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PharDose Lec [Monthly Exam]


Introduction to Drugs and Pharmacy

Agent intended for use in the diagnosis, mitigation, treatment, cure or prevention of disease in humans or animals (FDCA, 1938) Pharmacology Nature and mechanism of action of the drug on the biologic system [The Heritage of Pharmacy] Practice of drug therapy was from experience Early people believed illnesses were caused by demons or evil spirits in the body People performed incantations, the application of noisome materials and the administration of specific herbs or plant materials The First Apothecary Pharmakon (Gk.): charm or drug that can be used for good or for evil Knowledge of drug and their application to disease has always meant power Early Drugs Ebers Papyrus 60 ft. long, a foot wide 16th century BC Founded by Georg Ebers 800 formulas, 700 drugs Introduction of the Scientific Viewpoint Hippocrates Introduction of scientific pharmacy and medicine Rationalized medicine, systemized medical knowledge, and put the practice of medicine on a high ethical plane Hippocratic oath of ethical behavior Pharmakon beame for good only Father of Medicine Dioscorides First to deal with Botany De Materia Medica Claudius Galen Galenic pharmacy Galens Cerate, cold cream Emperor Fredrick II Had a decree, which separated pharmacy from medicine in 1240 AD Aureolus Theophrastus Bombastus von Hohenheim Aka Paracelsus Transformation of pharmacy from a profession based primarily on botanical science to one based on chemical science Early Research Karl Wilhelm Scheele Discovered lactic acid, citric acid, ocalic acid, tartaric acid, arsenic acid and oxygen Identified glycerin Invented new methods of preparing calomel and benzoic acid Friedrich Sertuner Isolation of morphine from opium Joseph Caventou and Joseph Pelletier Isolated quinine and cinchonine from chinchona Isolated strychnine and brucine from nux vomica Joseph Pelletier and Pierre Robiquet Isolated caffeine Pierre Robiquet Separated codeine from opium [Drug Standards] The United States Pharmacopeia and the National Formulary Pharmacopeia Pharmakon: drug Poiein: make Any recipe or formula or other standars required to make or prepare drug Lititz Pharmacopeia First American pharmacopeia Published in 1778 at Lititz, Pennsylvania

32-page booklet, 84 internal and 16 external drugs and preaparations Lyman Spalding Father of USP Proposed for a convention in 4 geographic districts United States Pharmacopeial Convention Revise USP every 10 years 1940 meeting: revise the USP every 5 years 1830 and 1840: pharmacists were invited 1850: full membership of pharmacists USP First published on December 15, 1820 in English and Latin 217 drugs American Pharmaceutical Association (APhA) 1852 National Formulary of Unofficial Preparations Formulary containing many f the popular drugs and formulas denied administration to the USP Changed to National Formulary on June 30, 1906 when President Theodore Roosevelt signed into law USP XX and NF XV USP: volume; NF: sections USP 23-NF 18 o Became official in 1995 USP Pharmacists Pharmacopeia To address the needs of pharmacist practioners Products Manufactured drugs Preparations Compounded drugs USP and NF Monographs Adopt standards for drug substances, pharmaceutical ingredients and dosage forms reflecting the best in the current practices of medicine and pharmacy Official parts of a monograph o Official title (generic or nonproprietary name) o Graphic or structural formula o Empirical formula o Molecular weight o Established chemical names o Chemical Abstracts Service (CAS) registry number USP Drug Research and Testing Laboratory o Provides direct laboratory assistance to the USP and NF o Main functions: evaluation of USP reference standards and evaluation and development of analytical methods Other Pharmacopeias Homeopathic Pharmacopeia of the United States (HPUS) Used by law enforcement agencies that must ensure the quality of homeopathic drugs Homeopathy o Coined by Samuel Hahnemann o Homoios = similar o Pathos = disease o Law of similars, like cures like International Pharmacopeia (IP) Published by WHO Intended as a recommendation to a national pharmacopeial revision committees to modify their pharmacopeias International Organization for Standardization International consortium of representative bodies constituted to develop and promote uniform or harmonized international standards Quality assurance (QA), quality control (QC), detectin of defective products, quality management (WM) [Drug Regulation Control] Food and Drug Act of 1906 First federal law in the US designed to regulate drug products Required drugs marketed interstate to comply with their caimed standards [The Federal Food, Drug and Cosmetic Act of 1938] Prohibits the distribution and use of any new drug or drug product without prior filing of a new drug application (NDA) and approval of the FDA

