1. Drug Product Development
Introduction
Active pharmaceutical ingredient (API): component that produces pharmacological activity (drug substance). May be produced by chemical synthesis, from natural product, enzymatic reaction, recombinant DNA, fermentation, etc.
New chemical entity (NCE): drug substance with unknown clinical, toxicological, physical, chemical properties. According to the FDA, NCE is an unapproved API.
Drug product: finished dosage form containing API and excipients.
Generic drug products: after patent expiration of brand drug. Therapeutically equivalent to the brand and has the same drug amount in the same dosage form. Must be bioequivalent (same rate and extent of absorption) same clinical results. May differ from brand in excipients (tablets only unless safety studies are done) or physical appearance.
Abbreviated New Drug Application (ANDA): submitted to the FDA for approval of generic drugs. Preclinical safety and efficacy studies are not required. Human bioequivalence is needed (on healthy human volunteers). Chemistry, manufacturing and controls for generics are similar to the brand. Specialty drug products: existing products developed for new delivery system or new therapeutic indication. Safety and efficacy studies are not required. Example nitroglycerin transdermal patch after sublignual tablets.
New drug approval
Preclinical (animal safety / pharma) IND Phase I (healthy human safety) Phase II (↓# patients)
Phase III (↑# patients) NDA FDA green light for marketing Phase IV (scale up) Phase V (continuous improvements).
Preclinical stage: animal pharmacology and toxicology to determine safety and efficacy. Formulation is not final.
Phase I: Submit an Investigational New Drug (IND) clinical studies on healthy volunteers to determine toxicity and tolerance. For oral drugs simple hard gelatin capsule.
Phase II: small number of patients under close supervision. Dose-response studies to determine optimum dosage for treatment. Determine the therapeutic index (toxic dose/effective dose). Develop final drug formulation (bioequivalent to that used in initial clinical studies). Start chronic toxicity studies for 2 years in 2 species.
Phase III: large-scale multicenter clinical studies with final dosage form (from phase II) to determine safety and efficacy in patients. Watch for new, rare, toxic or side effects.
NDA submission: FDA satisfaction with safety and efficacy for marketing.
Phase IV: scale-up in preparation for marketing. Only minor modifications on the formulation are allowed. Phase V: continuous drug product improvements after marketing.
Product development
New chemical entities
Preformulation:
Physical and chemical characterization of the drug and dosage form during preclinical phase. Includes general properties (particle size / shape, polymorphism, crystalline structure, density, surface area, hygroscopicity), solubility (dissolution, pH-solubility profile, various solvents), chemical properties (surface energy, pH stability profile, pKa, temperature stability, excipient interactions), stability analytical methods. Formulation development: continuing process.
Injections: final formulation is developed in preclinical phase, stability in solution is critical, few excipients allowed, no bioavailability for IV.
Topicals / local: final formulation developed in phase I, study release in in vitro diffusion cell models, local irritation and systemic absorption are the issues.
Oral drugs: final formulation in phase II.
Final product considerations: size, shape, color, taste, skin feel, viscosity, physical appearance, production equipment / site.
Product line extensions:
Dosage forms with change in physical form or strength but not use or indication. Usually occurs during Phases III, IV, V.
Regulatory approval: based on stability, analytical / manufacturing controls, bioequivalence studies, clinical trials
Solid products:
Different strength in a tablet or capsule form only bioequivalence required (simplest case). Easier if in vitro dissolution / in vivo bioavailability correlation exists.
Modified release: clinical trials required.
If new indication new NDA and new efficacy studies. Liquid products:
If an extension of a liquid same as above for solids
If an extension of a solid if big difference in extent / rate of absorption new clinical trials.
Preapproval inspections
Manufacturing facility is inspected prior to NDA / ANDA approval or after a major reported change to NDA / ANDA.
Includes: general cGMP inspection, reviews documentation, verifies traceability of information to documentation, consults the chemistry / manfucaturing / control (CMC) section of NDA / ANDA, make a final recommendation.
