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Chemical Stability of Drugs 13 Nov 2016 Revise: Types of drug/formulation instability, Importance of drug stability studies, Factors affecting drug stability, Definition of degradation reaction rate, Definition of degradation reaction order, How to determine the reaction order, Relation between reaction rate and reaction order, How to determine the reaction rate constant, Rates and Orders of Reactions For A ------ B , A + B--------C reactions rate [A] a rate [A] a[B] b a, a+b = the orders of the reaction Zero Rate = K first Rate=K[A] OR second,.. ?? Rate =K[A][B] Zero – Order Reactions For A ------- B dc k0 [ A]0 k0 dt • • • • Slope = ? Intercept = ? T0.5=? T0.9= ? First Order Reactions Decompostion of Hydrogen Peroxide at 25C in Aqeous Solution dc Kc dt C C010 kt 2.303 60 Ct (mole/L) C C0 e kt 70 50 40 30 20 10 0 0 10 20 30 40 t (minutes) 50 60 70 Apparent Zero Order Reactions Degradation in Suspensions dc Kc dt C is rendered constant in suspension, so Kc = K0, thus dc K0 dt Factors Affecting Drug Chemical Stability Temperature The effect of temperature on reaction rate is given by the Arrhenius Equation: k=Ae-Ea/RT By taking the log of both sides, the equation transforms into: log k= logA – Ea /2.303RT The pH Specific Acid – Base Catalysis • Read the figure • Importance of the pH profile in the formulation process General Acid – Base Catalysis • The catalytic effect resulting from the buffer components is called a general acid – base catalysis. • Importance of the pH profile in the formulation process Modes of Pharmaceutical Degradation & Protection Methods • Hydrolysis – Hydrolysis of esters and amides is the most common example, these reactions are dependent on H+ and OH- ions as catalysts so in order to stabilize the formulation, the pH must be adjusted to match the minima in the stability-pH profile if possible. • Oxidation – Can be prevented by a variety of approaches including the manufacturing and packaging under inert conditions, addition of antioxidants (ascorbic acid, Na sulphite, metabisulfite and bisulfate), the use of chelating agents, reduction in storage temperature and formulation at optimum pH for stability. • Photolysis Accelerated Stability Testing • Stability testing and shelf life determination is usually performed using accelerated stability protocols. • Accelerated stability protocols have been developed to reduce the time required to determine the products shelf life at the storage conditions. WHO Technical Report Series, No. 953, 2009 Stability testing of active pharmaceutical ingredients and finished pharmaceutical products. Objectives of the guidelines To exemplify the core stability data package required for registration of active pharmaceutical ingredients (APIs) and finished pharmaceutical products (FPPs). …….. General principles The purpose of stability testing is to provide evidence of how the quality of an API or FPP varies with time under the influence of a variety of environmental factors such as temperature, humidity and light. The stability programme also includes the study of productrelated factors that influence its quality, for example, interaction of API with excipients, container closure systems and packaging materials. In fixed-dose combination FPPs (FDCs) the interaction between two or more APIs also has to be considered. Guidelines for : Active pharmaceutical ingredient: will not be presented here Finished pharmaceutical product: will be presented here in part Definitions (WHO Technical Report Series, No. 863, 1996) The definitions given below apply to the terms used in these guidelines. accelerated stability testing Studies designed to increase the rate of chemical degradation and physical change of a drug by using exaggerated storage conditions as part of the formal stability testing programme. The data thus obtained, in addition to those derived from real-time stability studies, may be used to assess longer-term chemical effects under nonaccelerated conditions and to evaluate the impact of short-term excursions (deviations) outside the label storage conditions, as might occur during shipping. The results of accelerated testing studies are not always predictive of physical changes. batch A defined quantity of product processed in a single process or series of processes and therefore expected to be homogeneous. In continuous manufacture, the batch must correspond to a defined fraction of production, characterized by its intended homogeneity. climatic zones The four zones into which the world is divided based on the prevailing annual . climatic conditions mean kinetic temperature The single test temperature for a drug product corresponding to the effects on chemical reaction kinetics of a given temperature-time distribution. A mean kinetic temperature is calculated for each of the four world climatic zones according to certain formula. It is normally higher than the arithmetic mean