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125 Cards in this Set
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Keppra |
Anticonvulsant drug - treats epilepsy - Also sometimes used to treat neuropathic pain - S-enantiomer of etiracetam - Administered orally or IV - Available in 250mg, 500mg, 750mg and 1000mg tablets and oral solution |
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Keppra Inactive Ingredients |
Colloidal silicon dioxide, corn starch, hydroxypropylmethylcellulose, magnesium stearate, polyethylene glycol 4000, povidone, talc, titanium dioxide, and coloring agent
For 250mg tabs, FD&C Blue #2 For 500mg tabs, FD&C Blue #2 and yellow oxide For 750 mg tabs, FD&C Blue #2, FD&C yellow #6, and red iron oxide |
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Coloring Reagents |
Different colors help avoid errors when a single drug has multiple strengths
-FD&C: that particular color reagent has been approved by the FDA
-Coloring reagents may absorb through the drug which influences the dissolution of the drug and may have an effect on the bioavailability of the drug |
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Pharmacokinetics of Keppra |
Have been studies in healthy adult subjects, adults and pediatric patients with epilepsy, elderly subjects and subjects with renal and hepatic impairment. - Levetiracetam is rapidly and almost completely absorbed after oral administration - The pharmacokinetics is linear and time invariant, with low intra and inter subject variability. |
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Rapidly |
The speed at which the drug reaches the general circulation is quite fast - Drugs administered through extravascular route must travel from site of administration to site of measurement (blood/general circulation). |
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Almost Completely |
Almost the entire dose that has been administered will reach the general circulation - ex. If you give 500mg of a drug, you will get almost all 500mg |
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Why is it that not all the drug may reach the general circulation? |
When drug is administered orally, it goes through gastric juices, intestinal pH, liver (enzymes); interactions between these factors and drugs may cause the drug to be destroyed or only partially delivered to reach the general circulation and exhibit pharmacological effects.
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Linear Pharmacokinetics |
Keppra: The pharmacokinetics of levetiracetam is linear over the dose range of 500 to 5000mg.
Directly proportional relationship between concentration (either plasma concentration or amount of drug eliminated through urine) and administered dose
ex. Plasma concentration at a time (mg/mL) vs. Administered dose (mg)
ex. Cumulative amount of drug in urine at a time (mg) vs. Administered dose (mg)
-If dose is doubled, than concentration will also double |
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Non-linear Pharmacokinetics |
-Relationship between concentration and administered dose is NOT directly proportional
-- If you double the dose, the concentration will no be double (could be greater or smaller than double) -- ex. Dilantin, or Phenytoin - in order to increase the concentration, you have to calculate the dose -- ex. Alcohol - concentration may be higher than x amount of increased dose) |
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Time invariant |
A time-invariant system is a system whose output does not depend explicitly on time |
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Intra & Inter subject variability |
Intra: Same dose to same patient Inter: Same dose to different patients If intra & inter subject variability is low, it means that the drug will produce similar effects every time it is used (either by same or different patients). There will be small variation in the plasma concentration of the drug (consistently reaching the same numbers every time) |
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Extent of Bioavailability |
Keppra: The extent of bioavailability of levetiracetam is not affected by food.
Bioavailability is the fraction of an administered dose of an unchanged drug that reaches the systemic circulation
-Amount of administered dose will reach the general circulation either with or without food.
-IV administrations have 100% bioavailability
-If absorption is influenced by certain food, or if gastric irritation occurs -> take drug with food
Keppra: The oral bioavailability is 100% |
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Bio-availability parameters |
"The relative amount of administered dose that reaches the general circulation and the rate at which it reaches the general circulation." Peak time, peak plasma concentration, and AUC: -If peak concentration is high, and peak time is short, then drug absorption is rapid -High AUC means great extent of drug absorption -Rate of absorption: peak time & peak concentration |
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Keppra: protein bound & volume of distribution |
Levetiracetam is not protein bound (<10%) and its volume of distribution is close to intracellular and extra-cecullar water - <10% is good |
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Volume of Distribution |
The ratio of the dose present in the body and its plasma concentration, when the distribution of the drug between the tissues and the plasma is at equilibrium.
-Allows us to relate the amount of drug and the concentration of drug in the body -how the drug is distributed in the body once the drug reaches general circulation -Unit is mL or L
-If high volume of distribution, then drug is more lipophilic by nature -If low volume of distribution, then drug is more hydrophillic by nature Our bodies are lipophillic by nature (drugs needs to permeate through cell membranes) |
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Peak Plasma concentration |
Highest plasma concentration for a dose that was administered (mg/mL) (Cpmax) --ex. At 1 hour (Tmax), we reach the maximum concentration of the dose |
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AUC |
Area under the concentration vs. time curve (Functional plasma concentration in the body) -Extent of absorption for a drug -Directly proportional to dose administered -- if AUC is high = administered drug is high or absorbed drug is high -- Higher plasma concentration, higher AUC value
--Unit: mg/ml *hr |
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Absorption phase |
Absorption: Process by which drug molecules travel from site of administration to site of measurement.