Scale-up and post-approval changes (SUPAC)
Guidelines to # of manufacutring changes that require preapproval by the FDA.
Examples: minor formulation changes, change site of manufacture, batch size or , change manufacturing process / equipment.
1. Very minor changes not requiring approval are reported in an annual report. Examples: compliance with guidance, label description, deletion of colorant, expiration date extension, ∆ container / closure type (not size), analytical method
2. Changes being effected supplement: minor changes but require some validation, documentation. A supplement but no pre-approval is required. Examples: new specs, label changes on clinical info, different cGMP manufacturing facility but same process.
3. Preapproval supplement: major changes require specific preapproval. Examples: adding or deleting an ingredient, relaxing specs, deleting a spec or method, method of manufacture, in-process controls. Therapeutic and Bio-equivalence: must be shown for any change. Minor change comparable dissolution profiles. Major change in vivo bioequivalence study.
GMPs
Minimum requirements for manufacturing, processing, packing, or holding drugs. Include criteria for personnel, facilities, processes to ensure final product has the correct identity, strength, quality, purity. Quality Control (QC): department responsible for establishing process and product specifications. The QC dept test the product and verifies specs are met. This includes acceptance / rejection of incoming raw materials, packaging components, water, drug products, environmental conditions.
Quality Assurance (QA): a department that determines that the systems and facilities are adequate and that written procedures are followed.
2. Pharmaceutical Calculations and Statistics
Fundamentals of measurement and calculation
Inverse proportion: the inverse of the ‘scissors’ method is used in case of dilutions. Example: 100 ml of 10% solution is diluted to 200 ml, what is the final concentration? Inverse ‘scissors’ 200/10 = 100/x 5%.
Aliquot: used when the sensitivity of the measurement device is not great enough for the required measurement.
Example: balance sensitivity is 6 mg, accuracy is +/-5% minimum weighable quantity is: 5/100=6/x = 120 mg. If you need to weigh 10 mg drug add a diluent to get a final concentration of 120 mg drug in the diluted mixture (120x120 = 1440 mg) then weigh 120 mg of the diluted mixture.
Systems of measure: Apothecaries’ system of fluid measure, Apothecaries’ system for measuring weight, Avoirdupois system for measuring weight (pound, ounce, grain=65 mg), metric system.
Children doses
First choice: body weight or mass and mg/kg dosing. Fried’s rule for infants: (age in month / 150) x adult dose Clark’s rule: (weight in lb / 150) x adult dose
Child’s dosage based on body surface area: (BSA in m2 / 1.73) x adult dose
Percentage, ratio strength, concentrations
Percentage w/v, Percentage v/v, Percentage w/w, Ratio strength
Be careful 3 g drug in 27 g water is 10% solution (3/30) BUT 3 g drug in 30 g water is 9% (3/33). Molarity: number of moles of solute dissolved in 1 liter of solution
Molality: number of moles of solute dissolved in 1 kg of solution. Advantage over molarity: using weight avoids problems with volume expansion or contraction upon the addition of solutes.
Normality: is the number of equivalent weights of solute per liter of solution. Equivalent weight = atomic weight or molecular weight / valence. Preferred way of expressing concentration of acids, bases and electrolytes. One equivalent is the quantity that supplies or donates one mole of H+ or OH-. One equivalent of acid reacts with one equivalent of base.
Mole fraction: ratio of number of moles of one component to the total moles of a mixture or solution.
Dilution and concentration
Constant amount of drug volume is inversely proportional to concentration. Quantity1 x concentration1 = quantity2 x concentration2.
Allegation medial: method for calculating average concentration of a mixture of two or more substances. Allegation alternate: method for calculating number of parts (relative amounts) of two or more
components of known concentration to be mixed when final concentration is known. IMPORTANT. See example is page 16.
Dilution of alcohols: alcohol + water volume contraction. Use w/w instead of v/v for accuracy. Percentage strength: of concentrated acids is expressed in w/w. For diluted acid w/v. To determine the volume of concentrated acid for dilution, use specific gravity.
