Sterile Dosage Forms Lecture PDF

Sterile Dosage Forms Salma Essam, PhD Department of Pharmaceutics Faculty of Pharmacy Alexandria University Pharmaceutical requirements Isotonicity Theory If a solution is placed behind a membrane that is permeable onl...

Sterile Dosage Forms Salma Essam, PhD Department of Pharmaceutics Faculty of Pharmacy Alexandria University Pharmaceutical requirements Isotonicity Theory If a solution is placed behind a membrane that is permeable only to solvent molecules and not to solute molecules (a semipermeable membrane), osmosis occurs as the molecules of solvent (lower molecular weight) traverse the membrane to achieve equilibrium. Pharmaceutical requirements Isotonicity In practice Tonicity is defined as the ability of a solution (extracellular solution) surrounding a cell (semipermeable membrane) to cause that cell to gain or lose water by osmosis. Extracellular solutions can be isotonic, hypotonic or hypertonic. Pharmaceutical requirements Isotonicity In practice Body fluids, including blood and tears, have an osmotic pressure/osmolarity corresponding to that of a 0.9% solution of sodium chloride (isotonic): average of 284 mOsm/kg). Solutions with a lower osmotic pressure than body fluids or a 0.9% sodium chloride solution are commonly called hypotonic, whereas solutions having a greater osmotic pressure are termed hypertonic Pharmaceutical requirements Isotonicity In practice, for normal conditions: Hypotonic solutions Hypertonic solutions They have a lower osmotic They have a higher osmotic pressure than plasma. pressure than plasma. If mixed with blood they would If mixed with blood they would cause the blood cells to swell cause the blood cells to lose water and burst (hemolysis) as water by osmosis and shrink (crenation would be driven into the cells by occurs osmosis. Pharmaceutical requirements Isotonicity Pharmaceutically Parenteral products should aim toward being isotonic. If this is not achievable, excessive values of osmolality should be avoided as much as possible to minimize or prevent local damage on vascular endothelium and circulating blood cells. Isotonicity is not an essential requirement for small volume IV injections. Pharmaceutical requirements Pharmaceutically Isotonicity Intravenous infusions (LVP) should be made isotonic with human plasma. CNS (Intrathecal, epidural or intracisernal), intraarticular and intraocular injections should also be isotonic to avoid serious changes in osmotic pressure in sensitive tissues. It is considered desirable for subcutaneous, intradermal and intramuscular injections also to be isotonic to minimize local irritation. Pharmaceutical requirements Clarity (for solutions) Clarity is defined as the state or quality of being clear or transparent to the eye. Particles of approximately 50 μm may be detected in this manner. Reflective particles, such as fragments of glass, may be visualized in smaller size, about 25 μm. Particulate matter is defined in the USP as extraneous, mobile, undissolved substances, other than gas bubbles, unintentionally present in parenteral solutions. Pharmaceutical requirements Clarity (for solutions) One of the prime requisites of parenteral solutions is clarity. They should be sparkling clear and free of all particulate matter. They must be free of visible particles and contain only very low numbers of sub-visible particles. This is of particular importance for medicines administered intravenously. Pharmaceutical requirements Clarity (for solutions) Source & contaminants Contaminants include dust, cloth fibers, glass fragments, material leached from the glass or plastic container or seal. Sources of particulate matter include the raw materials, processing and filling equipment, the container, and environmental contamination. Pharmaceutical requirements Clarity (for solutions) Complications IV: pulmonary embolism IV: infusion phlebitis It has been shown that the development of infusion phlebitis (vein inflammation) may be related to the presence of particulate matter in intravenous fluids. IM: injection granuloma/muscle granuloma Pharmaceutical requirements Clarity (for solutions) Precautions & measures Manufacturing environment: clean surroundings, the use of laminar-flow hoods, and proper non-shedding garments. Both container and closure must be thoroughly clean, sterile, and non-shedding. The containers are carefully selected to be chemically resistant to the solution and of the highest available quality to minimize the chances of container components leaching into the solution. Pharmaceutical requirements Clarity (for solutions) Precautions & measures During manufacture, the parenteral solution is usually filtered just before it goes into the container. Parenteral solutions are carefully inspected for the presence of any foreign particles, such as glass, fibers, precipitates, and any floating material. Any parenteral product samples found containing particulate matter are discarded. “ Extra requirements Emulsions: no evidence of phase separation Suspensions: The use of appropriate particle size No aggregate formation Any sediment should be readily