-Site of administration: oral, subQ, etc. -ONLY IN EV ROUTE! ex.Drug goes in GI tract, then reaches the general circulation (peak plasma concentration)
-Absorption characteristics are different depending on EV site of administration being different
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Dose excreted in unchanged form |
Keppra: 66% of the administered dose is renally excreted in an unchanged form. - Excreted in unchanged form: there is no chemical change to the drug when it is coming out in the urine |
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Metabolites |
Keppra: The metabolites have no known pharmacological activity and are renally excreted. (34%) - Metabolites: chemically different form of a drug (by-product of a parent drug) -->Most metabolites have no known pharmacological activity and are renally excreted. -->Some metabolites have pharmacological activity (ex. allegra used to be on the market for allergies, but was taken out of the marked since it was seriously interacting with antibiotics; the metabolites of allegra made a new drug= venlafaxine) |
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Elimination Half-Life |
Keppra: Plasma half-life of levetiracetam across studies is approx. 6 to 8 hrs. It is increased in elderly (primary due to impaired renal clearance) and in subjects with renal impairment.
It describes how rapidly the drug is being removed from the body over time Unit: hr. T1/2=0.693/K
-- Every 6 to 8 hours, the body will lose 50% of the drug in the body -- If a drug has short half-life, it will be removed from the body quickly, K value will be high -- If a drug has long half-life, it will be removed from the body slowly (we won't have to re-administer dose quickly) -- Half-life is longer in elderly, or renally impaired subjects (elderly people have improperly functioning kidneys). When kidneys don't function properly, the drug stays in the body for a longer time (dose can be adjusted) |
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Rate of Absorption |
Keppra: Absorption of levetiracetam is rapid, with peak plasma concentration occurring at about an hour.
- Rapid: rate of absorption occurs quickly, reaching the general circulation in about an hour after administering the dose (peak time is short).
-Rate of absorption: peak plasma concentration(Cpmax) and peak time(tmax) -How rapidly the drug reaches general circulation from the site of administration |
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Extent of absorption |
Keppra: Food does not affect the extent of absorption (AUC) of levetiracetam; however, it decreases peak plasma concentration by 20% and delays the peak time by 1.5 hours.
- Extent of absorption: AUC (how much of the administered dose has reached the general circulation)(mg/mL*hr)
-Food does not affect extent of absorption(when patient takes medication with food, it has no effect on the amount of administered dose reaching circulation). Food decreases peak plasma concentration by 20% and delays peak time by 1.5 hours (smaller concentration of drug at a time) - (rate of absorption is slowed). |
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Steady State |
Keppra: Steady state is achieved after 2 days of multiple twice daily dosing.
-A condition where a certain concentration of drug in the body is reached, and dosage is maintained. The concentration will remain in that particular range through all the time the patient takes the medication. -- Concentration remains steady as long as you dose and dosing the same. -- Maintenance drugs (metoprolol, lisinopril, etc) (Dose is kept in effective range - 1 t bid for example) |
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Keppra Total Clearance |
-The total clearance of levetiracetam is reduced in patients with impaired renal function by 40% in the mild group (Cl)cr=50 to 80 ml.min-1, 50% in the moderate group (Cl)cr=30 to 50 ml.min-1 and 60% in the severe renal impaired group (Cl)cr<30 to 50 ml.min-1. -In anuric (end stage renal disease), the total body clearance decreased 70% compared to normal subjects (Clcr>80ml.min-1) - Dosage should be reduced in patients with impaired renal function receiving levetarecetam. |
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Total Clearance (Systemic Clearance) |
How the body is becoming free of a drug at a given time (ml/hr) (Cl)s=V*K(volume of distribution x elimination rate constant)
-Directly proportional to creatinine clearance -Affects elimination half life
If systematic clearance is low, creatinine clearance is low, then renal impairment is high, then dose will need to be adjusted (less will be needed since it is eliminated from the body slowly - half life is higher)
(Describes the removal of drug from a volume of plasma at a given time) |
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Creatitine Clearance |
The creatinine clearance test helps provide information about how well the kidneys are working. Normal range of 100-120 mL/min. -If it goes below normal range, that means that the kidneys are impaired or failing |
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4 Fundamental Pharmacokinetic Parameters |
Volume of distribution (mL, L) Elimination Half-Life (t1/2)(hr., min.) Systemic Clearance (Cl) (ml/hr., L/hr) Elimination Rate Constant (K) (hr.-1, min.-1)
-Only genetic or pathological abnormalities will change these parameters, not value changes in concentration |
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Relationship between fundamental parameters |
Elimination half-life(t1/2)(hr.) and elimination rate constant are related to each other: t1/2=0.693/K Systematic clearance (Cl)s (ml/hr.): (Cl)s= V * K - V is volume of distribution They are all affected if one of them changes: -If (Cl)s becomes changes, then V and K will change, which will also affect half life |
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MEC |
Minimum Effective Concentration
-the concentration that must be achieved in the plasma in order for drug to produce its therapeutic effect (mg/mL)
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MTC |
Minimum Toxic Concentration
-the plasma concentration of a drug that is reached which will produce toxic effects (mg/mL) |
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Routes of Administration |
IV: intravascular - intravenous solution is injected directly into general circulation (immediately available to produce effect) EV: extravascular - goes through absorption phase before reaching general circulation (oral, patch, suppository, etc) |
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Onset of Action |
The time at which the administered drug reaches the therapeutic range (or the drug begins to produce the effect)
Unit: hr. -Determined by: Formulation; Type of dosage form, Route of administration; Physicochemical properties |
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Duration of Action |
The time span, beginning the onset of action up to the termination of action
Unit: hr. |
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Termination of Action |
The time at which the drug concentration in the plasma falls below the minimum effective concentration (MEC)
Unit: hr.
