Quality Control Of Pharmaceuticals PDF

College of Pharmacy-Alamein Campus The Arab Academy for Science and Technology and Maritime Transport (AASTMT CPS 414: Quality Control of Pharmaceuticals Forced degradation studies Presented...

College of Pharmacy-Alamein Campus The Arab Academy for Science and Technology and Maritime Transport (AASTMT CPS 414: Quality Control of Pharmaceuticals Forced degradation studies Presented by: Professor Dr. Hadir Maher Shalaby Professor of Pharmaceutical Analytical Chemistry 1 Faculty of Pharmacy, Alexandria Prof. Dr. Hadir Maher University, Egypt Content Drug stability and drug degradation. Types of drug stability Origin of Degradation Products. Forced degradation studies. Guidance for forced degradation studies. 2 Prof. Dr. Hadir Maher 3 Prof. Dr. Hadir Maher  Drug stability & drug degradation Drug stability testing is a vital part of the drug development process, as it provides information on the optimal formulation, packaging, and storage conditions for the drug product, as well as the expiration date and the recommended usage instructions. Stability is used to determine: Why stability testing is necessary : - quality of a drug substance or - Chemical degradation may lead lowering drug product of concentration of drug in dosage form - shelf life for the drug product - toxic product may form due to - Recommended storage degradation of active ingredients conditions 4 Prof. Dr. Hadir Maher  Drug stability & drug degradation - Drug degradation is the process of chemical or physical transformation of the drug molecule or the drug product, resulting in the loss of quality, safety, or efficacy. Drug degradation can occur due to various mechanisms, such as hydrolysis, oxidation, photolysis, racemization, polymerization, and Maillard reaction. Drug degradation can lead to the formation of impurities, by-products, or degradation products, which may have adverse effects on the drug's performance, stability, or safety. 5 Prof. Dr. Hadir Maher  Factors affecting drug stability 1. Temperature: high temperature accelerate oxidation, reduction and hydrolysis reaction which lead to drug degradation 2. Moisture: a. Water catalyzes chemical reactions as oxidation, hydrolysis and reduction reaction b. Water promotes microbial growth 3. Light: affects drug stability through its energy or thermal effect which lead to oxidation 4. Pharmaceutical dosage forms: solid dosage forms are more stable than liquid dosage forms for presence of water. 5. Oxygen: exposure of drug formulations to oxygen affects their stability 6 Prof. Dr. Hadir Maher Factors affecting drug stability 6. Concentration: if rate of drug degradation is constant for the solutions of the same drug with different concentration. So, ratio of degraded part to total amount of drug in diluted solution is bigger than of concentrated solution. 7. Drug incompatibility: reactions between components of pharmaceutical dosage forms itself or between these components and cover of the container. 7 Prof. Dr. Hadir Maher Factors affecting drug stability 8. pH: Acidic and alkaline pH influence the rate of decomposition of most drugs. Many drugs are stable between pH 4 and 8. Weekly acidic and basic drugs show good solubility when they are ionized, and they also decompose faster when they are ionized. So, if the pH of a drug solution must be adjusted to improve solubility and the resultant pH leads to instability then to solve this tricky problem a water miscible solvent should be added into the product. It will increase stability by: - suppressing ionization - reducing the extreme pH required to achieve solubility - enhancing solubility and -reducing the water activity by reducing the polarity of the solvent. For example, 20% propylene glycol is placed in chlordiazepoxide 8 injection for this purpose. Prof. Dr. Hadir Maher Types of drug stability 1. Physical stability 2. Chemical stability 3. Microbiological stability 4. Therapeutic stability 5.Toxicological stability Prof. Dr. Hadir Maher 9  A. Physical degradation Definition: “Degradation, which results into the change of physical nature of the drug.” Types of physical degradation are as : 1. Loss of volatile components 2. Loss of H2O 3. Absorption of H2O 4. Crystal growth 5. Polymorphic changes 6. Color changes 10 Prof. Dr. Hadir Maher  A. Physical instability 1. Crystal formation in pharmaceutical preparations: Causes: a. Polymorphism phenomena: i.e. Chloramphenicol (change of amorphous to crystalline form). b. Saturated solution: by different temperature precipitation of solute may occur. c. In suspension: when very fine powder is used a part of suspending agent will dissolve then precipitate as crystal. 