Sterile Pharmaceutical Preparations Lecture 8 PDF

Sterile Pharmaceutical Preparations Lecture 8 Classification of Parenterals ✓ Solutions ✓ Small Volume Parenterals Volume-bas...

Sterile Pharmaceutical Preparations Lecture 8 Classification of Parenterals ✓ Solutions ✓ Small Volume Parenterals Volume-based Pharmaceutical ✓ Suspensions ✓ Large Volume Parenterals classification classification ✓ Emulsion  ✓ Dry powder Sterile Pharmaceutical Preparations Pharmaceutical Classification of Parenterals Solutions Suspensions Emulsions Dry powders  1. SOLUTIONS Water Aqueous Water+ co-solvent (IM & (Solubility and IV) stability) Solutions Non- aqueous Oils (fixed) (IM) Sterile Pharmaceutical Preparations Solutions  Most injectable products are solutions.  Solutions are usually aqueous, some are mixtures of water with glycols, alcohol or other non-aqueous solvents.  Most solutions have a viscosity & surface tension very similar to water, although streptomycin sulfate injection & ascorbic acid injection are quite viscous.  Parenteral solutions are generally filtered through 0.22 μm membrane filters to achieve sterility & remove particulate matter. Then, thermostable drug solutions should be terminally autoclave sterilized after filling, to assure sterility. Sterile Pharmaceutical Preparations Suspensions  One of the most difficult parenteral dosage forms.  For insoluble drugs, particle size range from 5 - 10 μm.  Given via IM route & characterized by a prolonged depot effect.  As the drug dissolution rate in the tissue fluids decrease, the absorption rate decrease “sustained effect”. Particle size distribution  To formulate a product that is easily Zeta potential re-suspended & can be ejected through 18 - 21 gauge needle; balance of various Rheological properties variables is required; …… Wettability & Surface tension Sterile Pharmaceutical Preparations The flow properties of parenteral suspensions are characterized on the basis of syringeability or injectability Syringeability Injectability refers to the handling characteristics of a refers to the properties of the suspension suspension while drawing it into the during injection. syringe. Injectability includes: Syringeability includes: Pressure required for injection. Ease of withdrawal from the container Evenness of flow. into the syringe. Freedom from clogging. Clogging & foaming tendency. Accuracy of dose measurement. Both are closely related to viscosity & particle characteristics Sterile Pharmaceutical Preparations Emulsions Parenteral emulsions are used for several purposes; 1. w/o emulsions of allergenic extracts (given SC) 2. o/w sustained-release depot preparations (given IM) 3. IV emulsions are rare (?) Parenteral emulsions should have a stable droplet size lower than 1μm (embolism) Parenteral emulsion formulations are limited due to: Limited selection of stabilizers & emulsifiers, owing to the constraints of autoclave sterilization & parenteral injection. Unwanted physiological effects; e.g. pyrogenic reaction & hemolysis. Sterile Pharmaceutical Preparations Lipid emulsion A class of IV emulsions. Fat is transported in blood stream as small droplets 0.5 - 1μm, consisting of a central core of triglycerides & outer layer of phospholipids. IV fat emulsions contain 10 - 20% oil. These emulsions yield triglycerides that provide essential fatty acids & calories during total parenteral nutrition (TPN) of patients unable to absorb nutrients through the GIT. IV fat emulsions composition usually include; soybean oil, safflower oil, cottonseed oil, egg phospholipids, soybean phospholipids & soybean lecithin. Sterile Pharmaceutical Preparations Dry Powder Many drugs are too unstable (physically The drug is formulated as a dry Thus, or chemically) in aqueous medium to be powder, that is reconstituted by formulated as a solution, suspension or water immediately before emulsion, e.g. antibiotics. administration. ❑ The pharmacist should be totally aware with the final reconstitution volume. ❑ The reconstituted product is usually an aqueous solution; however, the product may sometimes be an aqueous suspension, e.g. ampicillin trihydrate & spectinomycin hydrochloride. ❑ The most common form of sterile powder is a freeze dried or lyophilized powder. Sterile Pharmaceutical Preparations Advantages of Freeze Drying ✓ Water can be removed at low temperature, avoiding the damage of heat sensitive drugs. ✓ If freeze drying is done properly the dried product has a high specific surface area, which facilitates a rapid & complete reconstitution. ✓ Freeze dried dosage forms allow drug to be filled into vials as solution. This controls the quantity filled in each vial (more precise than filling powder). ✓ Since drug is filled as a solution, this minimize the concern with dust containment & potential worker exposure to hazardous drugs. Sterile Pharmaceutical Preparations Lecture 3 Limitations of freeze drying 1. Some drugs, e.g. biological products (proteins), liposomal products & vaccines are damaged by freeze drying. However, the damage can be minimized using protective agent in the formulation. 