Dr. Zahra Hesari Pharm D, PhD of Pharmaceutics Pre-formulation Dr. Zahra Hesari Pharm D, PhD of Pharmaceutics Session 3 Guilan university of Medical Sciences, Faculty of Pharmacy

Review potency Proteins Solid dosage form excipients Organic Salts (Dose) Hydrates & solvates Organic esters LogP pKa Membrane permeability

Drug and Drug Product Stability Drug samples of known purity Stability studies in the preformulation phase: Solid-state stability of the drug alone Solution-phase stability Stability in the presence of expected excipients Initial investigation: drug’s chemical structure Drug substances (Chemically): alcohols, phenols, aldehydes, ketones, esters, ethers, acids, salts, alkaloids, glycosides

Drug Stability Mechanisms of Degradation Most frequently chemical destructive processes Hydrolysis Oxidation Drug molecules interact with water molecules to yield breakdown products Great number of drugs are esters or contain such other groupings as substituted amides, lactones, and lactams Aldehydes, alcohols, phenols, sugars, alkaloids, and unsaturated fats and oils Loss of electron, increase in the positive valence, loss of hydrogen Free chemical radicals Autoxidations: (atmospheric oxygen- chain reaction)

Kinetics and Shelf Life Stability definition Stability concern types: Chemical Physical Microbiologic Therapeutic Toxicologic Chemical stability Storage conditions Proper container Anticipating interactions when mixing drugs and dosage forms Stability and expiration dating are based on reaction kinetics

Reaction kinetic Expiration dating Stability Study of rate of chemical change This rate is influenced by concentration of reactants, products and solvent, pressure and temperature.

Rate Reactions Reaction rate is a description of the drug concentration with respect to time. Most commonly in pharmacy Zero-order reaction First-order reactions

Q10 Method of Shelf Life Estimation Estimate shelf life for a product that has been stored or is going to be stored under a different set of conditions

Enhancing Stability of Drug Products Incorporation of excipients Increase the stability of the drug substance Hydrolysis: Hydrolysis & Oxidation reduction or elimination of water: waterproof protective coating over tablets keeping the drug in a tightly closed container substitute liquids such as glycerin, propylene glycol, and alcohol Anhydrous vegetable oil in injectable products Suspending in a nonaqueous vehicle rather than dissolving in an aqueous solvent Dry form for reconstitution (sp antibiotics) Refrigeration pH (5-6), buffering agents

Enhancing Stability of Drug Products Oxidation Humidity in presence of oxygen or light Combination with other chemicals Alteration in the color, precipitation or a change in odor Antioxidants: providing electrons and hydrogen atoms Aqueous preparations: sodium sulfite (Na2SO3, at high pH) sodium bisulfite (NaHSO3, at intermediate pH) sodium metabisulfite (Na2S2O5, at low pH) hypophosphorous acid (H3PO2) ascorbic acid Oleaginous (oily or unctuous) Preparations: alpha-tocopherol, Butyl hydroxy anisole ascorbyl palmitate

No generally suitable substitutes for sulfites Preservative Injectable drugs, such as antibiotics and local anesthetics inhalants and ophthalmic preparations few oral drugs FDA labeling regulations 0.2% of the population who are subject to allergic reactions Food products Antioxidant + other pharmaceutical additives Antioxidant + drug substance oxygen-free atmosphere during preparation and storage No generally suitable substitutes for sulfites potassium bisulfite, potassium metabisulfite, sodium bisulfite, sodium metabisulfite, sodium sulfite, and sulfur dioxide.

Oxidation Trace metals Light (catalyst) Temperature pH Purification of the source Chelating agents: calcium disodium edetate and EDTA Light (catalyst) packaging in light-resistant or opaque containers Temperature Keep in cool place pH Most favorable for each preparation Potassium Iodide Oral Solution, USP Yellow to-brown discoloration light-resistant containers addition of 0.5 mg of sodium thiosulfate for each gram of KI.

Formulation pharmacist may stabilize the preparation by the selective exclusion from the system of oxygen, oxidizing agents, trace metals, light, heat, and other chemical catalysts to the oxidation process. Antioxidants, chelating agents, and buffering agents may be added to create and maintain a favorable pH. Other less frequent destructive processes include polymerization, chemical decarboxylation, and deamination.

Drug-Excipient Compatibility Stress condition Guideline of accelerated stability studies Temp, pH, light, moisture, agitation, gravity, packaging, method of manufacture Experimental studies: Mixing drug with excipients Aqueous suspension of Drug-Excipients Factorial design water addition: yes/no, Temp: 25 or 40 ‘C Time: 1 or 4 week High temp & high humidity Intact drug & degradation product are measured Drug content, color, taste, related substances

Advanced analytical instrumentation Detect low levels of degradation products (less than 2%) Thermal analysis (DTA, DSC) Chromatographic methods (HPLC, LC/MS) Diffuse reflectance spectroscopy (DRS)

Stability Testing Pharmaceutical components and finished products FDA’s GMP and ICH guideline: “Stability Testing of New Drug Substances and Products” “Quality of Biotechnological Products: Stability Testing of Biotechnology/Biological Drug Products” “Photostability Testing of New Drug Substances and Products” “Stability Testing of New Dosage Forms” Drug stability is important during preclinical testing and in clinical (human) trials For marketed drug product is vital during shelf life

Stability assessment before approval for marketing: Influence of pharmaceutical ingredients Influence of the container and closure The manufacturing and processing conditions (e.g., heat) Packaging components Conditions of storage Anticipated conditions of shipping, temperature, light, and humidity Anticipated duration and conditions of pharmacy shelf life and patient use. In-process stability testing Packaging features

Extemporaneous compounded formulations USP guidelines on stability: nonaqueous liquids and solid formulations in which the manufactured drug is the source of the active ingredient, not later than 25% of the time remaining until the product’s expiration date or 6 months, whichever is earlier. nonaqueous liquids and solid formulations in which a USP or National Formulary (NF) substance is the source of active ingredient, a beyond-use date of 6 months. watercontaining formulations prepared from ingredients in solid form, a beyond-use date not later than 14 days in storage at cold temperatures. all other formulations, a beyond-use date of the intended duration of therapy or 30 days, whichever is earlier.

Thank You ! Handout