2. Loss of volatile substances from pharmaceutical dosage forms: Examples: a. Aromatic waters b. Elixirs c. Spirits d. Some types of tablets which contain aromatic water (Nitroglycerin tablets) 11 Prof. Dr. Hadir Maher  A. Physical instability 3. Loss of water: This can be seen in the following dosage forms: a. Saturated solution: by loss of water, they become supersaturated and precipitate as crystals is formed b. Emulsions: Loss of water lead to separation of the two phases and change to other type c. Creams: especially oil/water, they become dry by loss of water d. Pastes e. Ointments: especially aqueous base ointments Humectants is added to the previous dosage forms which defined as hydrophilic substances added to aqueous phase to absorb water from atmosphere and prevent its loss from the dosage forms. Examples: Glycerin 12 Prof. Dr. Hadir Maher  A. Physical instability 4. Absorption of water: This phenomena can be seen in the following pharmaceutical forms: a. Powders: Liquification and degradation may occur because of absorption of water b. Suppositories which base made from hydrophilic substances as Glycerin, Gelatin, polyethylene glycol. The consistency of these forms becomes jelly-like appearance. Depends on temp and humidity of surrounding material, e.g. · Glycerin suppositories may become opaque · Gelatin capsule may soften · Some deliquescent salts calcium chloride, potassium citrate. 13 Prof. Dr. Hadir Maher  A. Physical instability 5. Change in crystalline form: In polymorphic changes crystal forms are changed. This may cause alteration in solubility and possibly crystalline growth in aqueous suspensions Example: Cocoa butter which is capable of existing in different polymorphic forms. 6. Color Changes: Color changes are of two types. 1. Loss of color · pH change · Presence of reducing agent 2. Development of color · Exposure to light 14 Prof. Dr. Hadir Maher  B. Chemical instability Definition: “Change in the chemical nature of the drug is called as chemical degradation.” Types of chemical degradation are 1. Hydrolysis 2. Oxidation 3. De-carboxilation 4. Isomerization 5. Polymerization 6- Combination 7- Complexation or chelation 15 Prof. Dr. Hadir Maher  B. Chemical instability 1. Hydrolysis: “It is defined as the reaction of a compound with water.” Major cause of degradation of drug. Factors Effecting Hydrolysis: · Moisture · pH · Temp. · Type of the solvent 16 Prof. Dr. Hadir Maher 17 Prof. Dr. Hadir Maher  Hydrolysis of penicillin (beta-lactam ring) Prof. Dr. Hadir Maher 18  B. Chemical instability 2. Oxidation is defined as loss of electrons or gain of oxygen. Auto-oxidation: It is a reaction with oxygen of air which occur spontaneously without other factors. Pre-oxidants: Are substances catalyze oxidation process i.e. metals, some impurities. 19 Prof. Dr. Hadir Maher  Oxidation of adrenaline to give colored adrenochrome 20 Prof. Dr. Hadir Maher  B. Chemical instability Factors lead to oxidation Presence of oxygen Light: It can cause photo-chemical reactions: chemical reaction occur in presence of light. Temperature: Elevated temperature accelerate oxidation reaction pH : each drug has its ideal pH for stability. Any change in pH affect drug stability and may accelerate oxidation reaction. Pharmaceutical dosage form Oxidation reaction occur in solutions faster than in solid dosage forms. Presence of pre-oxidants as metals & peroxides Type of solvent used Oxidation reaction occur faster in aqueous solution than others. Presence of unsaturated bonds : as double and triple bonds (oils) which undergo easier than saturated bonds for oxidation. 21 Prof. Dr. Hadir Maher  B. Chemical instability 3- Polymerization In polymerization, small repeating units called monomers are bonded to form a long chain polymer. Formaldehyde polymerization to paraformaldehyde, to avoid this formaldehyde must be stored in suitable temperature and addition of methanol 15%. Ampicillin in high temperature forms polymers which cause allergy. Factors induce Polymerization 1. Temperature 2. Light 3. Solvent 4. pH 5. Impurities Ampicillin 22 Prof. Dr. Hadir Maher  B. Chemical instability conversion of drug to its isomer. Isomers have Identical molecular formulas but posses a different 4-Isomerization arrangement of atoms. Optical Isomerization – Conversion of optical active drug into less active E.g.: L-Adrenaline (epinephrine) is converted to d- Circular dichroism adrenaline by change of pH or temperature L-adrenaline is more therapeutically active than d- adrenaline, a although they have the same physical properties but different arrangement of atoms. Factors affect optical isomerization: Temperature , pH , Solvent and Impurities Geometric Isomerization Expressed by cis or trans Cis: Means the groups in the same direction: , Trans: Means the groups in opposite direction Cis is more therapeutically active than trans , E.g.: Vitamin A 23 Prof. Dr. Hadir Maher  Change in pH of the formulation, solubility change, …. For example, hydrolysis of aspirin can produce salicylic acid and acetic acid, which can lower the pH of the formulation and affect the drug's solubility and bioavailability. Unacceptable change in the products, change in color, odor production, …. Oxidation of epinephrine (also called adrenaline) can produce the highly colored (pink) adrenochrome, which can cause change in color and loss of potency. 