Electrolyte solutions
Divalent: calcium, ferrous, magnesium, sulfate. Trivalent: aluminum, ferric, citrate. All others are monovalent.
Milliequivalents (mEq)
Definition: amount in mg equivalent to a solute equal to 0.001 of its gram equivalent weight. Unit used to express concentration of electrolytes
Milliosmoles (mOsmol)
Osmotic pressure is directly proportional to the total number of particles in solution. Unit for measuring osmotic concentration: mOsmol.
For non-electrolytes: 1 millimole = 1 mOsmol (1 molecule = 1 particle) For electrolytes: number of particles depends on degree of dissociation.
Example: completely dissociated KCl 1 millimole = 2 mOsmol (2 particles, K and Cl for each molecule). Example: completely dissociated CaCl2 1 millimole = 3 mOsmol
↑ solute concentration ↑ interaction between dissolved particles ↓ actual osmolar concentration compared to ideal osmolar concentration.
Isotonic solutions
Isosmotic: solution with the same osmotic pressure.
Isotonic: solution with the same osmotic pressure as body fluids.
Hypotonic: solution with ↓ osmotic pressure than body fluid (opposite is hypertonic) Preparation of isotonic solutions
Colligative properties (e.g. freezing point depression) are representative of the number of particles in solution.
Dissolve 1 g MWt of non-electrolyte in 1 L of water depression of freezing point by -1.86 C. For electrolytes: freezing point depression = -1.86 x number of species produces upon dissociation. Freezing point depression of body fluids = -0.52 C.
Take dissociation of weak electrolytes into account.
In weak solutions, every 2 ions produce 1.8 ions, every 3 ions produce 2.6 ions (about 10% loss). NaCl equivalents
Definition: the amount of NaCl that is equivalent to the amount of particular drug in question. Isotonic fluid: 0.9% NaCl.
Example: NaCl equivalent for KCl to 0.78 1 gram KCl = 0.78 g of NaCl.
Calculating amount of NaCl required to adjust isotonicity: calculate the total amount of NaCl required (volume x 0.9%) calculate the NaCl equivalent of all substances in the solution calculate and add the difference as NaCl or another material (as NaCl equivalent).
Statistics
Frequency distribution: classify individual observations into categories corresponding to fixed numeric intervals (interval frequencies) plot number of observations in each category versus category
descriptor.
Normal distribution: bell-shaped (Gaussian) curve.
Estimates of population mean: the population mean is the best estimate of the true value. Sample mean: arithmetic average. Accuracy: degree to which measured value agrees with true value. Error (bias): difference between measured value and true value. Median: midmost value of a data distribution (average of two midmost values if even number of observations). Normal distribution median = mean. Median is less affected by outliers or skewed distribution. Mode: most frequently occurring value in a distribution, it is useful for non-normal distributions especially bimodal distributions.
Estimates of variability: infinite # of observations population variance. Finite # of observations sample variance. Range: useful to describe variability only in very small number of observations. Standard deviation: square root of variance. Precision (reproducibility): degree to which replicate measurements made exactly the same way agree with each other (expressed as relative standard deviation).
Standard deviation of the mean (standard error): estimate of variability or error in the mean obtained from N observations. SE = SD/(sq. root of N). Used to establish confidence intervals.
3. Pharmaceutical Principles and Drug Dosage Forms
I. Intermolecular forces of attraction
Atoms vary in electronegativity, so, electron sharing between atoms will be unequal. So, the molecule behaves like a dipole over a covalent bond.
Dipole moment (mu) = distance of charge separation X charge
When the negative pole of a dipole approach the positive pole of another molecular attraction called “dipole-dipole interaction”.
If similar poles approach molecular repulsion (intermolecular repulsive forces)
Types of intermolecular forces of attraction
Van der Waals forces (liquids)
Induced dipole induced dipole (London dispersion force): when a transient dipole in a nonpolar
molecule induces another transient dipole in another molecule. Force = 0.5-1 Kcal/mole
Dipole-induced dipole (Debye induction force): A transient dipole is induced by a permanent dipole.
