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As an active pharmaceutical ingredient, dapagliflozin propanediol monohydrate (D-PD) has been used in the solvated form consisting of dapagliflozin compounded with (S)-propylene glycol and monohydrate at a 1:1:1 ratio. However, dapagliflozin propanediol loses the solvent's reduced lattice structure at slightly higher temperatures. Due to its sensitive solid-state stability, the temperature and humidity are strictly controlled during the production and storage of dapagliflozin. Thus, crystalline molecular complexes containing pharmaceutical salts, solvates, monohydrates, and cocrystals have recently been developed as alternative strategies. This study investigated the dapagliflozin free base (D-FB), D-PD, and dapagliflozin l-proline cocrystals (D-LP). Their solid-state behavior was also evaluated in stress stability studies. The compounds were analyzed using scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), Fourier-transform infrared (FT-IR) spectroscopy, dynamic vapor sorption (DVS), and powder rheology testing. In addition, Carr's index, the Hausner ratio, contact angle, and intrinsic dissolution rate were calculated. Dapagliflozin exhibited distinct physical properties depending upon the differences in solid form and also showed significant differences in solid-state behavior in the stress stability test. In conclusion, D-LP was superior to D-FB or D-PD in physicochemical and mechanical properties.

Three-dimensional (3D) printing has become a promising manufacturing technique for pharmaceutical products. Fused deposition modeling (FDM) is the most affordable printing technology. But this technique has two major drawbacks: limited drug-loading capacity and the stability of thermolabile drugs. So, other techniques such as melt casting could be associated with FDM to overcome these limitations. In the melt casting method, the drug is mixed with a molten polymer and is poured in the mold and allowed to solidify. The present study for the first time describes the preparation of a multi-compartment polypill permits the physical separation of incompatible drugs by combination of FDM and melt casting techniques. A two-compartment polypill was made using FDM by Eudragit® L100-55 and simultaneously its compartments were filled by aspirin and simvastatin containing molten PEG 6000. Simultaneous usage of FDM and melt casting techniques could increase the drug-loading capacity of 3D-printed polypills. The low temperatures used in melt casting and the absence of solvent in this method would warrant the integrity of polypills, the complete separation of incompatible drugs, and their stability. The prepared polypills showed good uniformity in drug content which confirms the precision of FDM and melt casting techniques. Drug interaction was investigated before and after the accelerated stability test using DSC, which showed that 3D-printed polypills successfully preserved drugs from the interaction. For the first time, this study demonstrates the feasibility of the combination of FDM and melt casting techniques as an innovative platform for CVD polypills production.

Objective: The main objective of this work was to evaluate the performance of recently developed dynamic-mechanical thermoanalysis (DMTA) test as a rapid rheological alternative to conventi...

Objective: The aim was to study the stability of dry powder inhaler (DPI) formulations containing antibiotic with different preparation ways – carrier-based, carrier-free, and novel combined formul...

The present study is aimed at the development of a sunscreen cream for use in high altitude areas which have been found to possess superior sun protection factor (SPF) along with remarkable antioxidant activity. The topical formulation is a standard oil-in-water emulsion of a combination of United States Food and Drug Administration (US FDA) approved ultraviolet filters; along with melatonin and pumpkin seed oil. The in-silico optimized formulation was characterized using established methods and the stability study was carried out as per International Conference on Harmonization guidelines. The formulation was prepared after requisite pre-formulation analysis by Fourier-transform infrared spectroscopy, differential scanning calorimetric and thermogravimetric analyses; followed by characterization based on color, odor, phase separation, spreadability, specific gravity, homogeneicity, centrifugation and sensitivity. For the stability study, a total of three samples from three batches of the finished product were subjected to the stability study. The samples were analyzed for content uniformity, pH, in vitro SPF, rheology, zeta potential, droplet diameter and microbial analysis of the 0th day and also the the end of the storage period. Results obtained from the stability study indicated that the formulation possesses 50+ in vitro SPF value and remained stable for 6 months and 12 months under storage at 40 ± 2 °C and 75 ± 5% relative humidity; and −20 °C ± 5 °C respectively.