-It is possible for the onset of action,termination of action, tmax, and cpmax of a drug to differ from patient to patient
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Therapeutic Range |
The plasma concentration range, within which, the drug is likely to produce the therapeutic effects.
Unit: mcg/mL |
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Micromeritics |
The study of the science of small particles - Irregularly shaped powder particles |
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Diffusion |
The process by which molecules move from region of high concentration to the region of low concentration -Drug is continuously moving from site of administration to GI tract, then to general circulation |
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Dissolution |
The process of powder particles dissolving in the surrounding fluid to form a solution
-If dissolution is slow, absorption will be slow, onset of action will be longer, and Cpmax will be shorter -Dissolution rate: how rapidly particles are dissolving (mg/hr) (affects bioavailability of drug along with solubility) -The rate of dissolution is dependent on particle size. The smaller the particle, the higher the rate of dissolution |
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Porosity |
(E) Presence of air in powder material - % of open space in a powder sample -Irregularly shaped particles -Directly proportional relationship between particle size and porosity (derived property)
-Small particle size or high irregularity of particles, high porosity -Large particle size, low porosity |
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Tortuosity |
(T) Liquid passes through a CR tablet membrane to dissolve drug powder particles inside of it; when drug dissolves it comes out of the tablet in a zig-zag pathway (tortuous). - Take longer time to come out of capsule - Influenced by compressibility forces - High porosity, low tortuosity |
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True density |
Intrinsic property of drugs (fixed value) Unit: g/cc, g/mL Tells you how many grams (that much powder) occupy a cubic centimeter space -High true density, higher amount of drug occupies 1 cc |
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Bulk density |
Derived property of drugs Unit: g/cc, g/ml Influenced by particle size (will vary) |
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Surface Tension |
Interphase between air and liquid |
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Interfacial Tension |
Interphase between liquids - Immiscible liquids ex. Benzene and Water |
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Solubility |
Extent of a drug dissolving into solution
-Dissolution of solute into a solvent to form a solution
Unit: g/L, g/mL |
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Additional info on solubility |
-Its importance in dosage forms like, IV solutions, ophthalmic solutions, and other injectable and oral solutions (clear liquids - complete dissolution) -Solubility of a therapeutic agent is influenced by the salt it forms (Erythromycin : estolate, stearate, succinate, and base) (Calcium : carbonate [antacid products], gluconate [oral solution and injectable], and lactobionate [injectable]) (Iron: Feosol [ferrous sulfate], ferrous fumarate, Ferro-sequel [ferrous gluconate]) (Naproxen and naproxen sodium) (Hydroxyzine : hydrochloride and palmoate)
-different salts = different solubility |
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Drugs Unavailable in salt forms |
Predisone Dexamethasone Alprazolam Clonazepam Diazepam Lorazepam Temazepam (all ...pams) |
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Partition Coefficient of Drugs |
Measure of the degree of lipophillicity of a particular therapeutic agent -Measure how well a drug will pass through our body's cellular membranes -High lipophillicity, higher partitioning coefficient, high lipid solubility (every drug should posses some degree of water and lipid solubility in order to pass drug molecules through cell membranes) |
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Hydrophobicity and Contact Angle |
Hydrophobic particles will float on top of aqueous layer instead of submerging into the water, which will form a contact angle with the liquid
-High hydrophobicity, higher contact angle
-ampicillin: 35 degree contact angle -aspirin: 74 -precipitated sulfur: 121 -magnesium stearate: 121 (very hydrophobic) -indomethacin: 90 |
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Ionization of a drug |
The drug must be present in unionized form to be absorbed
-Ionized drugs will not absorb as easily |
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pka |
Dissociation constant of a particular drug -Fraction of drug available in unionized form (tells you where the drug is likely to be absorbed better in the body) |
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pKa values of some weak acidic drugs |
Compound - pka
Acetylsalicylic acid (Aspirin) - 3.5 Diclofenac (Voltaran) - 4.0 Ibuprofen - 4.4 Ketoprofen - 4.0 Naproxen - 4.3 Theophilline - 8.6 Warfarin - 5.1
(salts: sodium, calcium) (available in more unionized form at lower pH, likely to be better absorbed in the stomach - lower pH)
(-likely to be better absorbed at higher pH if in ionized form - more water soluble) |
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pKa values of some weak basic drugs |
Compound - pKa