dispersed upon shaking  Classification of parenterals Classification of parenterals USP designations: Small-volume parenterals (SVP) are injections with a volume of 100 mL or less. Large-volume parenterals (LVP) are single-dose IV injections with a volume of 100 mL–1000 mL. They’re administered by IV infusion (route of administration). Classification of parenterals SVP LVP 100 mL or less Volume 100-1000 mL (usually: 0.5-2 mL) Dosage unit Single or multiple dose Single dose May or may not be used: Dose unit: single (-) or multiple Preservatives Not used dose (+) Route: CNS & intraocular (-) Classification of parenterals SVP LVP Essential (Exceptions!) Hypotonic: 5% dextrose in water Not essential Isotonicity 0.45% NaCl (Routes!) Hypertonic: 3% NaCl 5% dextrose & 0.45% NaCl Can vary from pH physiological pH Should not vary from physiological pH restriction (pH 3-9) Should not be used (blood buffering Buffers Can be used system!) Classification of parenterals LVP When & why used? In maintenance therapy for the patient entering or recovering from surgery and for the patient who is unconscious and unable to take fluids, electrolytes, and nutrition orally. This provides nutrition and calories (dextrose solutions, amino acid solutions): total parenteral nutrition (TPN) In replacement therapy for patients who have suffered a heavy loss of fluid and electrolytes. This replenishes lost body fluids or electrolytes or correct existing electrolyte imbalance (saline solutions). Classification of parenterals LVP When & why used? IV admixtures: The combination of parenteral dosage forms to be administered as a unit product. It requires the measured addition of a medication to a 50 mL or greater bag or bottle of IV fluid. Classification of parenterals LVP  Parental dosage forms Parenterals: Dosage forms Liquid Dry powder Injection For injection Injectable suspension For injectable suspension Injectable emulsion Parenterals: Dosage forms Injection (injectable solution) Formulation concept & method: They may be solutions in water, mixtures of water with cosolvents (propylene glycols, PEG, alcohol,...), or other nonaqueous/oily solvents. They are manufactured by dissolving the drug and any excipients, adjusting the pH, sterile filtering the resultant solution (to also remove particulate matter), then autoclaving the final product in its sealed container. Parenterals: Dosage forms Injection (injectable solution) Route: given through any route of administration (aqueous solutions) Requirements: clear (free of particulate matter) Parenterals: Dosage forms Injectable suspension For water-insoluble drugs Formulation concept & method: It is one of the most difficult parenteral dosage forms to formulate. Two basic methods are used to prepare parenteral suspensions: (i) Sterile vehicle and powder are combined aseptically (ii) Sterile solutions are combined, and the crystals are formed in situ Parenterals: Dosage forms Injectable suspension Route: They can be administered by the intramuscular, intra-articular or subcutaneous routes of administration. When injected, the suspended particles will dissolve slowly and provide a prolonged effect. Parenterals: Dosage forms Injectable suspension Requirements: The use of appropriate particle size Any sediment should be readily dispersed upon shaking to give stable formulations The particle size range of suspended matter does not change with time and ensure the correct dose to be withdrawn and injected. Parenterals: Dosage forms Injectable emulsion For water-insoluble drugs. Formulation concept & method: Formulation options are severely restricted through a very limited selection of stabilizers and emulsifiers (sterilization, toxicity, …). Route: o/w emulsions can be administered via IM (depot injections) or IV (total parenteral nutrition; TPN) routes. w/o emulsions can’t be administered via IV to avoid oil embolism. Parenterals: Dosage forms Injectable emulsion Requirements: No evidence of phase separation for the emulsions Droplet size must be controlled and is usually less than 3 μm in diameter to prevent oil embolisms forming in the blood-stream. Parenterals: Dosage forms Dry powders For injection (Sterile powders for solution) or For injectable suspension (Sterile powders for suspension) They are formulations for drugs that are unstable in aqueous medium (e.g., antibiotics). Upon reconstitution, they yield solutions or suspensions conforming in all requirements for the specific injection. They consist of drug and other excipients to ensure the chemical and physical stability of the product in a final-use container. Parenterals: Dosage forms Dry powders For injection (Sterile powders for solution) or For injectable suspension (Sterile powders for suspension) They are reconstituted using sterile diluents. Reconstitution should be carried out using the specified diluent, it shouldn’t be replaced with WFI or exchanged with other diluents. Parenterals: Dosage forms Physicochemical drug properties and therapeutic considerations (Drug solubility and stability) Route of administration: IV: only aqueous or blood-miscible solutions and o/w emulsions IM: aqueous