2. Often, the stability of a drug in the solid state depends on its physical state (crystalline or amorphous). If freeze-drying produces an amorphous solid & the amorphous form is not stable then freeze- drying will not provide an acceptable product. 3. It’s a relatively expensive drying procedure. Sterile Pharmaceutical Preparations To Achieve Controlled Drug Delivery in Parenteral Preparations ✓ By decreasing the drug dissolution rate in tissue fluids resulting in decreased absorption rate & sustained effect. Increasing particle size (e.g. suspension). Increase viscosity (e.g. oil solutions, suspensions or using viscosity imparting agents). ✓ Use of implants (SC), e.g. potent hormones as testosterone & estradiol. ✓ Use of less soluble salts as Insulin-Zn ✓ Use of crystalline rather than amorphous form as Insulin Lente  INSULIN LENTE  Insulin zinc suspension An intermediate acting porcine or human insulin with zinc salt added such that the solid phase of the suspension contains a ratio of 7:3 Crystalline to amorphous insulin Sterile Pharmaceutical Preparations Lecture 3 Specification of Parenterals Absence Sterility of Clarity pyrogens Tonicity pH Sterile Pharmaceutical Preparations Sterility Sterility: an absolute term, means the absence of living microorganisms. Sterilization involves; the destruction of all living microorganisms and their spores or their complete removal from the preparation. ▪ In parenteral preparations the presence of pathogens is very serious; fatal in IV route. ▪ Sterilization can be achieved by several methods; the suitable method is determined by the nature of preparation & its ingredients. ▪ The product must pass a sterility test to proof the effectiveness of the sterilization method. ▪ To keep the product sterility; preservatives are added to the parenteral preparations.  Methods of sterilization ▪ Moist heat sterilization ▪ Dry heat sterilization ▪ Ionizing radiation sterilization ▪ Gaseous sterilization (ethylene oxide) ▪ Filtration (bacterial filters ): cannot be used for suspensions?  Preservation  Antimicrobial agents are added to multi-dose vials  Protect the injection from contamination during production, use and storage.  Preservatives are not added to LVP (single dose containers discarded after opening); why?  Not used if the drug itself has antimicrobial effect (methohexital sod. Injection)  Preservation Ideal preservative must be: 1. Effective against wide range of bacteria 2. Nontoxic in the concentration used 3. Stable 4. Compatible with injection components (No interaction)  Preservative uptake is more significant with natural and neoprene rubber  Much less uptake with butyl rubber closures.  Commonly used preservative in multi-dose injections Preservative Concentration (% w/v) Benzyl alcohol 1-2 Chlorocresol 0.1-0.3 Cresol 0.25-0.5 Methyl para hydroxybenzoate (Methyl 0.1 paraben) Propyl para hydroxybenzoate (propyl 0.1-0.2 paraben) Phenol 0.25-0.6 Thiomersal 0.01 NB: Benzalkonium chloride (4ry ammonium salts) is not used for injection (toxic). Sterile Pharmaceutical Preparations Clarity Parenteral solutions must be clear & completely free of any foreign particles e.g. dust, glass or fiber. Foreign particles are non-biodegradable, if injected will accumulate, causing Muscle granuloma, (IM route). Embolism (thrombosis): fatal, (IV route). Sterile Pharmaceutical Preparations Absence of Pyrogens Parenteral solutions must be non-pyrogenic (pyrogen-free). Pyrogens: Are organic metabolic products arising from microbial contamination causing many febrile reactions in patients if injected so, known as bacterial endotoxins. The causative material is a lipopolysaccharides (Lipid A linked to a central polysaccharide core) metabolic products from the outer cell wall of Gram-negative bacteria.  Sterile Pharmaceutical Preparations Injection of pyrogens in parenteral products can produce toxic effect; fever, chills, pain in the back & legs & malaise. High doses of pyrogens will activate the coagulation system & produce shock & ultimately death. The intensity of pyrogenic response & the degree of hazard caused is affected by: ✓ The medical condition of the patient; in seriously ill patient, pyrogenic reactions can cause shock like symptoms & may be fatal. ✓ The potency of the pyrogen. ✓ The amount of pyrogen. ✓ The route of administration; intrathecal is the most hazardous, followed by IV, IM & SC. Sterile Pharmaceutical Preparations Characteristics of pyrogens Water soluble Non-volatile Pass through bacterial filters Thermostable N.B: Since pyrogens are water soluble & thermostable; it may remain in water even after sterilization by autoclaving or by microbial filteration. Sources of pyrogens Solvent (water) Raw material Packaging material Equipment  Sterile Pharmaceutical Preparations Depyrogenation Depyrogenation is the elimination of all pyrogens from the solvents, raw materials & equipment either by; removal or inactivation. 