Alprazolam - 2.4 Clindamycin - 7.5 Codeine - 8.2 Erythromycin - 8.8 Metoprolol - 9.7 Oxycodone - 8.9 Promethazine - 9.4
(Other examples: Metoprolol Succinate and Tartrate, Enalapril Maleate, Metformin HCl, Propranolol HCl)
(...ate)
(-likely to be better absorbed from GI tract - available in more unionized form at higher pH)
(-likely to be better absorbed at lower pH if in ionized form - more water soluble) |
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Adsorption |
Surface phenomenon where powder particles of a chemical will bind with the powder particle of another chemical, or molecules from a solution may bind to the powder particle
ex. Charcoal (drug molecule from liquid may bind to solid particle), Kaolin (Kaopectate), and talc (moisture from atmosphere may bind to a drug molecule)
(Activated charcoal is commonly used during an overdose of a medication, such as an anti-hypertensive since it is a strong adsorbing agent. The drug will bind to charcoal and won’t reach general circulation)
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Hygroscopicity |
Ability of a powder to adsorb moisture from the atmosphere |
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Deliquescence |
The amount of moisture adsorbed is so high that the powder will dissolve and form a solution |
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Dosage Form Definition |
It involves applications of the majestic principles of physical pharmacy in developing, designing and evaluation of a safe and effective dosage form
-Each dosage form contains the labeled amount of therapeutic agent(s) or active ingredient(s) responsible for exerting the pharmacological effects. |
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Oral Liquid Forms |
Solution (clear liquid) - complete dissolution of solute into solvent Syrup (clear liquid) - contains flavoring syrup -->Bromfed syrup -->Promethazine syrup -->Promethazine VC syrup Elixir (clear liquid) - contains alcohol (used as a co-solvent or preservative) -->Ferrous Sulfate Elixir (9% alcohol) -->Phenobarbital Elixir (15% alcohol) -->Donnatal Elixir (20% alcohol) Suspension - therapeutic agent is insoluble, it is suspended in a liquid medium -->Carafate suspension -->Erythromycin suspension -->Griseofulvin suspension -->Phenytoin suspension -->Acyclovir suspension -->Bactrim suspension -->Kaopectate (OTC) (Kaolin & pectin) --> Pepto bismol (OTC) (Bismuth subsalicylate) -->MAALOX (OTC) (Magnesium Aluminum Oxide) Emulsion - not a clear liquid (surface tension and interfacial tension between aqueous phase and oil phase - immiscible liquids) |
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Tablet or Capsule Dosage Forms |
-Immediate release tablets (IR) -Effervescent tablets -Chewable tablets, oral disintegrating tablets/capsules -Controlled release or modified release (CR, XL, SA) -Coated tablets (Sugar or Film coated - used to mask taste or protect from atmospheric moisture) -Soft gelatin capsules (made of oil material - used to dissolve active ingredient)(liquid or paste material inside) -Hard gelatin capsules (powder material inside) |
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Additional Extravascular Dosage Forms |
-Inhalers -Transdermal (patches) -Semi solids: creams, ointments, gels (for topical applications), paste (most viscous), lotion -Liquid topical: tinctures(oral as well - contains higher alcohol % than elixir), emulsions(oral as well) -Suppository (vaginal, rectal & urethral) -Topical powder |
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Intra-vascular Dosage Forms |
Injectable: intravenous solution (administered directly into general circulation) and intramuscular injections (subQ) |
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Principles of Scale-Up Operations |
Small scale to large scale -Making 1 million tablets from the formulation of a drug for 500 tablets |
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G.M.P & G.L.P |
Good Manufacturing Practice - Good Laboratory Practice -FDA regulations and guidelines with regard to the manufacturing of a dosage form |
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S.O.P |
Principles of Standard Operating Procedures -Record of compounded medications |
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Additional industrial pharmacy parameters |
-Guidelines and regulations employed in the manufacturing of the clinical supplies -Ongoing stability program for each batch of each product manufactured -Principles of all unit operations involved in the manufacturing of an optimum dosage form. -->Mixing of 2 powders, mixing of powders and liquids, mixing liquids, milling, drying, evaporation, fluid and flow, etc. -Designing and the selection of the equipment for the manufacturing of a optimum dosage form. |
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Biopharmaceutics |
'The study of the factors influencing the bioavailability of a drug and the use of this information to optimize pharmacological and therapeutic activity of drug product''
-In this branch of pharmaceutics, one is involved in applying the principles of physical pharmacy, pharmaceutics, and pharmacokinetics in designing and developing the optimum dosage form (tab, cap, CR tabs, IR tabs, etc..) |
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Optimum Dosage Form |
Developing the formulation of a dosage form that will yield consistent bioavailability of a drug from the product each time a patient receives that medication through that dosage form.