or oleaginous solutions or suspensions Considerations for dosage form selection Parenterals: Dosage forms Desired onset and duration of action Drugs that are more soluble in body fluids show the most rapid absorption and onset of action. Sometimes, long action is desired to reduce the frequency of injections (depot preparations). Rapidity of onset: solutions > suspensions & aqueous preparations > oleaginous preparations Considerations for dosage form selection Excipients & additives Parenterals: Excipients & additives Vehicles & solvents Preservatives pH adjustment & buffers Tonicity adjustment agents Miscellaneous Parenterals: Excipients & additives The use of excipients should not adversely affect the action of the drug substance or cause any side effects or toxicity at the concentrations used in a given formulation. Parenteral preparations may require the use of excipients that should be biocompatible, be selected for the appropriate use and to be included at the minimum efficient concentration Parenterals: Excipients & additives Vehicles & solvents Water Nonaqueous vehicles Water-miscible solvents Oleaginous solvents (water-immiscible) Parenterals: Excipients & additives Water Tap/drinking/potable water is not normally used for the manufacture of pharmaceutical solutions, as it contains dissolved substances which could interfere with the formulation. Purified water is prepared by purification of tap water via distillation, or reverse osmosis. It is used for the preparation of non-parenteral solutions. Parenterals: Excipients & additives Water used in parenterals Water for injection (WFI) It is the most common vehicle used for parenteral products. Use: It is used as a vehicle in the manufacture of injectable products to be sterilized after preparation. For cleaning purposes of equipment and product-contact components during parenterals manufacture and rinsing of vials (pyrogen control). Parenterals: Excipients & additives Water used in parenterals Water for injection (WFI) Preparation: It is prepared by distillation or by membrane technologies (reverse osmosis or ultrafiltration). It is intended to be used within 24 hours after collection. It should be collected in sterile and pyrogen-free containers. Parenterals: Excipients & additives Water used in parenterals Water for injection (WFI) Requirements: Highly purified (low particle count, same as purified water) Pyrogen-free (not necessarily sterile, but there is a bacterial count restriction) Contains no added substances Parenterals: Excipients & additives Water used in parenterals Sterile water for injection (SWFI) Use: It is used as a solvent, vehicle, or diluent for already sterilized and packaged injectable medications of for their reconstitution. It’s used in reconstitution of single-dose injections. Parenterals: Excipients & additives Water used in parenterals Sterile water for injection (SWFI) Preparation: It’s sterilized and packed in sterile containers, not larger than a 1-liter size. It should be packed only in a single dose container, Requirements: Sterile Pyrogen-free Does not contain any added substance Parenterals: Excipients & additives Water used in parenterals Bacteriostatic water for injection (BWFI) Use: It is used as a sterile vehicle in the preparation of small volumes of injectable preparations. It’s used in the reconstitution of multiple-dose injections. Parenterals: Excipients & additives Water used in parenterals Bacteriostatic water for injection (BWFI) Preparation and requirements: It is sterile water for injection containing one or more suitable antimicrobial agents. It is packaged in containers not more than 30 mL, to prevent the administration of a large quantity of a bacteriostatic agent The container label must state the names and proportions of the antimicrobial agents used Parenterals: Excipients & additives Nonaqueous vehicles Water-miscible solvents Water-miscible cosolvents are widely used in parenterals to enhance drug solubility (cosolvents) and to serve as stabilizers. Common examples include glycerin, ethyl alcohol, propylene glycol, and polyethylene glycol 300. Concentrations range from 1–50%. Parenterals: Excipients & additives Nonaqueous vehicles Water-miscible solvents The selected vehicle must be nonirritating, nontoxic in the amounts administered, and not sensitizing. It must not exert a pharmacologic activity of its own, nor may it adversely affect the activity of the medicinal agent. Parenterals: Excipients & additives Nonaqueous vehicles Oleaginous solvents They may be used in case of limited drug water solubility or its susceptibility to hydrolysis Used in: Solutions: Oils are used to dissolve drugs with low aqueous solubility and provide a mechanism to slowly release drug over a long period of time. Emulsions: In TPN products, oils serve as a fat source and as carriers for fat-soluble vitamins. Parenterals: Excipients & additives Nonaqueous vehicles Oleaginous solvents Among the nonaqueous solvents employed in parenteral products are fixed oils (vegetable origin): peanut oil, corn oil, sesame oil, soybean oil or fatty acid esters like isopropyl myristate.