24 Prof. Dr. Hadir Maher  Toxic degradation products Photolysis of tetracycline can produce anhydro-tetracycline, which can cause nephrotoxicity and photosensitivity. 25 Prof. Dr. Hadir Maher  Toxic degradation products the drug pralidoxime (organophosphate insecticide poisoning) degrades via two parallel, pH-sensitive pathways. Under basic pH conditions, the toxic product cyanide is formed Memorize the name of drugs mentioned under each degradation type 26 Prof. Dr. Hadir Maher  Forced degradation studies Introduction The stability studies include 1- long term studies (12months), 2- intermediate term and 3- accelerated stability studies (6 months). As compared to stability studies, 4-forced degradation studies help in generating degradants in much shorter time, mostly a few weeks. Important 27 Prof. Dr. Hadir Maher  Forced degradation studies Forced degradation studies are also known as stress testing. Forced degradation is a process that involves degradation of drug products and drug substances at conditions more severe than accelerated conditions and thus generates degradation products that can be studied to determine the stability of the molecule. ICH guidelines mandatory oblige the forced degradation studies under a range of conditions, like pH, light, oxidation, dry heat, acidic, basic, hydrolysis etc. Moreover, it provides the separation of drug from degradation products. The FDA and ICH guidance mandate the requirement of forced degradation to recognize how the quality of a drug substance and drug product varies with time and different environmental factors. 28 Prof. Dr. Hadir Maher Overview of regulatory guidance The ICH guidelines that are applicable to forced degradation studies are: ICH Q1A, (Stress Testing), there are recommended conditions for performing forced degradation studies on drug substances and drug products. The recommendations are to examine the effects of temperature (above that for accelerated testing, i.e., >50°C), humidity (≥75% relative humidity), oxidation and photolysis. Testing in solution should also be performed across a wide pH range either as a solution or suspension. These samples are then used to develop a stability-indicating method. ICH Q1B gives recommended approaches to assessing the photo stability of drug substances and drug products. The actual design of photo stability studies is left to the applicant. ICH Q2B gives guidance on how to validate analytical methodology. there is a recommendation to use samples from forced degradation studies to prove specificity. Specificity is a key factor in determining whether or not the analytical method is stability indicating. ICH Q3A (R2) requires identification of each impurity with respect to both chemistry and safety perspectives. 29 Prof. Dr. Hadir Maher Objectives of forced degradation studies: The ICH guideline states that stress testing is intended to identify the likely degradation products which further helps in determination of the intrinsic stability of the molecule and establishing degradation pathways, and to validate the stability indicating procedures used. 30 Prof. Dr. Hadir Maher Origin of degradation products: The main reason of appearance of impurities in drug substance or product is due to its degradation. The chemical instability of the drug substance under the conditions of heat, humidity, solvent, pH, and light encountered during manufacture, isolation, purification, drying, storage, transportation, and/or formulation is main cause of its degradation. It is governed by inherent chemical stability of the drug substance. The major routes of degradation of any drug substance include hydrolysis, oxidation, heat and photolysis. The stress testing helps in generation all possible degradation products that may form under different conditions. 31 Prof. Dr. Hadir Maher Methods for the stability studies of drugs: Important 32 Prof. Dr. Hadir Maher  Stability Indicating Assay Method (SIAM) Stability Indicating Method (SIM) According to ICH guidelines, SIM is the method which is capable of detecting the loss in content of the active component and subsequent increase in degradation products. Ideally, loss in content of the active component and increase in degradation products should be monitored by a single analytical method. According to FDA, SIM is an analytical method capable for: ❑ Determining the drug substance accurately. ❑ Discriminating between the active ingredients and degradation product ❑ Detecting degradation products. 