-Each unit (tablet of capsule) will deliver exactly same amount of therapeutic agent at same rate from that particular dosage form |
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Pharmacokinetics |
The study of kinetics of absorption, distribution, metabolism, and elimination (ADME) of drugs and their corresponding pharmacologic, therapeutic, or toxic (PTT) responses in man and animals
-ADME by extravascular route, since absorption is not present in intravascular route of administration |
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Metabolism |
Process in which one chemical compound is converted to another chemical species |
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The Pharmacokinetic Parameters are used to: |
-Predict the plasma concentration of a drug following its administration by various routes and via various dosage forms -Determine the dose of a drug needed to attain the desired or effective plasma concentration of that drug in normal, renally impaired, young and elderly subjects, and in various disease states -Assess the bioavailability of a drug -For drug dosage adjustments in disease state, if necessary |
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Loading Dose & Maintenance Dose |
Loading dose is the first dose given to a patient that will allow you to reach the optimum dose rather quickly Maintenance dose, then allows you to keep the plasma concentration of the drug in the minimum effective concentration range Ex. Zithromax: Take 2 tablets at first, then 1 tablet daily |
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Excipients (or adjuvants) |
Inert and/or inactive ingredients required to produce a dosage form (no pharmacological activity)
-Inactive ingredients may include: diluent, binding agent, lubricant, glident, disintegrating agent, surface active agent, and coloring agents. -Each inactive ingredient is a chemical and it is essential for the formulation of a dosage form.
Ex. Digoxin tablets (0.125mg and 0.25mg) - each tablet weights about 100 mg, thus each tablet contains approx. 99.75 mg or 99.875mg of inactive ingredients -Digoxin has narrow therapeutic range
-Surface active agent: needed in hydrophobic drugs to reduce tension between powder and liquid, facilities dissolution -Lubricants: hydrophobic by nature, reduces friction (in large amounts will affect dissolution, and absorption will be slower) -Binding agent: powder compressed to make a tablet -Disintegrating agent: breaks particles apart -Glident: flows smoothly |
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Inactive ingredients in aqueous and controlled released dosage forms |
Inactive ingredients are needed to develop other dosage forms such as solution, suspension, controlled release tablets, suppository, creams, lotions, etc.
-Preservatives are required in all liquid dosage forms containing aqueous vehicles (when water is used as vehicle, we need to add preservatives or bacteria may grow - due to water pH) -Suspending agents or viscosity agents are essential in the formulation of suspension dosage form (so powder does not sit on bottom of container) -If alcohol is used as vehicle, additional preservatives do not need to be added since alcohol is already a good preservative by itself -Various polymers and waxy materials are used in developing different types of controlled released dosage forms -Skin permeation enhancers are necessary in transdermal (patches) products (facilitate transfer of drug from patch to general circulation) -Higher the specific gravity, the higher the viscosity (high friction) |
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Inactive ingredients adverse effects |
May have adverse effects on the bioavailability and performance of drug from dosage form if: -Used in excess or incorrect amounts -It interacts (physically or chemically) with active ingredient(s) in dosage form -It alters drug dissolution |
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Biopharmaceutics Division of FDA |
Responsible for approval of New Drugs and New Chemical Entities (NCE- such chemicals do not exist in market yet) -Usually brand name companies |
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NDA |
New Drug Application (Usually brand name company) -Entire process can take up to 6 to 8 years, and may cost the company about $700 million to a billion or more. -A company, generally, applies for a patent at the time of discovery of a NCE or therapeutic moiety -A company is required to conduct phase 1,2,3 studies and submit data to FDA (chemistry of a new chemical entity, pharmacological studies, toxicological studies, pathological studies, pre-formulation studies, determination of physical-chemical properties,etc..) |
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Patent |
Provides an exclusivity rights to a company for about total of 17 to 20 years (on new drug or chemical entity)
-Gives company about 8 to 10 years to make profits without having to worry about another company introducing same drug in the market |
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Blockbuster drug examples |
Mecavor (first statin), Neurontin, Lipitor, Plavix, Viagra, Zithromax
-First drugs to come out in the market of their own category |
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Drug Discovery Process |
The process of a chemical entity becoming a therapeutic agent 1. Identify-Validate pharmaceutical target 2. Identify lead molecule 3. Optimize lead molecule 4. Clinical trials -5,000 to 10,000 drugs discovered -> 250 go into pre-clinical studies -> 5 go into clinical trials -> 1 is approved by FDA |
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NDA Studies |