This paper describes the development and optimization of curcumin thermosensitive hydrogels (CTH), a kind of gel injection for intratumoral injection treatment.Aimed at increasing the content and stability of effective components, an optimal formulation of CTH was chosen based on the results from orthogonal tests and the optimal pH was determined by stability test. To investigate the hydrogels drug release in vitro, residence time by RP-HPLC and therapeutic effects on ascitic hepatocarcinoma cell strain with high metastasis potential in lymphatic system (HCA-F) solid tumors in mice.The selected optimal formulation of CTH was: 0.2% curcumin, 20% poloxamer 407, 4% poloxamer 188, 8% polyethylene glycol 400, 12% 1,2-propanediol and pH was 6.0. The drug release determined by RP-HPLC fit to the Higuchi model. The residence time of CTH was longer than the curcumin suspensions. Intratumoral injection of the CTH can effectively inhibit the growth of HCA-F solid tumors in mice.The CTH prepared in this test demonstrates proper gel temperature and viscosity. It improves the solubility of curcumin with a relatively long period of drug release in vitro and residence time. Intratumoral injection of the CTH can effectively inhibit the growth of HCA-F solid tumors in mice.

This study engaged in investigation of optimal formulation, characteristics analysis of Brucea javanica oil microemulsion (BJOM) in order to address safety concerns and make recommendations for improvements in BJOM safety during clinical use in vivo.Pseudo-ternary phase diagram techniques were used to determine the appropriate ratio of surfactant, cosurfactant and oil phases. Subsequent stability testing of BJOM was performed by dilution, centrifugation and accelerated stability testing. The results were expounded through additional assessment utilizing the classical thermostat method to establish the shelf life of the material. These results were utilized to evaluate the safety of BJOM by haemolytic, irritative and allergic testing in vitro. In addition, the cytotoxicity of BJOM was examined using the tetrazolium salt 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), with particular emphasis given to potential uses in cancer treatment.The most suitable method of preparation for BJOM was found to be a one to one ratio (Km 1:1) of Solutol HS15 surfactant matched with sorbitol cosurfactant in the ratio. The microemulsion droplets of BJOM possessed a spherical shape, uniform size and average diameter of 23.8 nm. The expiration date of BJOM was found to be 568 d. The safety study demonstrated no hemolysis activity at the experimental BJOM concentrations; however, mild hemolysis was observed at higher concentrations of Brucea javanica oil emulsion (BJOE), a common commercially available product. Irritation observed upon BJOM treatment can be primarily attributed to Brucea javanica oil (BJO) with little influence of BJOM excipients. In addition, BJOM caused no observed hypersensitivity or other visible allergic reactions in guinea pigs. The anticancer activity curves of BJOM and BJOE demonstrate that both BJOM and BJOE inhibit Hela cells, with BJOM demonstrating significantly more dramatic anticancer activity.An optimal formulation of BJOM superior to commercially available products and safe for medical application such as intravenous injection has been outlined along with its anticancer activity rating.

Different sized glass entry ports were evaluated for their drug collection efficiency during aerodynamic particle sizing of metered dose inhalers (MDIs) using cascade impaction. A comparison was made between collection efficiency in the entry port, impactor plates, and filter using the 1 L, 2 L, and 20 L glass entry ports and the USP and twin impinger entry ports. Entry port losses were dependent on the size of entry port selected, with 1-2 L ports showing optimal recovery on impactor plates, compared to the USP entry port. The 1 L entry port was further compared with the USP entry port in its ability to discriminate between subtle changes in particle size distribution (PSD) in an investigational hydrofluoroalkane (HFA)-based MDI formulation. Deliberately induced differences during product manufacture were easily detected using the 1 L entry port with the Andersen cascade impactor. The USP port was unable to distinguish among products with small particle size differences. An alternative entry port such as the 1 L glass entry port used in this study may provide better means of characterizing the PSD during formulation development and stability testing of MDIs.

