in a solid state

Ranitidine (RAN) is on top of the list of prescribed drugs, due to its popularity as a selective H2-receptor antagonist, which efficiently decreases the amount of acid produced in the stomach. RAN is not stable both in a solid state and in a solution, which creates manufacturing problems, requires appropriate storage conditions, and results in a short drug shelf-life.The aim of this work was to study the emission of volatile degradation products generated during photoexposition of ranitidine hydrochloride in a solid state. Significant changes in volatile profile of irradiated RAN were detected using HS-SPME–GC–MS. Sixteen major peaks were noticed on the chromatograms of irradiated ranitidine and the structures of some compounds were elucidated, while the presence of acetaldoxime, thiazole, dimethylformamide, dimethylacetamide and 5-methylfurfural was confirmed by means of the analysis of the authentic standards.

Factors Affecting Stability of Z-Ligustilide in the Volatile Oil of Radix Angelicae Sinensis and Ligusticum Chuanxiong and Its Stability Prediction

ABSTRACTThe purpose of this investigation is to obtain a suitable vehicle for Z-ligustilide in the volatile oil of Radix Angelicae Sinensis and Ligusticum Chuanxiong in which it is stable enough for the application in pharmaceutics, to investigate its degradation laws, and to predict its shelf-life at 25°C. Factors including temperature, light, pH value, co-solvents and antioxidants can all influence the stability of Z-ligustilide, thereinto antioxidants could markedly improve its stability in aqueous solution by almost 35%. The suitable vehicle for Z-ligustilide contains 1.5% tween-80, 0.3% Vitamin C, and 20% propylene glycol (PG).Furthermore, the degradation rates of Z-ligustilide were found to conform to a rate equation following Weibull probability distribution within a range of degradation ratio, and the equation could be expressed as follow:ln ln (1/1−α) = ln k + m ln tWhere α is degradation ratio; t is time; m and k are constants relating to the degradation rate. The degradation rate will get greater as the increasing of parameter k. According to the degradation law obtained from the equation, the drug shelf-life (10% of active ingredient degraded, T90) in this vehicle was predicted to be more than 1.77 years at 25°C through Arrehenius equation and accelerating experiments.The present investigation was undertaken to propose a kinetic treatment that may be applicable to any type of degradation of the active ingredient of pharmaceutical formulation, and also could provide a good foundation for the new drug development of Z-ligustilide, especially for injection formulation.

COMPARISON OF BRACKETING AND MATRIXING DESIGNS FOR A TWO-YEAR STABILITY STUDY

In the U.S. Food and Drug Administration (FDA) guidelines for stability testing of new drug products, both bracketing and matrixing designs were suggested as the statistical designs. More recently, they have increasing attention from pharmaceutical companies, because both designs reduce the cost of stability studies. The purpose of this paper is to investigate both designs in terms of the power of detection of significant difference between slopes, and use the mean square error to evaluate the precision of estimated drug shelf life. Additionally, the distributions of both designs are compared by using 1000 simulations.

Assessing distributions of estimated drug shelf lives in stability analysis.

A stability study is usually conducted to ensure that a drug product can meet the approved specifications prior to its expiration dating period (shelf life). Several approaches for determination of drug shelf life assuming random batches have been proposed. In this paper, we examine sampling distributions of the estimated shelf lives proposed by Shao and Chow (1994, Biometrics 50, 753-763). An application to some stability data from the pharmaceutical industry is presented.

Cumulative illuminometer and shelf life of drugs in daylight indoors

An instrument used for measuring cumulative illuminance via pulse counting method was introduced. Photodegradation of drugs in daylight and various lamplights was studied. The shelf life of drugs in daylight indoors was predicted with hydroxyprogesterone caproate injection as a model. The cumulative illuminance of unsteady daylight was measured with the patented pulse counting method in the experiment. The equivalent influences of light from different sources on the photostability of the model drug were observed. Results show that the daylight can be replaced by lamplight in photostability studies. The photodegradation of hydroxyprogesterone caproate injection obeys the zero order kinetics: c= c O− k( Et), and its shelf life in daylight indoors is about 1.1 years.