Pharmacological: studies are conducted in animals to establish and prove the claimed pharmacological effects, safety, and efficacy of compound Toxicological: toxicity related info Pathological: examination/evaluation of various organs and tissues in animals, following the administration of the new compound Pre-formulation: Receive new drug and dosage form request, determine physical-chemical requirements to suit dosage form, obtain info though literature search Physical-chemical properties: macroscopic & microscopic examinations, polymorph, solvates, and hydrates, solubility, pKa's, partition co, dissolution rates, normal and exaggerated conditioning Characterization of powder properties: micromeritics, particle size and size distribution, derived properties, porosity, bulk density, angle of repose, Carr's index, hausner's index, true density, MP, dissociation constant |
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Microscopic Examinations |
Particle size, size distribution, examination of regularity or irregularity of powder particles -All this informations tells you about the crystal of the compound |
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Polymorphic chemicals |
Ability of a drug to exist in more than one crystalline form -Same chemical structure, though is likely to possess different physical-chemical properties for each crystal such as melting point and solubility -Pharmacological activity would not change in all crystalline forms |
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Normal and exaggerated conditioning |
Stability studies - if drug is stable at high temperatures, it will be likely to be stable at lower/room temperature |
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Intrinsic vs. Derived Property |
Intrinsic property: fixed value for a compound, will not change if particle size changes (ex. true density, DSC, partition coefficient, dissolution rate constant, dissociation rate constant = pKa, MP, BP, FP, osmotic pressure, equilibrium solubility, other colligative properties)
Derived property: values depend on particle size of a particular drug (pbach: porosity, bulk density, angle of repose, carr's index, hausner's index)(dissolution rate) |
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Angle of Repose |
Measurement of flow of powder material due to frictional force that exist between particles |
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Carr's index/Hausner's index |
Measurement of compressibility of powder material into a tablet dosage form
(if it doesn't have compressibility, it must be turned into capsule dosage form) |
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Melting point |
Intrinsic value: Tells you which temperature the particular substance will melt, and how pure the crystalline form of that substance is
Temperature at which a solid passes into a liquid state (0C)
-What will happen to a particular substance if melting point is low? It will melt if heat is applied -If melting point is different than known value, then given crystal form is not pure
-Property of solids -Low melting points turn solids into liquid in lower temperatures |
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IND |
Investigational New Drug -Application prior to NDA |
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Physical chemical stability |
Affects expiration date of a drug and degradation over time
-Expiration dates for a dosage form should be established by using same container as the ones which will be used in the market (usually 2 years) |
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Single dose pharmacokinetics |
One dose administered to many patients, and parameters/properties are observed -Elimination half life, absorption rate, AUC, eliminated drug, etc. |
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Multiple dose pharmacokinetics |
More than one dose of same drug given at a time interval and parameters/properties are observed |
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In vitro- in vivo correlation |
In vitro: outside the body In vivo: inside the body -Correlation between drug parameters which are measured outside, then inside of the body |
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Phase 1 |
Exploratory Trial -The new drug is administered to a small number (20 to 100) of human volunteers, who are normal healthy adults -The purpose of such testing is to determine the safety, tolerance, the ADME characteristics, and preferred route of administration -Such studies help establish safe dosage range and purported efficacy of the new compound in humans |
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Phase 2 |
Trials in Support of Claims -Efficacy and safety tests are then conducted on a limited number (100 to 500) of patients who have the disease or for which the drug has been developed |
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Phase 3 |
Expanded Clinical Evaluations -Further studies are conducted on a larger scale (1000 to 5000), both domestically and internationally, to assess drug's safety and efficacy in pre-diagnosed volunteers, and to determine the optimum dosage schedule -Once the clinical data are collected and evaluated, a NDA is prepared and submitted to the FDA and it's counter part in foreign countries for approval -Following the successful completion of Phase 3 studies and submission of NDA, a company may receive an NDA approval. This is then followed by manufacturing, marketing, and sales |
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Phase 4 |
Continuing Surveillance -The new drug may further be evaluated in a response to a government request to support the NDA. Additional safety data is collected |
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Phase 5 |
Continuing Market Support Studies -Testing of a new drug may be conducted in search of additional marketing claims, new formulations, and new combinations |
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What happens after patent expiration? |
A brand name may try to extend the patent by going to court, or develop a different dosage form (like CR dosage form), or market an active metabolite of the parent compound -this is when generic companies will enter the market with the generic version of that particular drug |
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Bio-equivalence Division |
Responsible for approval of generic products |