Required drugs to be safe for human use but did not require it to be efficacious Durham-Humphrey Amendment of 1952 Prescriptions for legend drugs may not be refilled without the consent of the prescriber Refill status was further regulated with the passage of the Drug Abuse Amendments of 1965 and Comprehensive Drug Abuse Prevention and Control of 1970 Kefauver-Harris Amendments of 1962 To ensure a grater degree of safety for approved drugs and manufacturers were now required to prove a drug to be both safe and effective Sponsor of a new drug is now required to file an investigational new-drug application (IND) before it can be tested on humans Comprehensive Drug Abuse Prevention and Control Act of 1970 To consolidate and codify authority over drugs of abuse in a single statue Schedule I o Drugs with no accepted medical use o Substances with high potential of abuse o Heroin, LSD, mescaline, peyote, methaqualone, marijuana Schedule II o Drugs with accepted medical uses and a high potential for abuse, may lead to severe psychologic or physical dependence o Morphine, cocaine, methamphetamine, amobarbital Schedule III o If abused, it may lead to moderate psychologic or physical dependence o Specified quantities of codeine, hydrocodone Schedule IV o Low potential for abuse, may lead to low psychologic or physical dependence o Specified quantities of diphenoxin, diazepam, oxazepam Schedule V o Specified quantities of dihydrocodeine, diphenoxylate FDA Pregnancy Categories Category X Strongest May be implicated as a teratogen and the risk benefit ratio does not support the use of the drug Category A No risk in to the fetus Category B No risk to animal reproduction studies No adequate and well-controlled studies in pregnant women Category C Animal reproduction studies have shown an adverse effect on the fetus Category D There is positive evidence of human fetal risk Black Box Warning Strongest labeling requirements for high-risk medicines All anti-depressant medications Most serios warning Ads are not allowed Drug Listing Act of 1972 Enacted to provide the FDA with the legislative authority to compile a list of marketed drugs to assist in the enforcement of federal laws Drug Price Competition and Patent Term Restoration Act of 1984 Changes to speed the FDA approval of generic drugs and the extension of patient life for innovative new drugs Prescription Drug Marketing Act of 1987 Established new safeguards on the integrity if the nations supply of prescription drug Dingell Bill or Drug Diversion Act Intended to reduce the risks of adultered, misbranded, repackaged or mislabeled drugs entering the legitimate marketplace through secondary sources

Reimportation, Sales restrictions, Distribution of samples, Wholesale distributors Dietary Supplement Health and Education Act of 1994 Forbids manufacturers or distributors of products (vitamins, supplements) to make any advertising or labeling clams that the use of the product can prevent or cure a specific disease The FDA and the Food and Drug Administration Modernization Act of 1997 FDAs mission: to protect the public health against risks associated with the production, distribution and sale of food and food additives, human drugs and biologicals Enacted to streamline FDA policies and to codify manu of the agencys newer regulations Center for the Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) Federal Register (FR) and Code of Federal Regulations (CFR) Provide the most definitive information on federal laws and regulations pertaining to drugs Drug Product Recall A drug may be recalled if it presents a threat or potential threat to consumer safety Voluntary recall: manufacturer recalls the drug Class I o Will cause serious adverse health consequences or death Class II o May cause temporary or medically reversible adverse health consequences Class III o Not likely to cause adverse health consequences [The Pharmacists Contemporary Role] The Mission of Pharmacy to serve society as the profession responsible for the appropriate use of medications, devices and services to achieve optimal therapeutic outcomes Pharmacy is the health profession that concerns itself with the knowledge system that results in the discovery, development and use of medication and medication information in the care of patients. Medications o Refers to legend and nonlegend agents used in the diagnosis treatment, prevention and cure of disease Devices o Equipment, process, biotechnological entities, diagnostic agents Services o Patient, health professional and public education services Definition of Pharmaceutical Care component of pharmacy practice which entails the direct interaction of the pharmacist with the patient for the purpose of caring for that patients drug-related needs Patient-centered Goal: to optimize the patients health-related quality of life and achieve positive clinical outcomes Pharmacists should be o A problem solver o Able to achieve health outcomes through effective medication use o Able to collaborate with others o Life-long learner