Force = 2 Kcal/mole
Permanent dipole (Keesom orientation force): 4 Kcal/mole
Hydrogen bonds
Hydrogen ions are small and have a large electrostatic field, so it approaches highly electronegative atoms (O, F, Cl, N, S) and interact electrostatically to form a hydrogen bond. Force = 5 Kcal/mole.
Ion-ion, ion-dipole, ion-induced dipole
Force of positive-negative ion interaction in the solid state = 150 Kcal/mole. Covalent and ionic forces are much stronger than van der Waals forces.
States of matter
Gases
Molecules move in straight path at high speed until they randomly collide with another molecule, creating pressure. Intermolecular forces ~ zero.
Ideal gas law:
Pressure (P) x Volume (V) = number of moles (n) X Molar Gas Constant (R) X Temperature (T) Gases in pharmacy: anesthetics (nitrous oxide, halothane), compressed oxygen, liquefiable aerosol propellants (nitrogen, CO2, hydrocarbons, halohydrocarbons), ethylene oxide for sterilization of heat labile objects.
Volatile liquids (ether, halothane, methoxyfurane) are used as anesthetics. Amyl nitrite (volatile liquid) is inhaled as a vasodilator in acute angina.
Sublimation: a solid is heated directly to the gaseous or vapor state (or vice versa, also called deposition)
without passing through the liquid state. Examples: camphor, iodine.
Liquids
Van der Waals intermolecular forces are sufficient to impose some ordering. Hydrogen bonding cohesion in liquids.
Surface and interfacial tension
Molecules at the surface of the liquid experience a net inward pull from the interior and they tend to contract. This makes liquids assume a spherical shape as it is the volume with minimum surface and least free energy.
Surface free energy / surface tension: the work required to the surface area A of the liquid by 1 unit area. Example: SFE for water = 72 mN/m.
Interfacial tension: at the surface of two immiscible liquids.
Viscosity
Viscosity = shear stress / shear rate
Non-Newtonian viscosity: exhibit shear dependent or time dependent (apparent) viscosity.
Shear dependent viscosity: Shear thickening (dilatancy) as in suspensions of small deflocculated
particles with high solid content. Shear thinning (pseudoplastic): as in polymer solutions. Plastic
(Bingham body): as in flocculated particles in concentrated suspensions that have yield value.
Time dependent viscosity: yield value of plastic systems may be time dependent. Thixotropic systems
compared to structural breakdown. It occurs in heterogenous systems with three dimensional structural network (gel-sol transformation). Negative (anti)thixotropy: viscosity with shear up to an equilibrium (sol-gel transformation).
Solids
High intermolecular forces.
Crystalline solids: fixed molecular order, distinct melting point, anisotropic (properties are nto the same
in all directions).
Amorphous solids: randomly arranged molecules, nondistinct melting point, isotropic (properties are the
same in all direction).
Polymorphs: substance has more than one crystalline form. Different molecular arrangments /
crystalline lattice structure, melting point, solubility, dissolution rate, density, stability. Polymorphs are common in steroids, theobroma oil, cocoa butter.
Latent heat of fusion: heat absorbed when 1 g of solid melts.
III. Physicochemical behavior
Homogenous systems
Solution: homogenous system in which a solute is molecularly dispersed or dissolved in a solvent. Nonelectrolytes: substances that do not form ions in solution, e.g., estradiol, glycerin, urea, sucrose.
Solution doesn’t conduct electricity.
Electrolytes: form ions in solutions. Solution conducts electricity. Can be strong (completely ionized in
water; HCl, NaCl) or weak (partially ionized; aspirin, atropine).
Colligative properties:
Depend on the total number of ionic and nonionic solute molecules in solution. They are dependent on ionization but independent of other chemical properties of the solute.
Vapor pressure depression: (Raoult’s law): partial vapor pressure is equal to the product of the mole
fraction of the component in solution and the vapor pressure of the pure component.