Exponential Heating in Drug Stability Experiment and Statistical Evaluation of Nonisothermal and Isothermal Prediction

A new nonisothermal heating model (exponential heating model) for drug stability experiments, based on a theoretical study of simulated nonisothermal data, is presented. In the model, the heating rate dT/dt is increased by 2–4 times at every increase of 10°C in temperature: dT/dt=a(T−T0)/10•(dT/dt)0 where a is the times by which the heating rate is increased at every increase of 10°C. A computation method with optimization and Simpson integration for the experiment was also introduced. The estimates for the shelf-life and activation energy obtained by the exponential and other nonisothermal heating models were statistically evaluated and were compared with those obtained by the isothermal method under various conditions. The results indicated that under the same experimental conditions, the estimates obtained by the exponential heating model were significantly more accurate and precise than those obtained by the linear, reciprocal, and logarithmic heating models. The accuracy and precision of the estimates were independent of the shelf-life of drugs and experimental period. The estimates obtained by the isothermal method were somewhat more accurate and precise than those obtained by the exponential heating model. However, the experimental period needed by the isothermal method was about five times longer than that needed by the exponential heating model. The results also showed that in each of the heating models, the estimates are more accurate and precise by increasing the extent of drug degradation, changing temperature range or sampling frequency, or by having the mean temperature closer to room temperature. To demonstrate its applicability, the exponential heating model was used to study the stability of vitamin C tablets and predict their shelf-life.

On stability designs in drug shelf-life estimation.

In this paper, various stability designs, including matrixing and bracketing designs for determining drug shelf-life, are considered. We propose a criterion for design selection based on the precision of drug shelf-life estimates. For a fixed sample size, it is recommended that the design with the best precision for estimating the shelf-life should be used. For a fixed desired precision, the design with the smallest sample size is the best choice of design. An example is presented to illustrate the proposed method.

Estimation of the shelf-life of drugs with mixed effects models

This paper proposes a normal mixed effects model for stability analysis. An EM algorithm is developed to compute the maximum likelihood estimates of regression coefficients of the fixed effects and random effects, and variance components. The likelihood ratio test is used for the preliminary testing of batch-to-batch variation. An example from a marketing stability study is given to illustrate the proposed procedure.

Statistical Inference in Stability Analysis

Statistical inference for drug shelf-life in stability analysis is considered. We propose a model that takes into account the batch-to-batch variation in assay results. Tests for batch-to-batch variation as well as the effects of some covariates such as time, package type, and dosage strength are proposed. When there is no batch-to-batch variation, we show that the method currently used in the pharmaceutical industry for determining the labeled drug shelf-life is statistically valid. In situations where batch-to-batch variation is present, we propose a method of determining the labeled shelf-life which ensures, with given statistical assurance, that the future batches of the drug product have shelf-lives longer than the labeled shelf-life. An example concerning a new drug application stability analysis conducted in a pharmaceutical company is discussed.

On the estimation of variance components in stability analysis

Chow and Shao (1989, 1991) indicated that the presence of batch-to-batch variation has an impact on the determination of drug shelf-life in stability studies. In this paper, we propose two unbiased estmators for batch-to-batch variation. The proposed estimators are compared in terms of their corresponding variances. An example concerning a stability study is discussed to illustrate the use of the proposed estimators.

Theoretical Design of a Variable Activation Energy Time-Temperature Integrator for Prediction of Food or Drug Shelf Life

AbstractSuccessful application of a time/temperature integrator (TTI) requires that it has on activation energy similar deterioration reaction of the food or drug it is to monitor. Based on the 3M Monitor Mark, a new tag was designed, the principal of which is a simultaneous diffusion and chemical reaction process. The combined process could be modelled by a response function f(x) = x2 = Kct*. The overall activation energy could be increased (compared to the simple diffusion process) if the activation energy and half life for the chemical reaction are chosen appropriately. An equation was development to estimate the amount of diffusing substance needed. Theoretically, it is feasible to design a new tag that will have essentially the same activation energy as food or drug quality loss.

Graphs and stochastic relaxation for hierarchical Bayes modelling.

This expository paper describes two useful tools for the statistical analysis of processes that generate repeated measures and longitudinal data. The first tool is a graph for a visual description of dependency structures. The second tool is a stochastic relaxation method ('Gibbs sampling') for fitting hierarchical Bayes models. Graphs are concise and accessible summaries of stochastic models. Graphs aid communications between statistical and subject-matter scientists, during which formulations of scientific questions are modified. An uncluttered picture of the dependency structure of a model augments effectively its corresponding formulaic description. Stochastic relaxation is a computationally intense method that allows experimentation with broader classes of models than were previously thought feasible because of analytic intractability. Stochastic relaxation is intuitive and easily described to non-statisticians. Several sample graphs show how hierarchical Bayes models can use stochastic relaxation to obtain their fits. An example based on estimating drug shelf-life demonstrates some uses of graphs and stochastic relaxation compared with several frequentist growth curve analyses that use restricted maximum likelihood and generalized estimating equations approaches.

Estimating Drug Shelf-Life with Random Batches

The problem of assessing the shelf-lives of drug products in the market is considered. We focus on the situation where the drug characteristic of interest has a linear relationship over time and batch-to-batch variation is present. Two methods for assessing shelf-lives are proposed based on the weighted least squares method under a regression model with random coefficients. An application to some stability data from the pharmaceutical industry is presented.