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ANDA |
Abbreviated New Drug Application -Generic companies must prove to FDA that their generic product is as good as or better than the brand name product -Generic companies are required to perform: formulation studies, stability studies, in vitro-in vivo correlation studies (NOT required to perform Phase 1-3 studies) -Must submit: Physical-chemical characterization and stability of drug dosage form, compatibility studies of drug in dosage form with containers and closures, method of manufacture of dosage form, drug analysis |
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Bio-equivalence studies |
Generally conducted by independent companies by selecting 12 to 18 normal healthy subjects (not in patient population) -Reference product is always the innovator (brand name product) -The plasma concentration vs. time data is evaluated and compared for the rate of absorption and extend of absorption |
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States of Matter |
Gases, liquids, and crystalline solids -Influenced by temperature and pressure |
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Gaseous State |
-Gas molecules, due to vigorous and rapid motion, travel in a random path -They tend to collide with one another and the walls of the container where they're confined -Gas molecules posses kinetic energy (higher than other 2 states of matter) -Gases are held together by intermolecular forces and they do not have regular shape -Properties: pressure (mmHg) and volume (L or cc) -Gas Laws (t,p,v): Boyle's, Charles, Gay Lussac -When gas is cooled, it loses its kinetic energy in form of heat and the velocity of molecules decrease -If subjected to pressure, gas molecules are brought within Van der Waal's interaction forces and pass into a liquid state -Major application in pharmaceutical sciences: interpretation of blood gases in patients (Oxygen and Carbon Dioxide)(Gases dissolved in blood based on their solubility) -Compressible |
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Liquid State |
-Considerably denser than gases -Occupy a definite volume and takes shape of container -Not compressible and possess less kinetic energy than gases -Flow very readily, and flow is influenced by friction -Can freeze (become solid) -Have boiling point (become gases), vapor pressure, and surface tension |
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Vapor Pressure |
-When one mole of solvent is converted to vapor -The kinetic energy present in the liquid molecules is not evenly distributed among molecules (some have more kinetic energy, thus higher velocity than others) -When a liquid is placed in a container, the molecules with greater energy break away from the surface of the liquid and pass into a gaseous state and some of the molecules return to the liquid state as a result of condensation -When the rate of vaporization and rate of condensation become equal at a definite temperature, the vapor (gas) become saturated and dynamic equilibrium is established -The pressure of the saturated vapor above the liquid is then known as equilibrium vapor pressure. Such vapor pressure is recorded and reported in mm Hg. -If temp. increases, more molecules will approach the velocity needed to escape and pass into gaseous state. Then, vapor pressure will increase with increased temperature -Higher velocity= escape faster from container -Vapor pressure is influenced by temperature -Each liquid has its own kinetic energy, molecules with greater kinetic energy will escape quicker than molecules with lower kinetic energy -Equivalent condition: rate of vaporization and rate of condensation are equal (equilibrium condition)- temp. influenced the equilibrium condition -Acetone escapes faster than benzene and water |
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Relationship between vapor pressure and absolute temperature |
Clausius-Clapeyron equation: log P2/P1 = [dHv(T2-T1)]/2.303R.T1*T2 -Where P1 and P2 are vapor pressures at absolute temp. T1 and T2 -Absolute temp. is (K=273.15+C) -dHv= molar heat of vaporization (heat absorbed by 1 mole of a liquid when it passes into vapor phase) (cal/g) -R= molar gas constant (1.987 ca.mole-1.deg-1) -The heat of vaporization (dHv) varies slightly with temperature -If the temperature of the liquid is increased while keeping pressure constant or the pressure is decreased while the temperature is constant, all the liquid will pass into the vapor state |
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Heat of vaporization examples |
The heat of vaporization varies for different liquids ex. For water, it is 539 cal./g For Ethyl alcohol, it is 204 cal/g For carbon disulfide it is 85 cal/g -Higher heat of vaporization, higher BP |
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Boiling point and heat of vaporization |
Helium: -268.9 C (BP), 6.0 cal/g (dHv) Nitrogen: -195.8 C (BP), 47.60 cal/g (dHv) Propane: -42.20 C (BP), 102.0 cal/g (dHv) Methyl chloride: -24.40 C (BP), 102.0 cal/g (dHv) Isobutane: -10.2 C (BP), 88.0 cal/g (dHv) Butane: -0.40 C (BP), 92.0 cal.g (dHv) Ethyl ether: 34.60 C (BP), 90 cal/g (dHv) Ethyl alcohol: 78.30 C (BP), 204 cal/g (dHv) Water: 100 C (BP), 539 cal/g (dHv)
-High dHv, high BP |
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Boiling Point |
The temperature at which the vapor pressure of a liquid (increases and becomes) equal to the atmospheric pressure (unit: Temperature) -If a liquid is heated until the vapor pressure equal to atmospheric pressure, the vapor is seen to form bubbles in the liquid that rise rapidly through the liquid and escape into gaseous or vapor phase -At the BP, all absorbed heat is utilized to convert the liquid into the vapor and the temperature does not rise until the liquid is completely vaporized -The pressure at sea level is 760 mmHg. At higher elevation, the atmospheric pressure decreases and the boiling point of a liquid decreases. At a pressure of 700 mmHg, water boils at 97.5C, and at 17.5 mmHg, water boils at 20 C -The temperature at which thermal agitation can overcome the attractive forces between the molecules of a liquid (BP, heat of vaporization and vapor pressure provide indication of magnitude of attractive forces) -The stronger the attractive forces, the higher the BP (the more compact a compound will be) |