Boiling point elevation and freezing / melting point depression
Osmotic pressure: Osmosis is the process by which solvent molecules pass through semipermeable
membrane from dilute solution to concentrated solution. That is because solvent molecules have lower chemical potential in concentrated solution. Osmotic pressure is the pressure that must be applied to solution to prevent the flow of pure solvent. It is defined by the van’t Hoff equation.
Electrolyte solutions and ionic equilibria
Arrhenius dissociation theory: an acid is a substance that liberates H+ (donates protons) in water, a base liberates OH- (accpets protons). Lowry Bronsted theory: applies to both aqueous and
nonaqueous systems. In water, a free proton combines with water forming hydronium ion (H3O +
). A strong acid in water can behave as a weak acid in a different solvent.
Lewis theory: defines acid as a molecule or ion that accepts an electron pair from another atom. A base
donates an electron pair to be shared with another atom.
pH is the negative logarithm of molar H+ concentration.
As pH , H+ concentration exponentially.
Ionization: is the complete separation fo the ions in a crystal lattice when the salt is dissolved.
Dissociation: is the separation of ions in solution when the ions are associated by interionic interactions.
For weak electrolytes, dissociation is reversible. According to the law of mass action, concentration of dissociation products results in dissociation. pKa is the dissociation constant of a weak acid. pKb is used for weak bases.
Acids and bases that can accept or donate more than one proton will have more than one dissociation constant.
Henderson-Hasselbalch equation: describes the relationship between ionized and nonionized species
of a weak electrolyte (base is UP). pH = pKa when [dissociated species] = [nondissociated species], i.e., 50% ionization.
Solubility of a weak electrolyte varies as a function of pH. Solubility of a weak acid with pH. Opposite is true for weak bases.
Buffer: a mixture of salt with acid or base that resists changes in pH when small quantities of acid or salt
are added. Buffer is a combination of weak acid and its conjugate base (salt) (more common), or a weak base and its conjugate acid (salt).
Buffer capacity: is the number of gram equivalents in an acid or base that changes the pH of 1 liter
buffer by 1 unit. Maximum buffer capacity occurs when pH = pKa. Higher concentration of buffer constituents buffer capacity due to the acid or base reserve.
Heterogenous (disperse) systems:
Suspension: two phas system that is composed of solid material dispersed in a liquid. Particle size is >
0.5 mm.
Emulsion: heterogeneous system that consists of one immiscible liquid dispersed in another as droplets.
Droplets diameter > 0.1 micron. Emulsions are inherently unstable because the droplet tend to coalesce. An emulsifying agent is used to prevent coalescence.
In ideal (not real) dispersion, the dispersed particles are uniform in size and do not interact.
Stokes’s law defines Sedimentation rate. The rate with particle size and the difference in density between particles and medium. The rate with medium viscosity.
High particulate (dispersed phase) concentration leads to particle collision and aggregation, coalsecnce, instability.
Avoidance of particle-particle interactions: if particles have similar electrical charge (e.g. from the
surfactant). Zeta potential (magnitude of the charge) is the difference in electrical potential between the particle charged surface and dispesion medium. When zeta potential is high (<25 mV), interparticulate repulsive forces > attractive forces, which results in deflocculation and stability.
Coalescence of droplets in O/W emulsions is by electrostatic repulsion of similarly charged particles.
Creaming: is the reversible separation of a layer of emulsified particles. Mixing or shaking may be
sufficient to reconstitute the emulsion.
Phase inversion: from o/w to w/o emulsion or vice versa.
IV Chemical kinetics and drug stability
Degradation rate depends on concentration, temperature, pH, solvents, additives, light, radiation, catalysts (polyvalent cations), surfactants, buffers, complexing agents.
Order of reaction: the way in which the concentration affects rate.
Zero order: rate is independent of concentration, e.g., 5 mg/hr, i.e., straight line concentration vs. time. First order: rate depends on the first power of concentration, e.g., 5% / hr. Concentration
exponentially with time. Straight line log concentration vs. time. t1/2 = 0.693/k, t90% = 0.104/k. Half life is concentration independent.