The stability data requirements for human pharmaceuticals in the European Community (EC) are based on a series of Directive and Regulation requirements and on a series of advisory guidelines that have been developed and adopted through the International Conference on Harmonization (ICH) procedures or, where there is no relevant ICH project, through the Committee for Proprietary Medicinal Products (CPMP). There are relevant requirements that cover new drugs and finished products containing them and also for existing active ingredients and products containing them. The sources of the relevant information and the data requirements are discussed and summarized.

This paper reviews contemporary trends in the stability testing of pharmaceutical products. In particular, it considers the progress toward globalization and harmonization and indicates stability problems, which probably will be the focus of attention for pharmaceutical scientists and regulators in the near future. Attention is specifically directed to monitoring stability in the channels of distribution.

The International Conference on Harmonization (ICH) Tripartite Guideline "Stability Testing of New Drug Substances and Products" sets out the stability testing requirements for a registration application within the three areas of the European Union, Japan, and the United States. These areas are assigned to climatic zone II with the storage condition of 25 degrees C/60% RH. This paper describes the adjustments that are necessary to extend the guideline to countries of climatic zones III and IV. At first storage conditions were derived with 30 degrees C/35% RH for climatic zone III and 30 degrees C/70% RH for climatic zone IV. Both conditions contain a margin of safety compared to calculated and measured data in warehouses. Furthermore, they cover the extreme temperatures above 30 and 40 degrees C which may arise in these climatic zones. Six months at 40 degrees C/75% RH was fixed as storage condition for accelerated testing to assess organoleptic and physicochemical test criteria and to make predictions for chemical stability. The predictive factor is 3.3 for 30 degrees C (6 months at 40 degrees C corresponds to 20 months at 30 degrees C). Extreme temperatures which may arise during shipment are covered by the results of stress investigations (e.g., 3 months at 50 degrees C). The next adjustment is necessary for the selection of the packaging containers. They must reflect the requirements for solid, semisolid, and liquid dosage forms caused by the two storage conditions. In the evaluation the temperature difference of 10 degrees C (40-30 degrees C) instead of 15 degrees C has to be considered, which limits the preliminary shelf lives in critical cases to 18 months instead of 24 months. Finally, statement/labeling must reflect the storage conditions. All of the other basic principles for the drug substances and drug products, such as selection and number of batches, test criteria, test procedures, specifications, testing frequency, and storage period can be applied without any change.

Dissolution testing for various pharmaceutical dosage forms is an integral part of release and stability testing requirements. In order to assist in such testing, a spreadsheet has been written and validated to perform dissolution calculations using Microsoft Excel software. The spreadsheet has been written for a dissolution experiment where the volume of the dissolution medium is held constant for the vessel by replacing removed dissolution medium with fresh dissolution medium at each time point. The spreadsheet corrects for the amount of dissolved drug substance removed at each time point and reports results in terms of percent of label claim dissolved for each vessel. The use of computer software to assist in data manipulation in the pharmaceutical industry requires adequate documentation, and therefore a validation protocol has been written and is described. An example of the formulas used to generate the spreadsheet is also given and can be easily used by readers to implement design of their ...

The stability program for clinical samples as presented is based on the ICH Tripartite Guideline for Stability Testing of New Drug Substances and Products and the same principles that the program followed throughout the development of a drug product. But the Guideline and the basic principles were adapted to deal with the specific problems encountered with clinical samples. The expiration dates represent minimum shelf lives, storage conditions, and storage periods, and the minimum shelf lives correspond the duration of the clinical trials in phases I to III. Shelf lives are established on the basis of stress and accelerated tests to provide all batches with an open expiration date. They are supported and confirmed by long-term tests conducted under the storage conditions presenting climate zone II, 25°C/60% RH. The self lives determined apply to all the batches of the relevant development stage, although only the batches in the final phase of development originate from a validated manufacturing ph...

The results of an independent survey of the stability of omeprazole solid dosage forms (20 mg) show that products available in many countries worldwide exhibit a very wide range of stability characteristics. Stability testing under the ICH accelerated test conditions (40°C/75% RH; 6 months) was performed on a total of 34 products obtained in 13 countries by independent sampling officers. The samples were visually examined for physical change and analyzed for their total content of impurities, remaining omeprazole, and the amount of omeprazole released in vitro. Twenty-seven of the products (79%) exhibited a change in one or more of the stability-indicating parameters during the 6-month study. These included 16 products that had more than 10% of decomposition products at 6 months and 10 other products that contained 2-10% of decomposition products at 6 months. In most samples, the formation of decomposition products was accompanied by a corresponding measurable decrease in the content of omeprazole...

Strong efforts have been undertaken to harmonise the requirements for the investigation of the stability of drug substances and drug products. Since the results of these investigations are used to assign labelling which properly reflects the stability of the substances/products under the climatic conditions encountered in the region of distribution and use, a thorough examination of the climatic conditions in the EC, Japan and the USA was conducted. According to this study, the EC, Japan and the USA may be practically assigned to a region for which there is an annual mean kinetic temperature of up to 25 degrees C.In fact, the climatic study indicates that 25 degrees C/60 per cent RH is general well above the mean kinetic temperature for the 35 major European, Japanese and American cities in the study. In addition the mean kinetic temperature encompasses the data in warehouses as well as measured seasonal and daily fluctuations up to and above the extreme temperature of 30 degrees C allowed by the ...

A review of the methodology for determination of the storage conditions for stability testing according to Schumacher/Grimm is presented in this paper. The purpose is to provide scientific information useful for the definition of storage conditions for stability testing of pharmaceuticals suitable to the region where the product will be dispensed. Special attention is given to stability testing in the new markets located in developing countries with very hot and humid climates. Finally, storage conditions for stability testing in the Brazilian regions were derived and examined comparatively with the guidelines of the world health organization (WHO) and regulatory bodies. The storage conditions were derived from the calculated values of the mean kinetic temperature and the relative humidity (RH). These parameters were estimated from daily values of dry and dew point temperatures of all Brazilian capitals from 1998 to 2002; collected in the morning (9 a.m.), in the afternoon (3 p.m.), and at night (9 p.m.). The Brazilian Center of Weather Forecast and Climatic Studies of the National Institute of Spatial Research (CPTEC/INPE) kindly furnished these data. Significant differences of the mean kinetic temperature (MKT) and relative humidity (RH) for Brazilian regions were observed. These results indicate the existence of a high climatic diversity between the Brazilian regions, making challenging the definition of a single storage condition for the stability testing. Some regions present RH values higher than 80%, giving support to the concerns of the WHO, indicating the necessity of revision of existing guidelines for stability testing mainly for very hot and humid regions.

Extensive work has been done in the field of drug adjuvant interaction studies using differential scanning calorimetry (DSC), but conclusive interpretive techniques could not be reached since very few workers supplemented their work by conventional isothermal stability testing methods. This work compared the drug adjuvant thermogram with results obtained from isothermal stability studies and used it to reiterate the results of the drug adjuvant thermograms. In the formulation of ascorbic acid in a cosmetic preparation, the various adjuvants were tested for interactions first by the isothermal stability testing technique, which was followed by DSC scanning of the drug adjuvant. The results of the two methods were compared and correlated.

Regulatory stability testing requirements for various types of ophthalmic products, including eyedrops, eye ointments, ophthalmic inserts, injections, irrigating solutions, lens washes, and lenses, are not always straightforward. The International Conference on Harmonization (I CH) guidelines do not completely address all of the stability conditions required for these types of pharmaceutical products and medical devices; regulatory agencies around the world still differ on the exact data requirements, storage conditions (especially temperature and humidity conditions), and certain testing methods. These uncertainties make the development of a global ophthalmic product very difficult. This article reviews many of the appropariate internationally recognized, regulatory guidelines and many of the important points to consider in stability studies for new ophthalmic products. Discussions of regulatory experiences and Expert Reports provide insight to common questions frequently asked by regulatory agencies on these types of products.