The Omnibus Budget Reconciliation Act of 1990 Established a requirement for each state to develop and mandate DUR programs to improve the quality of pharmaceutical care Required patient counseling

New Drug Development and Approval Process

Treatment IND For orphan drugs Targeted to patients who have rare diseases Supplemental New Drug Application (SNDA)

For certain changes in a previously approved NDA, such as labeling or formulation change

Abbreviated New Drug Application (ANDA) Used to gain approval to market a duplicate of a product Biologics Licensing Application (BLA) Biologic products (human blood products and vaccines) Investigational New Animal Drug Application (INADA) New Animal Drug Application (NADA) Supplemental New Animal Drug Application (SNADA) [Drug Discovery and Drug Design] Alexander Fleming Penicillin International Conference on Harmonization Fosters multinational drug approvals Sources of New Drugs Serendipity By accident Reserpine Tranquilizer and hypotensive agent Rauwolfia serpentine Periwinkle Vinca rosea Treatment of diabetes mellitus Antitumor capabilities Paclitaxel Ovarian cancer Semisynthetic drugs New structures from modified plant constituents Recombinant DNA Most fundamental Genetic materials can be transplanted from higher species into a lowly bacterium (gene-splicing) Manipulation of proteins within the cells of lower animals Human insulin, human growth hormone, hep B vaccine, epoetinalpha and interferon Recombinant DNA Manipulation of proteins within the cells of higher animals Used in home pregnancy testing products Human Gene Therapy Used to prevent, treat, cure, diagnose or mitigate human diseases caused by genetic disorders AT CG Gene Therapy Medical intervention base on the modification of the genetic material of living cells Ex vivo: outside the body In vivo: within in the body Goal Drug Would produce the specifically desired effect, be administered by the most desired dosage route Methods of Drug Discovery Random/Untargeted Screening Testing of large number of synthetic organic compounds or substances of natural origin Used initially to detect an unknown activity of the test compound or substance Non-random/Targeted Screens Determine the specific activity or a compound/substance Biostaysis Used to differenciate the effect and potency of the test agent High-throughput Screening Capable of examining 15,000 chemical compounds a week Molecular Modification Chemical alteration of a known and previously characterized organic compound for the purpose of enhancing its usefulness as a drug Mechanism-based drug design Molecular modification to design a drug that interferes specifically with the known or suspected biochemical pathway or mechanism of a disease process Enalaprilat (enalapril), ranitidine, sertraline (for depression) Molecular graphics Use of computer graphics to represent or manipulate the structure of the drug molecule

Lead Compound Prototype chemical compound that has a fundamental desired biologic or pharmacologic activity Finasteride Prodrugs A compound that requires metabolic biotransformation after administration to produce the desired pharmacologically active compound Conversion of an inactive prodrug to an active compound occurs through enzymatic biological cleavage May be designed for solubility, absorption, biostability and prolonged release o Absorption: a drug may be made more water or lipid soluble o Biostability: could result in site-specific action (dopamine&levodopa) o Prolonged release: may extend therapeutic activity FDAs Definition of a New Drug Any drug that is not recognized as being safe and effective in the conditions recommended for its use Combination of 2 or more drugs or a change in the usual proportions of drugs A proposed new use, new dosage schedule, new route of administration or new dosage form Drug Nomenclature C16H19N3O5Sx3H2O (amox) Name must reveal every part of the compounds molecular structure Non-proprietary/Generic name: shortened name [Biologic Characterization] Cell cultures Used to screen toxicity before progressing to whole-animal testing Computer models Help predict the properties of substances and their probable actions in living systems Pharmacology pharmaco = drugs Science concerned with drugs, their sources, appearance, chemistry, action and uses Pharmacodynamics: study of biochemical and physiologic effects of drugs and their mechanism of action Pharmacokinetics: deals with the absorption, distribution, metabolism/biotransformation and excretion (ADME) of drugs Clinical pharmacology: the study of the effects and actions of drugs in humans Whole-animal studies are used to evaluate the pharmacologic effects of the agent on specific organ systems Primary objective of animal studies: to obtain basic information on the drugs effects that may be used to predict safe and effective use in humans Drug Metabolism Bodys means of transforming nonpolar drug molecules into polar compounds First-pass effect: rapid drug metabolism ADME studies: performed through the timely collection and analysis of urine, blood and fecal samples and through a careful examination of animal tissues and organs through autopsy Toxicology Deals with the adverse or undesired effects of drugs Acute or short-term toxicity studies Designed to determine the toxic effects if a test compound when administered in a single dose or in multiple doses over a short period, usually a single day Doses are ranged to find the largest single dose that will not produce a toxic effect 30-day post period Subacute or subchronic studies Minimum of 2 weeks of daily drug administration at three or more dosage levels to two animal species Initial human dose is usually one tenth of the highest non toxic dose Chronic toxicity studies: 90-180 days