Temperature: T reaction rate (Arrenius equation).
Solvent: may change pKa, surface tension, viscosity, reaction rate, etc. Additional reaction pathways
may be created (e.g. aspirin in ethanol).
pH: H+ catalysis occurs at pH, OH- catalysis occurs to pH. Rate constant at intermediate pH range is usually lower than at or pH. pH of optimum stability (point of inflection) is measured.
Aromatic esters (benzocaine, procaine, tetracaine) t1/2 is presence of caffeine due to complex formation.
Modes of pharmaceutical degradation:
Hydrolysis: most common. Occurs for esters, amides, lactams. H+ and OH- are the most common
catalysts. Esters easily hydrolize and should be avoided in liquids.
Oxidation: by oxygen in the air or in solvent. Oxidizable compounds should be packed in an inert
atmosphere (nitrogen or CO2). Oxidation involves free radical mechanism and chain reaction. Free radicals take electrons from other compounds. Antioxidants react with free radicals by providing electrons. Antioxidants include: ascorbic acid, tocopherols, sodium bisulfite, sodium sulfite, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate.
Photolysis: degradation in sunlight or room light. Molecules may absorb the proper wavelenght of light
(usually <400 nm) and acquire sufficient energy to undergo reaction. Prevent by using opaque container or amber glass bottle. Examle: sodium nitroprusside in water.
Determination of shelf life. It’s affected by storage temperature. Preparation is considered fit if it varies
from nominal concentration by no more than 65% provided the decomposition products are not more toxic. Stability testing at 4 C and room temperature (22C). Rate of decomposition is determined. Temperature-ccelerated stability is also conducted. Arrhenius equation can be used. T90% can also be calculated.
Drug dosage forms:
Oral solutions
May contains polyols (e.g. sorbitol, glycerin) to ↓ crystallization, modify solubility, taste, mouth feel. Advantages (over solid forms): more homogenous, easier to swallow, ↑ bioavailability and ↓ onset of action for slow dissolution drugs. Disadvantage: bulkier, degrade faster, ↑ interactions with constituents
Types of water:
Purified water USP: obtained from distillation, reverse osmosis, ion exchange. Solids < 10 ppm. pH =
57. It can not be used for ophthalmics or parenterals.
Water for injection USP: purified water that is pyrogen free
Sterile water for injection USP: water for injection that is sterilized and packaged in single dose
containers < 1 liter for type I or II glass
Bacteriostatic water for injection USP: sterile water for injection containing bacteriostatic agent(s) in
one or multiple dose containers < 30 ml in type I or II glass.
Sterile water for inhalation USP: purified by distillation or reverse osmosis and rendered sterile. It
contains no antimicrobials.
Sterile water for irrigation USP: water for injection that is sterilized and contains no antimicrobials.
Oral drug solutions
Syrups: contains ↑ sugar concentration. Sweet and viscous. Syrup NF (simple syrup): 85% w/v sugar.
Sugars have low solvent capacity for water soluble drugs because hydrogen bonding between sugar and water is very strong. Dilute sucrose solutions are excellent media for microbial growth. As sugar
concentration approaches saturation, the solution becomes self-preserved, however temperature
fluctuations may cause sugar crystallization. Syrup USP is self-preserved with ↓ crystallization potential.
Elixirs: contain alcohol as a solvent (5-40%). Elixirs become turbid when diluted by aqueous liquids.
Alcohol ↑ salt taste. Salts also have limited solubility in alcohol. Aromatic elixir NF: mixture of two alcohol concentrations resulting in 22% alcohol.
Miscellaneous solutions
Aromatic waters: are saturated aqueous solutions of volatile oils. Used for flavoring. Stored in tight,
light resistant containers. Adding large amount of water soluble drug may cause insoluble layer to form (salting out) due to better attraction with the water solvent than the oils.
Spirits (essences): volatile substances in 50-90% alcohol. It water is added, oils separate. Used
medicinally or as flavors. Store in tight containers.