By Incorporating restriction errors into experimental design models, the developmental scientist is forced to consider what restrictions on randomization have been placed on his experiment whether they are inadvertent or planned. With the experimental design in mind along with the restriction errors the scientist should be able to eventually establish a very reasonable design model and analysis for that experiment.One of the more fundamental tools of pharmaceutical research and development, particularly in the design of dosage forms, is that of the accelerated stability test (1). In general, accelerated testing done early in the development scheme is designed to screen the formulation for the effects caused by changing variables. Variables are anything associated with the formula or the manufacturing of the formula. Many developmental scientists would change only one variable at a time. While this may be sound advice occasionally, it is time consuming and could actually miss the most important eff...

Stability-indicating analytical methods are developed to monitor the stability of pharmaceutical dosage forms during the investigational phase of drug development, and, once the drug is marketed, for the ongoing stability studies which must be conducted. The development of these methods for pharmaceutical dosage forms forms can be approached from several avenues. Methods can be developed which measure the amount of drug remaining, the amount of drug lost (or the appearance of degradation products), or both.Traditionally, the analytical methods used to monitor the stability of dosage forms have involved a generally non-specific spectrophotometric or titrimetric procedure for the assay of the active coupled with thin layer chromatography for the estimation of impurities and degradation products. In the last five years, this approach has changed dramatically. Currently, the method of choice for the quantitation of the active and degradation products is rapidly becoming high performance liquid chromat...

The Food and Drug Administration (FDA) is proposing that a satisfactory three-month stability testing of a drug product at 37 to 40 °C and 75% or higher relative humidity can be employed to project a tentative expiry date of two years from the date of manufacture. This proposal is theoretically analyzed and its limitation is established. A successful projection of the expiry date according to FDA's proposal depends on the drug level at the end of the accelerated stability testing, the activation energy, and the temperature of the accelerated condition and the normal storage condition. The applicability of this method in assessing the stability characteristics of pharmaceutical formulations in the development process is discussed.

The errors involved in the estimation of the activation energy of the drug degradation and the projected shelf life of a drug product when employing an incorrect kinetic order in the accelerated stability test were analyzed. The activation energy of a zero order degradation and the projected shelf life of a drug product are overestimated when the kinetic data are treated in first order fashion. The overestimation in the activation energy increases with the temperature range of the accelerated test and the instability of the drug. The over-estimation in the projected shelf life increases with the activation energy and increases as the normal

A new Note for Guidance on stability testing, data analysis, interpretation and labelling requirements for submission of information in Marketing Authorisation (MA) applications in the Member States of the European Community (EC) has recently been published. 25°C is recommended as the kinetic mean testing temperature for Real-time studies to allow products to be marketed in both Zone I (temperate climate) and Zone II (Mediterranean) European countries. Since climatic Zones I and II also include the USA, Canada and Japan, use of these storage test conditions would enable companies to generate data which could be used for marketing products in all of these territories

Borrowing the mathematics used in the nonisothermal kinetic method, a new and simpler mathematical treatment of the concept of the Equilibrium Temperature Time Equivalents (ETTE) is presented. The effect of the ETTE in the pharmaceutical product stability assessment is discussed. The analysis shows that due to the stability characteristics of most drug candidates, the ETTE has very little effect on the stability data treatment.

The use of stability testing and expiration dating as a tool for assuring product integrity is generally accepted by pharmaceutical companies and governmental agencies alike. Equally accepted is the notion that it would be impossible for anyone to forward one simple stability testing formula or rule for reasonably assuring the integrity of every product of every manufacturer. In fact, within The Upjohn Company, widely differing concerns arise with respect to stability testing as a proposed new product matures into established product status. The purpose of this presentation is to discuss some of the objectives and operational procedures used at Upjohn with respect to the stability testing of a product at various stages in its existence.