Carcinogenic Studies Undertaken when the compounds has shown sufficient promise s a drug to enter human clinical trials Long term (18-24 months) Reproduction studies To reveal any effect if an active ingredient on mammalian reproduction Rabbit is the preferred choice Genotoxicity or mutagenicity studies Performed to determine whether the test compound can affect gene mutation of cause chromosome or DNA damge Salmonella typhimurium strains are used [Early Formulation Studies] Preformulation Studies Drug solubility Poor soluble compounds (less than 10 mg/mL aqueous solubility) Partition coefficient Drug molecules must first cross a biologic membrane of protein and lipid Measure of its distribution in a lipophilic-hydrophilic phase system and indicates its ability to penetrate biologic multiphase systems Dissolution rate Speed at it which a drug substance dissolves in a medium Physical form Reducing particle size = absorption is increased Stability Durations and environments of light and air and packaging is essential Initial Product Formulation and Clinical Trial Materials Initial product is formulated using the information gained during the preformulation studies Phase 1 studies Capsules are employed containing the active ingredient alone Phase 2 studies Final dosage form is selected Clinical supplies or clinical materials Comprise all dosage formulation used in the clinical evaluation of a new drug Blinded studies Controlled studies At last one of the parties does not know which product is being administered [The Investigational New Drug Application] Sponsor of a new drug must file an IND before the drug may be given to human subjects Sponsor must delay the use of drug in human subject for not less than 30 days Clinical hold is issued when there is concern that human subjects will be exposed to unreasonable and significant risk of illness or injury The Clinical Protocol Purpose and objectives of the study Estimate number of patients involved Approval of the authorized IRB 1994: National Institue of Health (NIH) issued its policy that women and minorities be included in all NIH-supported research Purpose of IRB: to protct the safety of human subjects by assessing a proposed clinical protocol, evaluate the benefits against risks, and ensuring that the plan includes all needed measures for subject protection Pre-IND Meetings May include advice on the adequacy of data to support an investigational plan, the design of a clinical trial FDA Review of an IND Application Objecttives o Protect the safety and rights of the human subjects o Help ensure that the study allows the evaluation of the drugs safety and effectiveness o Stamped then sent to the Center for Drug Evaluation Research (CDER) or the Center for

Biologics Evaluation and Research (CBER) for review FDA Drug Classification By chemical type of therapeutic potential Phases of a Clinical Investigation Phase 1 Initial introduction of the investigational drugs into humans for the purpose of assessing safety 20 to 100 subjects Initial dose is one tenth of the highest no-effect dose Designed to determine the human pharmacology of the drug, structure-activity relationships, side effects associated with increasing doses and early evidences of effectiveness Rate of absorption, concentration of drug in blood over time, rate of mechanism Phase 2 Controlled clinical studies to evaluate the effectiveness of a drug in patients with the condition Asses side effects and risks that may be revealed Additional date on the drugs pharmacokinetics and doseresponse and dose ranging (Phase 2a studies) Dose determination studies (Phase 2b) Drug product is refined Phase 3 Include several hundred to several thousand patients in controlled and uncontrolled trials Objective is to determine the usefulness of the drug in an expanded patient base Completed studies (Phase 3a) Additional studies (Phase 3b) Clinical Study Controls and Designs Blinded studies Identity of the investigational drug and the control are not revealed Single blind studies Patient is unaware of the agent administered Double blind studies Neither the patient nor the clinician is aware or the agent administered Parallel designs Applicable to most clinical trials Crossover designs Useful in comparing different treatments within individuals Drug Dosage and Terminology Minimum effective concentration (MEC) An average blood serum concentration that can be expected to produce the drug's desired effects Minimum toxic concentration (MTC) Second level of serum concentration Median effective dose Amount that will produce the desired intensity of effect in 50% of the individuals tested Therapeutic index Relationship between the desired and undesired effects of the drug Defined as the ratio between a drugs median toxic dose and its median effective dose (TD50/ED50) Age Pharmacogenetics Body weight BSA Sex Pathologic state Tolerance Ability to endure the influence of a drug, particularly during continued use Concomitant drug therapy Effects of a drug may be modified by the prior or concurrent administration of another drug Time and conditions of administration Dosage form and route of administration Treatment IND Permits the use of an investigational drug in the treatment of patients not enrolled in the clinical study but who have serious or immediately life-threatening disease [The New Drug Application]

Purpose: to gain permission to market the drug product in the US FDA Review and Action Letters Review clock: 180-day period Phase 4 Studies and Postmarketing Surveillance Phase 4: continued clinical investigations Postmarketing Reporting of Adverse Drug Experience 15 working days [Supplemental, Abbreviated and other Applications] ANDA Nonclinical laboratory studies and clinical investigations may be omitted, except those pertaining to the desired bioavailability Usually for duplicates [International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use] Focused on quality, safety and efficacy

Current Good Manufacturing Practices and Current Good Compounding Practices

[Standards for Current Good Manufacturing Practice] Established by the FDA to ensure that minimum standards are met for drug product quality [cGMP for Finished Pharaceuticals] Active ingredient or active pharmaceutical ingredient (API) Any component that is intended to furnish pharmacologic activity or other direct effect in the diagnosis, prevention of diseases Batch A specific quantity of a drug of uniform specified quality produced according to a single manufacturing order during the same cycle of manufacture Batchwise control Use of validated in-process sampling and testing methods Certification Documented testimony Compliance Determination through inspection Component Any ingredient used in the manufacture of a drug product Drug product A finished form that contains an active drug and inactive ingredients Lot A batch Master record Record containing the formulation, specifications, manufacturing procedures Quality assurance Provision to all concerned the evidence needed to establish confidence Quality audit Documented activity performed in accordance with established procedures on a planned and periodic basis Quality control unit Organizational element designed by a firm Representative sample A sample that accurately portrays the whole Reprocessing Activity whereby the finished product or any of its components are recycled Strength Concentration of the drug substance per unit dose or volume Process validation Documented evidence that a process does what it purports to do Validation protocol A prospective experimental plan to produce documented evidence that a system has been validated Expiration Dating Determined by the appropriate stability testing Tamper-Evident Packaging Film wrapper Sealed around product and/or product container; fi lm must be cut or torn to remove product