Tinctures: stable alcohol solutions of chemicals or soluble constituents or vegetable drugs. Prepared
using extraction using maceration or percolation. Alcohol content varies widely.
Fluidextracts: liquid extracts of vegetable drugs that contain alcohol as a solvent, preservative, or both.
Prepared by percolation. Ten times as concentrated and potent as tinctures (100% vs. 10%).
Mouthwashes: use alcohol or glycerin to dissolve volatile ingredients.
Astringents: locally applied solutions that ppt protein. Astringents ↓ cell permeability without causing injury. They cause constriction, wrinkling and blanching of skin. They ↓ secretions and are used as antiperspirants. Examples: alulminum acetate, aluminum subacetate, calcium hydroxide.
Antibacterial topical solutions: e.g. benzalkonium chloride, strong iodine, providone-iodine. .
Suspensions
Magmas: suspensions of finely divided material in a small amount of water.
Drugs may be packed dry to avoid instability in aqueous dispersions.
Sustained effect: requires dissolution or diffusion step. Stability: drug degradation is slower than in a
solution. Taste: for insoluble drugs used in suspension. Solubility: when solvent is not available. Example: only water can be used in ophthalmics, but suspension offer an alternative.
Preparation: first solids are wetted by levigation (addition of nonsolvent levigating agent to solid material
to form a paste). A surfactant can be used. Then suspending agent is added as aqueous dispersion by geometric dilution.
Suspending agents: A. Hydrophilic colloids
↑ viscosity by binding with water. Support microbial growth and require preservation. Mostly anionic, except methyl cellulose (neutral) and chitosan (cationic), therefore incompatible with quaternary antimicrobials. Insoluble in alcohol.
Acacia: used as 35% water dispersion (mucilage). Neutral pH. Tragacanth: 6% mucilage (less needed).
Methyl cellulose: heat and light stable polymer. Soluble in cold but not hot water. Prepared using
boiling water.
Carboxy methyl cellulose: anionic and water soluble. B. Clays
Anionic silicates. Strongly hydrated and exhibit thixotropy. Examples: bentonite (5% magma), veegum.
Emulsions
Advantages:
↑ Solubility: e.g. oil soluble drug in aqueous formulation. ↑ Stability: usually better than in aqueous solution. ↑ Drug action: as in IM injections. ↑ Taste: oil soluble drug hidden in aqueous outer phase. ↑
Appearance: as in oily material for topical application.
Phases of emulsions: most are 2-phases. Internal phase (dispersed or discontinuous phase) in an external phase (dispersion medium or continuous phase).
Type of emulsion is determined by relative phase volumes and emulsifying agent used (more important). Maximum volume of internal phase is 74%.
Emulsifying agents: lower interfacial tension and form a film at the interface.
Natural emulsifying agents: see hydrophilic colloids under suspending agents (acacia, tragacanth,
celluloses). Also pectin, gelatin and agar. Agar: ↑ viscosity. Gelatin: 1%, can be anionic or cationic.
Preparation methods:
1. Wet gum (English) method: emulsion of fixed oil, water, acacia. Make mucilage of water and acacia,
then add oil gradually.
2. Dry gum (Continental) method: emulsion of fixed oil, water, acacia. Fixed oil added to acacia and
then water is all added at once followed by rapid titration.
Electrolyte in high concentration can break the emulsion. Add last. Alcohol can dehydrate and ppt hyrocolloids. Use in ↓ concentration.
3. Bottle method: similar to dry method. Used for volatile oils.
4. Nascent soap method: by mixing equal portions of oil and alkali solution to form soap, which acts as
an emulsifying agent. Example: olive oil (contains oleic acid, free fatty acid) and lime water calcium oleate for calamine lotion.
The drug can be added after emulsion formation if it is soluble in the external phase. If drug is soluble in internal phase, it should be dissolved first during emulsion formation.
Synthetic emulsifying agents:
1. Anionic: Soaps form w/o except alkali soap. Examples: SLS 2. Cationic: e.g. benzalkonium chloride. Incompatible with soap.
3. