Dose Form – Chapter 4-JodiJohnson

Dose Form – Chapter 4-JodiJohnson - 9/12/2010...

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Unformatted text preview: 9/12/2010 Drugs seldom administered alone They are part of a formulation Non-medicinal agents Pharmaceutical & Formulation Considerations Jodi Johnson Amount of drug too small – milligram qty Need fillers/diluents Patients could not be trusted to get correct amount if just given drug alone Besides patient safety: Protect the drug from the atmosphere Protect drug from gastric acid of the stomach Conceal actual taste of medicine – flavors Make suspensions – for drugs that are insoluble or unstable ◦ Pharm ingredients or excipients thicken suspend etc ◦ Solubilize, thicken, suspend, etc Clear liquid dosage forms – syrups and solutions Provide rate controlled drug action – ER tabs etc Optimal drug action from topical admin sites ointments, creams, etc Insertion into one of the body’s orifices – rectal, vaginal Drugs directly in the bloodstream IV Inhalation therapy 1 9/12/2010 ◦ Various formulations developed – each batch thereafter must meet this specification ◦ Made into several dosage forms and strengths To determine most efficacious and convenient tx of that disease Consider therapeutic issues Consider therapeutic issues continued ◦ Physical description majority are solid materials – most popular formulation solids, liquids, gas most liquids usually cannot be formulated into a tablet – except Nitroglycerin SL important for marketing – what appeals to patients ◦ Microscopic examination Indicates particle size and range of the raw material crystal structure - spherical and oval powders flow easier than needle-shaped powders Tx’d locally or systemically Usual age of patient Nature of the illness Typical condition of the patient Will this patient typically be on several other medications – then unique size/shape/color will be a benefit benefit Pre-formulation studies necessary ◦ Melting point depression Used to determine the purity of a drug substance Sometime the compatibility as well 2 9/12/2010 ◦ The phase rule Provides a visual picture of when ingredients are mixed ◦ Particle size Of drug substance will affect formulation and efficacy Significantly influences oral absorption profiles of certain drug ◦ Polymorphism The crystal or amorphous form of the drug substance – amorphous preferred Exhibit different physicochemical properties ◦ Solubility Drug must possess some aqueous solubility for therapeutic efficacy ◦ Solubility and particle size Small increases in solubility can be accomplished by particle size reduction ◦ Solubility and pH Adjust pH to enhance solubility Usually not an effective means of enhancing solubility Weak acids/bases may require extreme changes in pH Little effect other than on electrolytes ◦ Dissolution The time it takes for the drug to dissolve in the fluids at the absorption site = rate limiting step Can increase dissolution step by decreasing particle size ◦ Membrane permeability Passive diffusion, active transport, and facilitated Drugs must cross a membrane to exert their effect on the body It must enter the systemic circulation to exert therapeutic effect 3 9/12/2010 ◦ Partition coefficient Lipid – water solubility ◦ pKa/dissociation constants the extent of dissociation or ionization of drug substances important on formulation as well as kinetics kinetics - the extent of ionization of a drug effects absorption, distribution, and elimination Oxidation – loss of electrons Destroys Aldehydes, alcohols, phenols, sugars alkaloids and unsaturated fats and oils ◦ Drug stability: mechanisms of degradation Most common destructive processes Hydrolysis & oxidation Hydrolysis – drug molecules interact with water to produce breakdown products Most important single cause because many drugs contain Esters, substituted amides, lactones, and lactams –all are susceptible to hydrolysis Stability The extent to which a product remains the same as when it was first created – shelf life (within limits) Five types of stability for RPh to consider Chemical Ph Physical Microbiologic Therapeutic Toxicologic 4 9/12/2010 ◦ Rate reactions Describes drug concentration with respect to time Zero order and first order kinetics ◦ Q10 methods of shelf life estimation A way to estimate the shelf life Reduction or eliminate oxygen to protect against oxidation Keep it dry Away from light Results in a change of color or precipitate Use antioxidants to react with one or more compounds in the drug to prevent oxidation (allergic rxns to sulfur) Sodium sulfite for high pH values Sodium bisulfate for intermediate pH values Sodium metabisulfite at low pH values Hypophosphorous acid Ascorbic acid ◦ Enhancing stability of drug products Against such things as hydrolysis and oxidation Reduction or eliminate water to protect against hydrolysis Protect from humidity – waterproof coating Tightly closed container Tightly closed container Replace/reduce water in liquid preps with glycerin, propylene glycol, and alcohol Create a dry powder for reconstitution Refrigeration pH - between 5 and 6 is optimal for most hydrolysable drugs ◦ Stability testing FDA regulates – Current Good Manufacturing Practice During every stage of development – ensure quality Product containers need to be considered for stability Long term storage requirements Humidity requirements Instability may be noted by a color change, ppt, odor, taste, texture etc. 5 9/12/2010 ◦ To produce a final dosage form of a drug you need additional Pharmaceutical ingredients Solutions – 1 or more solvents are used to dissolve the drug substance Flavors/sweeteners to make more palatable Colorants – appealing Preservatives to prevent microbial growth Stabilizers i.e. antioxidants and chelating agents to prevent decomposition ◦ Handbook of pharmaceutical excipients Excipients - an inert substance which is added to a drug to provide bulk Has monographs on more than 250 excipients Page 127-131 Table 4.3 Examples of Pharmaceutical ingredients ◦ Harmonization of standards Pharmacopeias Standards for each drug substance and excipients used in pharmaceuticals USP-NF Diluents or fillers to increase bulk to make tablets Binders cause adhesion of the powdered drug and pharm subs Antiadherents or lubricants to assist smooth tablet formation tablet formation Disintegrating agents to promote tablet breakup after patient take it Coatings to improve stability control disintegrations, or enhance appearance Then you have ointment, creams, and suppositories ◦ Appearance and palatability Most drugs are unfit for consumption in their natural state Need for excipients including sweeteners, flavors ,etc Flavoring pharmaceuticals Liquids Age dependent Sweetening pharmaceuticals Sucrose Artificial – aspartame, saccharin 6 9/12/2010 Coloring pharmaceuticals For esthetics Things that have natural color i.e. sulfur(yellow) and cyanocobalamin (red) not pharm colorants Natural and synthetic color additives in ophthalmic parenteral and No color additives in ophthalmic, parenteral, and newborn baby products ◦ Sterilization and preservation Most alcohol containing subs are self-sterilizing Most aqueous preps i.e. syrups, emulsions, suspensions, some semisolid preps Provide an excellent growing environment for microbes ◦ Preservative selection Based on: Preventing the most likely contaminants from growing Soluble enough in water to achieve adequate concentrations in the aqueous phase of a system with two or more phases Preservative selection – continued Based on: Proportion of preservative remaining undissociated at the pH of the prep makes it capable of destroying the microbe Does not affect safety of patient not affect safety of patient Adequate stability Compatible with all other ingredients Does not adversely affect preps container or closure ◦ Mode of action Preservatives interfere with microbial growth, multiplication, and metabolism through a variety of mechanisms Modification of cell membrane permeability and leakage of cell constituents Lysis and cytoplasmic leakage Irreversible coagulation Inhibition of cell metabolism Oxidation of cell constituents hydrolysis 7 9/12/2010 ◦ Preservative utilization Examples of preservatives Benzoic acid, sodium benzoate, alcohol, etc page 140 Cannot be toxic to the patient 8 ...
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This note was uploaded on 10/15/2010 for the course PHCY 6100 taught by Professor Teixeira during the Fall '10 term at Univeristy of Wyoming- Laramie.

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