33 Prof. Dr. Hadir Maher  The objective of stress testing is to identify primary degradation products DEGRADATION and not to completely degrade the API. The conditions studied should TYPE: cause degradation to occur to a small extent, typically 10–30% loss of API as determined by assay when compared with non-degraded API. The target should be chosen so that some degradation occurs, but not enough to generate secondary products. 34 Prof. Dr. Hadir Maher 1-Hydrolysis degradation Hydrolytic study under acidic and basic condition involves catalyzation of ionizable functional groups present in the molecule. In general temperature and pH are the major determinant in stability of the drug prone to hydrolytic decomposition. Hydrolysis of most of the drugs is dependent upon the relative concentration of hydronium and hydroxyl ions. Hence pH at which each drug is optimally stable can be determined. The function groups likely to undergo acid-basic hydrolysis are: Amides, Esters, Imides, Carbamates, Alcohols, Aryl amines Procedure for conducting hydrolytic degradation: For Acid stress Reflux with 0.1N HCL at 60°C for 30 minutes. For Base stress Reflux with 0.1N NaOH at 60°C for 30 minutes. For water stress Reflux with water at 60°C for 30 minutes. Adjust degradation conditions depending on the results seen. 35 Prof. Dr. Hadir Maher 2-Oxidation degradation The mechanism of oxidative degradation of drug substance involves an electron transfer mechanism to form reactive anions and cations. Drugs that are susceptible to oxidation are: Catechols, Thiol (Sulfur atoms are oxidized to the corresponding sulfoxides and ultimately sulfones), Alcohols, aldehydes Hydrogen peroxide is widely used for oxidation of drug substances in forced degradation studies but other oxidizing agents such as metal ions, oxygen, and radical initiators can also be used. It is recommended 0.3-3% (w/w) hydrogen peroxide concentrations with duration of 2-7 days and a limit of 40 °C to avoid the potential for unwanted O-O homolytic bond cleavage to form hydroxyl radicals, which are very strong oxidants that lead to oxidative degradation that is rarely observed in drug formulations. Procedure for conducting oxidative degradation: For oxidation stress: Treat with 1% H2O2 at less than 30°C for 30 min. The oxidative stress testing is initially carried out in 3% H2O2 at room temperature for 6 hr and it can be increased/ decreased to achieve sufficient degradation. 36 Prof. Dr. Hadir Maher 3-Photolytic degradation Exposure of drug molecules may produce photolytic degraded products. The rate of photo degradation depends upon the intensity of incident light and quantity of light absorbed by the drug molecule. Hence, light can also act as a catalyst to oxidation reactions. The function groups that are likely to undergo photo-reactivity are: -CO, -C=C, -OH, -N-O, Suphide and polyenes. Procedure for photolytic degradation: Photolytic degradation is carried out by exposing the drug substance (in solid as well as in the solution form) or drug product to a combination of visible and UV light. Expose the tablet powder contents of capsule to ultraviolet radiation up to minimum of 200 watts hour/m² and minimum of 1.2 million lux hour for visible light and photo stability chamber. If photo stability chamber is not available, expose the tablet powder/content of capsule to intense ultraviolet radiation (both at longer, 360 nm, and shorter, 254 nm, wavelengths) up to minimum of 7 days in UV cabinet. 37 Prof. Dr. Hadir Maher  4-Thermal degradation In general, rate of a reaction increase with increase in temperature. Many APIs are sensitive to heat or tropical temperatures. For example, vitamins, peptides, etc. Effect of temperature on thermal degradation of a substance is studied through Arrhenius equation. Every 10°C increase in temperature result in: Doubling the reaction rate. Decreasing the reaction time by factor of two. Degradation in 1year at 30°C = Degradation in 6 months (24 weeks)at 40°C So degradation in 1year at 30°C = Degradation in 3 weeks at 70°C To predict 2 years shelf-life at room temperature (30°C), 6-weeks study time is recommended at 70°C. Procedure for thermal degradation: Thermal degradation study is carried out at 40°C to 80°C. The most widely accepted temperature is 70°C at low and high humidity for 1-2 months. High temperature (>80˚C) may not produce predictive degradation pathway. 38 Prof. Dr. Hadir Maher 39 Prof. Dr. Hadir Maher