1. Water Depyrogenation 2. Packing Materials & Equipment Distillation is the principle & most Depyrogenation reliable method to eliminate pyrogens Removing pyrogens from surfaces by from water. rinsing with pyrogen-free water. By dry heat at 250°C for 45 min (for Reverse osmosis (USP) Filtration of water under high pressure thermostable glass ware & equipment). through semi-permeable membrane that (not for plastic) separate all substances and most ions Heating with strong alkali or oxidizing Positively charged membrane filters. solution, destroy pyrogens. Ultrafiltration. Sterile Pharmaceutical Preparations pH (Hydrogen ion concentration) The pH of the blood is neutral (7.4), maintained by natural buffer systems: Carbonic acid / bicarbonate system. Phosphoric acid / phosphate system. Protein system. Ideal pH of the parenteral preparations is 7.4. However, some drugs for injection require different pH values than neutrality either: To maintain product stability if drug is unstable at neutral pH. Also, drug solubility may strongly depend on the solution pH (some drugs are insoluble at pH 7.4). Sterile Pharmaceutical Preparations Non-neutral parenterals For non-neutral SVP (not for IV administration) Formulate at the suitable pH for the stability or solubility. Use buffers to stabilize the solution against chemical degradation that might occur if the pH changes. The buffer system should have a low buffering capacity (?) so as not to disturb significantly the body’s buffering systems when injected (allows rapid neutralization of the SVP by the natural buffer systems). Buffer systems for parenterals consist of either; a weak base / salt of weak base or a weak acid / salt of weak acid. Frequently used buffers for injectable products include: ✓ acetates (1 - 2%) ✓ phosphates (0.8 - 2%) ✓ citrates (1 - 5%) ✓ amino acids (used as buffers for polypeptide injectables) The acceptable pH range for non-neutral SVP is 4 - 9 for tissues. Higher or lower values are very irritant and damaging to sensitive cells.  NON-NEUTRAL LVP  IV infusions should not contain buffering system (comment?) 1. Large volume needs large amount of buffer (toxicity) 2. To allow neutralization (full neutralization of large amount of buffer is difficult even if low buffer capacity is used) Sterile Pharmaceutical Preparations Non-neutral parenterals For non-neutral LVP ( for IV administration) IV infusions should not contain buffering system. IV infusions of non-neutral pH should be injected very slowly. ✓ To prevent change in blood pH by the large volume (allow rapid neutralization). Any decrease or increase in blood pH can result in systemic acidosis or alkalosis which are life threatening. ✓ Avoid precipitation of the drug in the circulation. The accepted pH range for non-neutral LVP is 3 - 10.5. Sterile Pharmaceutical Preparations Tonicity (Osmotic pressure) If a semi-permeable membrane separates Semipermeable membrane Pressure water from electrolyte solution, water will pass from its compartment to the salt compartment. The pressure required to overcome water pressure is the osmotic pressure. Sterile Pharmaceutical Preparations Parenteral preparations should be isotonic (have the same osmotic pressure as blood plasma). Isotonic solution If parenterals have osmotic pressure < plasma, …… hypotonic If parenterals have osmotic pressure > plasma, …… hypertonic Injection of hypertonic solutions is painful to tissues with nerve supply (IM, SC) and may be destructive to delicate nerve cells in the spinal cord (intrathecal injections). Hypotonic Hypertonic Sterile Pharmaceutical Preparations IV injectable solutions should be isotonic or nearly isotonic. Due to osmotic pressure changes and the resultant exchange of ionic species across RBCs membranes, non-isotonic solutions (specially if volume > 100 ml) can cause: Hemolysis (if solution is hypotonic), this is irreversible and fatal. Crenation (shrinkage) of RBCs (if solution is hypertonic), this is reversible. Commonly used tonicity adjusting agents for parenterals are; electrolytes and mono- or disaccharides e.g. dextrose (4 - 5%) sodium chloride (0.5 - 0.9%). Sterile Pharmaceutical Preparations Tonicity adjustment The amount of solute required to be added or the dilution required to become isotonic. Hypertonic parenteral solutions can be made Hypotonic parenteral solutions can be made isotonic by dilution. isotonic by addition of; electrolytes e.g. sodium chloride Hypertonic solutions for IM or SC injections osmotic agents e.g. mannitol, glucose. can be injected but painful. N.B: both mannitol and glucose are Hypertonic IV infusions can be extremely incompatible with some drugs. irritant to the patients’ veins