temperature. expiry date The date given on the individual container (usually on the label) of a drug product up to and including which the product is expected to remain within specifications, if stored correctly. It is established for each batch by adding the shelf-life period to the date of manufacture. shelf-life The period of time during which a drug product, if stored correctly, is expected to comply with the specification1 as determined by stability studies on a number of batches of the product. The shelf-life is used to establish the expiry date of each batch. real-time (long-term) stability studies Experiments on the physical, chemical, biological, biopharmaceutical and microbiological characteristics of a drug, during and beyond the expected shelf-life and storage periods of samples under the storage conditions expected in the intended market. The results are used to establish the shelf-life, to confirm the projected shelflife, and to recommend storage conditions. Stability The ability of a pharmaceutical product to retain its chemical, physical, microbiological and biopharmaceutical properties within specified limits throughout its shelf-life. stability tests A series of tests designed to obtain information on the stability of a pharmaceutical product in order to define its shelf-life and utilization period under specified packaging and storage conditions. Guidelines for Finished pharmaceutical product General The design of the stability studies for the FPP should be based on knowledge of the behaviour and properties of the API, information from stability studies on the API and on experience gained from preformulation studies and investigational FPPs. Selection of batches Data from stability studies should be provided on at least three primary batches of the FPP. The primary batches should be of the same formulation and packaged in the same container closure system as proposed for marketing. The manufacturing process used for primary batches should simulate that to be applied to production batches and should provide product of the same quality and meeting the same specification as that intended for marketing. In the case of conventional dosage forms with APIs that are known to be stable, data from at least two primary batches should be provided. ………….. Stability studies should be performed on each individual strength, dosage form and container type and size of the FPP……… Container closure system Stability testing should be conducted on the dosage form packaged in the container closure system proposed for marketing. ….. Storage conditions In general an FPP should be evaluated under storage conditions with specified tolerances that test its thermal stability and, if applicable, its sensitivity to moisture or potential for solvent loss. The storage conditions and the lengths of studies chosen should be sufficient to cover storage, shipment and subsequent use with due regard to the climatic conditions in which the product is intended to be marketed. In general “significant change” for an FPP is defined as: • A change from the initial content of API(s) of 5% or more detected by assay, or failure to meet the acceptance criteria for potency when using biological or immunological procedures. (Note: Other values may be applied, if justified, to certain products, such as multivitamins and herbal preparations.) • Any degradation product exceeding its acceptance criterion. • Failure to meet the acceptance criteria for appearance, physical attributes and functionality test (e.g. colour, phase separation, resuspendability, caking, hardness, dose delivery per actuation). ………………………..……. Statements and labelling A storage statement should be established for the label based on the stability evaluation of the FPP. Where applicable, specific instructions should be provided, particularly for FPPs that cannot tolerate freezing. Terms such as “ambient conditions” or “room temperature” must be avoided. There should be a direct link between the storage statement on the label and the demonstrated stability of the FPP. An expiry date should be displayed on the container label. Long-term stability testing conditions Four different long-term testing conditions were defined, which match with the climatic conditions of the target markets categorized in just four different climatic zones. This concept is described in regulatory guidelines and pharmacopoeias and has become an established standard in developing finished pharmaceutical products (FPPs). It was then recommended to split the current Climatic Zone IV (hot and humid) into two zones: Climatic Zone IVA – for which 30 °C/65% RH will remain the standard long-term testing condition – and Climatic Zone IVB for which, if justified, 30 °C/75% RH will become the long-term testing condition. EFFECT OF STORAGE TEMPERATURE ON THE STABILITY OF TOTAL PARENTERAL NUTRITION ADMIXTURES PREPARED FOR INFANTS Acta Poloniae Pharmaceutica n Drug Research, Vol. 72 No. 5 pp. 843n849, 2015 Introduction: Read from the article Materials Vitamines, Amino acids, salts, lipids,… Methods involve determination of: Physical Stability: Zeta potential, particle size, Chemical stability: for ascorbic acid and L-alanyl-Lglutamine Microbiological stability Zeta-potential measurements ( )أهميتها؟؟ Carried out at 25C using Zetasizer apparatus. An electric field is applied to the dispersion of particles, which would then move with a velocity related to their zeta potential. This velocity is measured and converted to “ electrophoretic mobility” which is used in the calculation of Zeta potential, in mV, using Smoluchowsky equation . The zeta potential values indicates the instability of these systems with the values smaller than ―30 mV. The results showed decreasing tendency especially in samples stored at low temperature. Smoluchowsky Equation Results: zeta potential The most important condition of the nutrition is that the foods should be digested and the nutrients in the digestive system can convert into small molecules. A suitable zeta potential (negative electrical charge) is required, i.e., the nutrients have to get easily into the cells and to leave from there. As long as the negatively charged nutrients and positively charged intracellular fluid are maintained in equilibrium, the cell metabolism is proper and the way you feel is good. Figure 1 illustrates that the negative zeta potential remained under each storage temperature in the whole 14- day-storage period. Figure 1. Zeta potential values measured at different storage temperatures as a function of storage time. Particle size measurements Mean droplet size (MDS), size distribution and polydispersity of the emulsion droplets were measured at 25C using Zetasizer apparatus. Dynamic Light Scattering (DLS) is used to measure particle diameter. Particle size range for size measurement is from 0.6 nm to 6 μm. Results : Particle size … If a patient is unable to be nourished, the parenteral infusion is lifesaver, but efforts should be made to induce fewer side effects with it. It is particularly important that the fat emulsion must have smaller particle size. Under each storage conditions the particle size of the admixtures not even come close to 10 microns during 14 days long study. The larger particles, which were present in average in 4.6%, did not exceed an average size of 5 microns long red blood cells. Determination of the ascorbic acid concentration Ascorbic acid was diluted in deionized water to obtain solutions at appropriate concentrations for implementation. They were freshly prepared before use. The samples were ultrafiltrated with 10 kDa filter before the chemical analysis. Results: Ascorbic acid stability ….. However, it was not possible to detect ascorbic acid at 25C and 30C after 24 h. Samples, which were stored at 2-8C, contained ascorbic acid after 48 h, but after 3 days, the ascorbic acid became immeasurable, hence completely decomposed in each sample (Fig. 2). Figure 2. Changes in the concentration of ascorbic acid in the samples stored at 2-8C Examination of the stability of L-alanyl-L-glutamine The stability assay took 14 days at three temperatures (28C, 25C, 30C). The L-alanyl-L-glutamine was diluted in deionized water to obtain solutions at appropriate concentrations for implementation. In contrast to the ascorbic acid, L-alanyl- L-glutamine can be stored for 14 days without decomposition at each of the examined temperature. Figure 3 confirms that the concentration changes of Lalanyl-L-glutamine remained within the acceptable limits. Figure 3. Changes in the concentration of L-alanyl-L-glutamine at different temperatures as a function of storage time Microbiological examinations The parenteral formula was studied at three different temperatures (2-8C, 25C, 30C) for 14 consecutive days. Aerobic bacterial and mycological cultures were prepared according to the pharmacopoeia monographs. The samples were treated and evaluated according to the rules of microbiological sample processes. Result: Each sample remained sterile within the whole storage interval. DISCUSSION AND CONCLUSION There were no significant differences in the average particle size and zeta potential values of admixtures depending on the storage temperatures. After examination of the samples, the storage time exceeded even 14 days at all three temperatures. Moreover, the results show that the values were the best at 30C. …… According to the results of the physicochemical examinations, 10-day storage period of this type of TPN admixtures at room temperature can be accepted. Their storage does not require refrigeration (2-8C), thus they can be administered without special preheating ensuring better physiological tolerance. Because of the rapid decomposition of vitamin C, the water-soluble Soluvit multivitamin has to be added into the admixture in every day, while the glutamine can be mixed with the amino acid infusion because of its adequate stability.