Blister/strip pack Individually sealed dose units; removal requires tearing or breaking individual compartment Bubble pack Product and container sealed in plastic, usually mounted on display card; plasticmust be cut or broken open to remove product Shrink seal, band Band or wrapper shrunk by heat or drying to conform to cap; must be torn to open package Foil, paper, plastic pouch Sealed individual packet; must be torn to reach product Bottle seal Paper or foil sealed to mouth of container under cap; must be torn or broken to reach product Tape seal Paper or foil sealed over carton flap or bottle cap; must be torn or broken to reach product Breakable cap Plastic or metal tearaway cap over container; must be broken to remove Sealed tube Seal over mouth of tube; must be punctured to reach product Sealed carton Carton flaps sealed; carton cannot be opened without damage Aerosol container Tamper-resistant by design Records and Reports Production, control and distribution documents must be kept for at least one year after expiration [Current Good Compounding Practices] US Pharmacopeia-National Formulary First compounding monographs became official in 1998 (Beyond-use dates) For non aqueous liquids and solid formulations Where the manufactured drug product is the source of the active ingredient, not later than 25% or 6 months Where a USP or NF substance is the source, nlt 6 months For water-containing formulations Nlt 14 days when stored at cold temperatures Low-risk preparations at room temp Nmt 48 hours (Refrigerated) nmt 14 days Medium-risk at room temp Nmt 30 hrs (Refrigerated) nmt 9 days High-risk preparations at room temp Nmt 24 hours (Refrigerated) nmt 3 days Low, Medium, High-risk s (-25 - -10 degrees C) 45 days in solid state Low-risk and medium-risk compounding Involves sterile products an equipment Food and Drug Modernization Act of 1997 To ensure patients access to individualized drug therapy and prevent unnecessary FDA regulation of health professional practice A compounded product is exempt if the drug product is compounded for an individual patient Mtdland decision: compounded preparations are not new drugs National Association of Boards of Pharmacy Subpart (A), General Provisions Compounding means the preparation of Components into a Drug Manufacturing means the production, preparation, propagation, conversion, or processing of a Drug or Devices Subpart (B), Organization and Personnel Discusses the responsibilities of pharmacists and other personnel engaged in compounding. Stresses that only personnel authorized by the responsible pharmacist shall be in the immediate vicinity of the drug compounding operation Subpart (C), Drug Compounding Facilities Describes the areas that should be set aside for

compounding, either sterile or not Subpart (D), Equipment States that equipment used must be of appropriate design, adequate size, and suitably located to facilitate operation for its intended use Subpart (E), Control of Components and Drug Product Containers and Closures Describes the packaging requirements for compounded products. Subpart (F), Drug Compounding Controls Discusses the written procedures to ensure that the finished products are of the proper identity, strength, quality, and purity, as labeled. Subpart (G), Labeling Control of Excess Products and Records and Reports Describes the various records and reports that are required under these guidelines. [Packaging, Labeling and Storage of Pharmaceuticals] Containers That which hold the article and is or may be in direct contact with the article at all rimes Well-closed container Minimally acceptable container Protects the contents from extraneous solids and from loss of the article Tight container Protects the contents from contamination by extraneous liquids, solids or vapors, efflorescence, deliquescence or evaporation Capable of tight re-closure Hermetic container Impervious to air or any gas Sterile hermetic container Hold preparations intended for injection Single-dose container Cannot be resealed Fusion-sealed ampules, prefilled syringes and cartridges Glass Type I: highly resistant borosilicate glass Type II: treated soda lime Type III: soda lime NP: general purpose soda lime Polyvinyl chloride (PVS) Rigid and has good clarity Blister packaging Unsuitable for gamma sterilization Polyethylene terephthalate (PET), Amorphous polyethylene terephthalate glycol (APET), polyethylene terephthalate glycol (PETG) Permeability Process of solution and diffusion Glass are less permeable than plastic Humidity Test for a minimum of 12 months at 25 degrees C Desiccants Oxidation Greater degree in plastic than in glass Leaching Movement of components of a container into the contents Soft-walled plastic containers of PVC: IV solutions for blood transfusion Sorption Binding of molecules to polymer materials Child-resistant and Adult-Senior Use Packaging Potson Prevention Act Reduce accidental poisoning through ingestion of drugs Child-resistant containers (5 years and below) Align the arrows, press down and turn, squeeze and turn, latch top Storage Cold 8 degrees C Cool 8-15 degrees C Warm 30-40 degrees C

Dosage Form Design: Pharmaceutical Formulation Considerations

Pharmaceutical ingredients Nonmedicinal agents [The Need for Dosage Forms] To protect the drug substance from the destructive influences of atmospheric oxygen or humidity (coated tablets, sealed ampules) To protect the drug substance from the destructive influence of gastric acid after oral administration (entericcoated tablets) To conceal the bitter, salty, or offensive taste or odor of a drug substance (capsules, coated tablets, flavored syrups) To provide liquid preparations of substances that are either insoluble or unstable in the desired vehicle (suspensions) To provide clear liquid dosage forms of substances (syrups, solutions) To provide rate-controlled drug action (various controlledrelease tablets, capsules, and suspensions) To provide optimal drug action from topical administration sites (ointments, creams, transdermal patches, and ophthalmic, ear, and nasal preparations) To provide for insertion of a drug into one of the bodys orifices (rectal or vaginal suppositories) To provide for placement of drugs directly in the bloodstream or body tissues (injections) To provide for optimal drug action through inhalation therapy (inhalants and inhalation aerosols) [General Considerations in Dosage Form Design] Master formula Formulation that best meets the goals for the product Systemic use: oral administration Preformulation Studies Provides the framework for the drugs combination with pharmaceutical ingredients in the fabrication of a dosage form Physical Description Particle size, crystalline structure, melting point and solubility Microscopic Examination Gives an indication of particle size and size range of the raw material along with the crystal structure Heat of Vaporization The amount of heat absorbed when 1g of a liquid vaporizes Measured in calories Melting Point Depression Characteristic of a pure substance Temperature at which the pure liquid and solid exist in equilibrium The Phase Rule Two-component (binary) or three-component representations Represent the melting point as a function of composition of two or three systems Particle Size Polymorphism Exhibit different physiochemical properties Solubility Determined by the equilibrium solubility method Solubility and pH Dissolution Time it takes for the drug to dissolve May be increased by decreasing the drugs particle size Constant surface method o Uses a compressed disc of known area o Eliminate surface are and surface electrical charges as dissolution variables o Intrinsic dissolution rate o Mg dissolved per minute per cm squared Membrane Permeability Early assessment of passage of drug molecules across biologic membranes Partition Coefficient Measure of a molecules lipophilic character pKa/Dissociation Constants Drug and Drug Product Stability Drug Stability Mechanisms of Degregation

Hydrolysis: solvolysts process in which drug molecules interact with water molecules to yield breakdown products Oxidation Autoxidation: occur spontaneously under the initial influence of atmospheric oxygen and proceed slowly at first then more rapidly Drug and Drug Product Stability: Kinetics and Shelf Life Stability: extent to which a product retains within specified limits and throughout its period of storage and use the same properties and characteristics that it possessed at the time of its manufacture Chemical, physical, microbiologic, therapeutic, toxicologic Reaction kinetics: study of the rate of chemical change and the way this rate is influenced y concentration of reactants Rate Reactions Description of the drug concentration with respect to time Q10 Method of Shelf Life Estimation Lets the pharmacist estimate shelf life Enhancing Stability of Drug Products Reduction or elimination of water Anhydrous vegetable oils may be used to reduce the chance of hydrolytic decomposition in injectable Decomposition by hydrolysis may be prevented in other liquid drugs by suspending them in a nonaqueous vehicle Reconstitution Antioxidants o Aqueous: sodium sulfite, sodium bisulfite, sodium metabisulfite, hypophosphorous acid, ascorbic acid o Oleaginous preparations: alpha-tocopherol, butyl hydroxyl anisole, ascorbyl palmitate Trace metals Polymerization (two or more identical molecules that form a new and generally larger molecule), chemical decarboxylation and deamination Stability Testing Accelerated stability testing o Use of exaggerated conditions of temperature, humidity, light and others [Pharmaceutical Ingredients and Excipients] Definitions and Types Solvents Used to dissolve the drug substance Flavors and sweeteners Used to make the product more palatable Colorants Enhance appeal Preservatives Prevent microbial growth Diluents or fillers For tablets Increase bulk of formation Binders Cause adhesion of the powdered drug and pharmaceutical substances Antiadherents/lubricants Smooth tablet formation Disintegrating agents Promote tablet breakup Handbook of Pharmaceutical Excipients and Food and Chemicals Codex Handbook of Pharmaceutical Excipients More than 250 excipients Appearance and Palatability Flavoring Pharmaceuticals Increase in the number of hydroxyl groups seems to increase the sweetness Sweetening Pharmaceuticals Aspartame, saccharin and cyclamate Delaney Clause: no new food additive may be used if animal feeding studies or tests showed that it caused cancer Saccharin Study and Labeling Act Coloring Pharmaceuticals Sulfur (yellow), riboflavin (yellow), cupric sulfate (blue), ferrous sulfate (bluish green), cyanocobalamin (red), red

mercuric iodide (vivid red) Coal tar: black Preservatives Sterilization and Preservation 15% V/V alcohol will prevent microbial growth in acid media, 18% in alkaline media Preservative Selection Cellulose derivatives: polyethylene glycols, natural gums: tragacanth