The theme of this presentation is based on the premise that, despite the existence of differences in specific stability testing protocols between different types of products of the same manufacturer and between similar products of different manufacturers, it is possible to generalize somewhat and to identify elements common to any stability testing program. In terms of stability testing, a drug product may be viewed as passing through a series of distinct, identifiable stages in its development, which represents a progression of stability testing with product maturation. Within this progression, a range of testing protocols, methods and mathematical models may be utilized with each successive program designed to augment the data base of the product and thereby strengthen and expand the conclusions reached during each preceding phase. Differing types and amounts of information are sought at each stage which are important to the assignment of an expiration date, thus giving rise to widely differing ...

This paper shows how the Box method, based on the statistical technique known as “split-plot” in general use for replicate measurements, may be used to quantify and compare in vitro dissolution curves of controlled release solid oral dosage forms. In this case, it is applied to the interpretation of the findings of a stability test on controlled-released lithium tablets formulated with a wax matrix and containing 10.8 mEq lithium per tablet. The findings showed that the total amount of lithium dissolved after the tablets had been stored for a period of six months was slightly greater than before storage; the dissolution mean rate went from 1.06 mEq/h to 1.17 mEq/h and the dissolution rate curve profile apparently registered less variation.The method described here for the comparison of dissolution curves is particularly useful when the curves do not follow a set kinetic process and has proved sensitive to slight changes in the dissolution profile.

A previous publication (1) analyzed a statement originated from the Food and Drug Administration (FDA) that a drug product which is stable for three months at 37–40° and 75% or higher relative humidity can be given a tentative expiry period of two years from the date of manufacture. Conditions which can be uesd to make a successful projection using such a proposal have been established. These conditions are applicable only to pharmaceutical systems which do not contain an overage. The theoretical discussion is extended in this communication to analyze the effect of the overage on the proposed projection of the expiry period. The analysis shows that the inclusion of the overage lowers the threshold activation energy needed to satisfy the FDA's proposal

Directly compressed thiamine hydrochloride tablets formulated with single or binary blend of vehicles were used in this investigation. The change in the physical characteristics of vitamin tablets stored under different relative humidity conditions was statistically assessed and scored by relative ranking. Although Emcompress is known to accelerate drug decomposition (1,2) the results obtained with tablets formulated with this vehicle alone or in combination with other vehicles failed to show that the use of this vehicle may give rise to any discernible changes in the physical characteristics of the tablets. Although formulations containing Celutab as the vehicle are chemically stable (2) the tablets compressed with this vehicle showed a high degree of change in physical characteristics. The results obtained in this study indicate that Avicel alone or a blend of Avicel with either Celutab or Anhydrous lactose are suitable vehicles for the manufacture of thiamine hydrochloride tablets of high stabi...

Today Stability Tests are an integral part of Industry's Quality Assurance Programme. The stability predictions derived from the results of the Tests; represent a comprehensive assessment of quality, which applies to all batches and includes organoleptic, physicochemical, chemical and where applicable, microbiological criteriaThe aim is to describe, from Industry's point of view, what outlay is necessary for stability Testing for worldwide marketing and what degree of confidence lies behind the stability predictionsAlong the way from a new drug substance to routine production, 3 phases in Stability Testing can be distinguished- Preliminary and Stress experiments- Long term testing- Follow-up studiesEach phase has its own specific aim. The outlay and scope devoted to each phase must be appropriate to the particular problem. It is shown, which storage conditions are necessary, especially for the worldwide introduction of a drug product, the testing criteria, testing methods, number of batches and sa...

The difficulties in the development of reasonably stable emulsions and suspensions and the problems associated with the evaluation of such products are, for the most part, related to their non-equilibrium state. A conceptual understanding of the thermodynamics of these dispersions, particularly their surface and/or interfacial free energy, will facilitate successful formulation of such disperse systems. A strategy that fails to utilize surface behavior to stabilize thermodynamically unstable formulations is unlikely to be productive whereas a strategy based on an appreciation of the surface properties of the system is much more likely to succeed. Stability testing of liquid disperse systems is one of the most difficult problems faced by pharmaceutical and cosmetic chemists. The scientist is often asked to predict the shelf-life of a product or choose between experimental formulations based on estimates of how well they will hold up with time. While there are no standardized tests available to dete...