so they should be injected slowly in small volumes or into a large Solutions are made isotonic with isotonic saline vein. solution (0.9 % NaCl). In some cases, hypertonic IV infusions are deliberately prescribed to patient with severe. hypoantremia (low sodium concentration in blood). Sterile Pharmaceutical Preparations Formulation of Parenteral Products Active Solvents drug (vehicles) Container Additives  Sterile Pharmaceutical Preparations Active drug A successful therapeutic response following parenteral administration of drug requires an adequate drug concentration at the site of action. Require drug absorption from injection site. No absorption step IV Absorption process is A major consideration is: IM & SC determined by: ✓ Assuring adequate drug ✓ Physicochemical properties solubility in the of the drug. administered solution. ✓ The formulation used. ✓ Minimizing probability of ✓ Physiological factors, e.g. drug precipitation at the vascularity at injection site, injection site. fat distribution in the tissues, amount of exercise and tissue condition. Sterile Pharmaceutical Preparations Prodrug Chemical modification of the drug: ✓ It may improve the properties of the parent drug. ✓ The preparation of an ester, or salt or other modification may increase stability, alter drug solubility, enhance depot action, avoid formulation difficulties and decrease pain on injection. ✓ The modified drug that converts to the parent active drug is called a prodrug. ✓ This conversion occurs within the body or after reconstitution, e.g. dry powders. Antibiotic prodrugs Steroids prodrugs Benzathine penicillin, Methylprednisolone Procaine penicillin, (as methylprednisolone sodium succinate). Metronidazole phosphate, Hydrocortisone Chloramphenicol sodium succinate. (as hydrocortisone sodium succinate). Sterile Pharmaceutical Preparations Polymorphism ✓ Is the existence of several crystal forms of a chemical that exhibit different physical properties. ✓ Polymorphism affects both solubility and dissolution rates. ✓ Physical stability of the polymorph in a particular solvent is important in parenteral formulation pH & pK The effect of pH on solubility and stability of solution and suspension formulations affects physical and chemical stability as well as maximize or minimize solubility. pH is also important to predict the compatibility of drugs with various infusion fluids. Sterile Pharmaceutical Preparations Solvents and vehicles for injection Non- Aqueous aqueous Sterile Pharmaceutical Preparations Aqueous vehicles Water for injection, USP ✓ The most frequently used solvent for manufacturing injections. ✓ This water is purified by distillation of deionized water or by reverse osmosis and meets the same standards for the presence of total solids as purified water, USP (not more than 1mg/100mL). ✓ It may not contain added substances. ✓ Water for injection is not required to be sterile (to be sterilized after preparation), but it must be pyrogen free. ✓ Should be stored in tight containers at temperatures below or above the range in which microbial growth occurs. ✓ Naturally, the water should be collected in sterile and pyrogen-free glass containers and intended to be used within 24 hours after collection.  Sterile Pharmaceutical Preparations Aqueous vehicles Sterile water for injection, USP ✓ Packaged in single-dose containers not larger than 1 L. ✓ Must be pyrogen free and sterile. ✓ It may not contain any antimicrobial agent or other added substance. ✓ This water may contain slightly more total solids than water for injection because of the leaching of solids from the glass tanks during sterilization. ✓ This water is intended to be used as a solvent, vehicle, or diluent for already sterilized and packaged injectable medications, e.g. reconstitution of multiple antibiotics, the water is aseptically added to the vial of medication to prepare the desired injection (dry powder sterile ampicillin sodium, USP is reconstituted by aseptic addition of sterile water for injection). Sterile Pharmaceutical Preparations Aqueous vehicles Bacteriostatic water for injection, USP ✓ Is sterile water for injection containing one or more suitable antimicrobial agents. ✓ It is packaged in prefilled syringes or in vials containing not more than 30 mL of the water. ✓ The container label must state the names and proportions of the antimicrobial agent or agents. ✓ The presence of the bacteriostatic agent gives the flexibility for multiple-dose vials, the preservative will destroy the microorganism which may contaminates the vial contents after withdraw from the vial. ✓ Because of the presence of antimicrobial agents, the sterile vehicle must be used only in parenterals that are administered in small volumes. Its use in LVPs is restricted by the excessive and perhaps toxic amounts of the antimicrobial agents that would be injected with the medication. ✓ Upon using