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Latent Heat of Vaporization |
The heat absorbed when a liquid vaporizes at normal boiling point (Hv)(cal/g)
-Describes the quantity of heat taken up when a liquid vaporizes and is liberated when vapors condense to liquids |
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Boiling point trends |
The boiling point of normal hydrocarbon, simple alcohols and carboxylic acids increase with an increase in molecular weight, since the attractive Van der Waal's forces become greater with increasing number of carbon atoms since the molecules become more compact -BP of straight chain primary alcohols and carboxylic acids increase about 18oC for each additional methylene group -Branching of a chain produces a less compact molecule with reduced intermolecular attraction and a decrease in the BP of a liquid. Molecules of a liquid, held together by London force, exhibit low BP and low heat of vaporization -Straight chain with MW of 450, and branched chain with MW of 450 - BP of branched chain will be lower |
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Osmotic Pressure |
Differences in vapor pressure in two different solutions |
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Solids |
Crystalline, amorphous, and polymeric |
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Crystalline solids |
-Definite shape and orderly arrangement unit (repetitious 3-D units) -Incompressible (unlike gases) -Arranged in fixed geometric pattern or lattice -Definite MP (reported as single degree or range of 1-2 degrees), passing sharply from solid to liquid state -Strong intermolecular forces, very little kinetic energy -Characterized by shape, particle size, and MP -Few solids are volatile (sublimation point), harness, elasticity, compassion, flow, and porosity -Binding forces can be electrostatic attraction between oppositely charged ions (ex. sodium chloride where cubic lattice of sodium ions are interpenetrated by a lattice of chloride ions)(ex. diamond and graphite where atoms are held together by covalent bonds) (ex. molecules being held together by binding units) -In organic compounds, molecules are held together by Van der Waals forces and hydrogen bonding, which account for the weak binding and low melting points in most therapeutic agents |
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Hydrous and Anhydrous |
-Hydrous: the presence of water molecules which determine the solubility and dissolution of a drug, and also effects the performance of a drug -Anhydrous: no water present, also influence solubility, dissolution and performance or drug |
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Crystalline solids examples |
Cubic (ex. sodium chloride) Tetragonal (ex. urea) Hexagonal (ex. iodoform) Rhombic (ex. iodine) Monoclinic (ex. sucrose) Triclinic (ex. boric acid) |
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Sublimation point |
Process in which a compound will go from solid state to vapor state ex. iodine |
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Amorphous Solids |
-Non-crystalline powder material -No definite order or extended crystal structure -Referred to as super-cooled liquids because of random order of arrangement and distortion of shape under pressure -No definite MP (transition to liquid occurs over several degrees) -Drug in this form lacks a good hard crystal structure and strong forces, thus they are more soluble and more bioavailable than crystalline solid form -Higher thermodynamic energy than crystalline (reflected in differences in solubility and dissolution rate) -If stored, the amorphous solid may revert to more stable form (not desired form); this may occur during bulk processing or within the dosage form and may present a major problem for developing dosage form |
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Pharmaceutical material that exist in amorphous and crystalline solid states |
Petrolatum, pork and human insulin, some antibiotics (Novobiocin) Insulin zinc suspension, Lente Iletin (Lilly), Novolin L, Lente L (Novo, Nordisk), Humulin L (70% crystalline and 30% amorphous insulin suspension) -If you want to give insulin and you want quick onset of action, give insulin that has more amorphous form -If you want a longer duration of action, give insulin with greater crystalline form |
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Important properties of solids |
-X-ray diffraction -Melting point -Equilibrium or saturation solubility -Polymorphism -Hydrated or anhydrous form -Particle size and size distribution, absolute or true and apparent or bulk density, specific surface, surface area, contact angle, hygroscopicity and deliquescence |
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Graph |
A graph a visual representation illustrating how one variable changes with another variable -Y axis: dependent variable (plasma conc., amount or % of drug dissolved or in urine, rate of degradation) -X axis: independent variable Straight line: y=mx+b |
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Linearized equation |
One variable is in log form (dependent variable) y=mx+b ln y= ln b + mx |
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Endothermic solute and absolute temperature |
S= Ke^(-dHs/RT) ln S= - (dHs/R)(1/T) + ln k log S= - (dHs/2.303*R)(1/T) + ln k S: equilibrium solubility (g/L) dHs: heat of solution (cal/g) R: gas constant (1.987 cal/mol.deg) T: absolute temperature (K) k: Y-intercept -negative slope -straight line |
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Heat of solution |
Heat absorbed or liberated when one mole of a solute is dissolved in a definite quantity of a pure solvent to yield a solution (cal/g) |