Dosage Form Design: Biopharmaceutical and Pharmacokinetic Considerations

Biopharmaceutics Relationship between the physical, chemical and biologic sciences as they apply to drugs, dosage forms and drug action Pharmacokinetics Area of study that elucidates the time course of drug concentration in the blood and tissues (ADME) Metabolism Major process by which foreign substances are eliminated from the body Principles of Drug Absorption Passive Diffusion Passage of drug molecules through a membrane that does not actively participate in the process High to low concentration Ficks Law: the rate of diffusion or transport across a membrane is proportional to the difference in drug concentration on both sides of the membrane First-order kinetics pK: pH at which a drug is 50% ionized Specialized Transport Mechanisms Active: lower to higher concentration [Dissolution and Drug Absorption] Diffusion layer: layer of solution Dissolution rate of a drug may be increased by increasing the surface area (reducing particle size) Crystal or Amorphous Drug Form Amorphous form of a chemical is usually more soluble than the crystalline form Novoviocin and chloramphenicol palminatate are inactive when administered in crystalline form but is active in amorphous form Penicillin: crystalline form > amorphous form Salt Forms Addition of ethylenediamine to theophylline increases the water solubility of theophylline fivefold [Bioavailability and Bioequivalence] Bioavailability Rate and extent to which an active drug ingredient or therapeutic moiety is absorbed from a drug product and becomes available at the site of action Depends on the drugs absorption or entry in the systemic circulation Bioequivalence Comparison or bio availabilities of different formulations, drug products or batches of the same drug product Used to determine the amount or proportion of drug absorbed, the rate at which the drug was absorbed. Duration of the drugs presence in the biologic fluid or tissue correlated with the patients response, relationship between drug blood levels and clinical efficacy and toxicity [Routes of Drug Administration] Local effects: direct contact of the drug to the site of action Systemic effect: entrance of the drug into the circulatory system and transport to the cellular site of its action Bioavailability is lowest for drugs that undergo a significant first-pass effect Oral Route Systemic drug effects Most natural, uncomplicated, convenient and safe means of administering drugs Disadvantages: slow drug response, destruction of certain drugs by the acid reaction of the stomach Dosage forms applicable Tablets

o o o o

Prepared by compression or molding that contains medicinal substances Diluents are fillers used to prepare tablets Disintegrants are used for the breakup or separation Enteric coatings: safe passage through the acid environment

Capsules o Enclosed in either a hard or soft shell, generally composed of gelatin Suspension o Finely divided drugs in a suitable fluid vehicle o Drug particles must be suspended in an insoluble vehicle o Useful means to administer large amounts of solid drugs Solution Elixir o Solutions in a sweetened hydroalcoholic vehicle Syrups o Use sucrose solution Absorption Sublingual: with nitroglycerin and certain steroid sex hormones Tetracycline drugs must not be taken with milk Rectal Route Suppositories o Promotion of laxation, soothing of inflamed tissues, promotion of systemic effcts Parenteral Route Para = beside Enteron = intestine Dosage Forms Applicable Slow absorption = prolonged drug action; subcutaneous or IM: depot or repository injection Subcutaneous (Hypodermic) Injections Injection through the skin into the loose subcutaneous tissue Insulin More capillaries = more surface are for absorption = faster rate of absorption Forearm, upper arm, thigh or buttocks Intramuscular Injections Aqueous or oleaginous solutions or suspensions Intravenous Injections Injected directly into the vein Intradermal Injections Administered into the corium of the skin (0.1mL) Epicutaneous Route Topically Nitroglycerin (antianginal), nicotine (smoking cessation), estradiol (estrogenic hormone), clonidine (antihypertensive), and scopolamine (antinausea, anti motion sickness) Local action Ointments o Simple mixtures of drug substances in an ointment base Creams o Semisolid emulsions les viscid and lighter than ointments Pastes o Stiffer and less penetrating o Employed for its protective action Medicinal powder o Relieves diaper rash, chafing, and athletes foot Lotions o Emulsions or suspensions generally in an aqueous vehicle o Nongreasy Ocular, Oral, Otic and Nasal Routes Local effects\