bacteriostatic water for injection, the chemical compatibility of the bacteriostatic agent with the drug being dissolved or suspended, should be considered. Sterile Pharmaceutical Preparations USP labeling requirements demand that the label state: Not for use in neonates (?) Due to problems encountered with neonates and toxicity of the bacteriostatic agent, benzyl alcohol. This toxicity results from the high cumulative amounts (mg/kg) of benzyl alcohol and the limited detoxification capacity of the neonate liver. Benzyl alcohol poisoning is recognized as gasping syndrome. No problems occurred in older infants, children, or adults. Sterile Pharmaceutical Preparations Aqueous vehicles Other aqueous vehicles that may be used in place of sterile water or bacteriostatic water for injection for reconstitution or administering drugs are: Sodium chloride injection, USP is a sterile isotonic solution of sodium chloride in water for injection. It contains no antimicrobial agents Bacteriostatic sodium chloride injection, USP is a sterile isotonic solution of sodium chloride in water for injection. It contains one or more suitable antimicrobial agents Ringer’s injection, USP is a sterile solution of sodium chloride, potassium chloride, and calcium chloride (in concentrations similar to those of physiologic fluids) in water for injection. Lactated Ringer’s injection, USP has different quantities of the three salts in Ringer’s injection, and it contains sodium lactate. Sterile Pharmaceutical Preparations Non-aqueous vehicles Although an aqueous vehicle is generally preferred for injection, limited water solubility of a drug (e.g. digitoxin) or its susceptibility to hydrolysis by water (e.g. barbiturates) may limit the use of aqueous vehicles, and the formulator must turn to one or more non-aqueous vehicles. Properties of non-aqueous vehicles for injection: ✓ Nonirritating, nontoxic and not sensitizing in the amounts administered. ✓ Must not exert a pharmacologic activity of its own, nor adversely affect the activity of the drug. ✓ Should be physically and chemically stable at various pH levels. ✓ Its viscosity must allow ease of injection. ✓ Fluidity, must be maintained over a wide temperature range. ✓ Boiling point, should be sufficiently high to permit heat sterilization. ✓ Should be miscible with body fluids. ✓ Should have low vapor pressure to avoid problems during heat sterilization. Sterile Pharmaceutical Preparations Non-aqueous vehicles Non-aqueous solvents used in parenteral products are either oils e.g. fixed vegetable oils or water miscible solvents, e.g. glycerin, polyethylene glycols, propylene glycol and ethyl alcohol. These non-aqueous vehicles may be used provided they are safe in the amounts administered and do not interfere with the therapeutic efficacy of the preparation. Water miscible solvents Are used to enhance the drug solubility and serve as stabilizers, e.g. diazepam injection. USP and phenytoin sodium USP. Mixed solvents systems do not show disadvantages as fixed oils, but may be irritant or toxic if used in high concentrations or large volumes, (e.g. a solution containing high ethanol %, produces pain on injection). Sterile Pharmaceutical Preparations Non-aqueous vehicles Oils The USP specifies restrictions on the fixed vegetable oils in parenteral products: ✓ Must remain clear when cooled to 10°C to ensure stability and clarity of the injectable product during refrigeration. ✓ Oils must not contain mineral oil or paraffin (not absorbed by body tissues). ✓ The fluidity of a vegetable oil generally depends on the proportion of (unsaturated : saturated) fatty acids. Although the toxicity of vegetable oils is generally considered to be low, some patients exhibit allergic reactions to specific oils. Thus, when vegetable oils are employed in parenteral products, the label must state the specific oil. The most commonly used fixed oils in injections are corn oil, cottonseed oil, peanut oil, and sesame oil. Oleaginous injections are restricted to IM route. They must not be administered intravenously, as the oil will occlude the pulmonary microcirculation. Sterile Pharmaceutical Preparations Non-aqueous vehicles Oils Oils are mainly used with steroids, to produce sustained release products, e.g. sesame oil used to obtain slow release Fluphenazine esters (IM). Injection Oil Category Dimercaprol Peanut Antidote to arsenic, gold & mercury poisioning Estradiol cypionate Cottonseed Estrogen Estradiol valerate Sesame or castor Estrogen Fluphenazine decanoate Sesame Antipsychotic Fluphenazine enanthate Sesame Antipsychotic Hydroprogesterone caproate Castor Progestin Progesterone in oil Sesame or peanut Progestin Testosterone cypionate Cottonseed Androgen Testosterone cypionate & Estradiol cypionate Cottonseed Androgen & Estrogen Testosterone enanthate Sesame Androgen Testosterone enanthate & Estradiol valerate Sesame Androgen & Estrogen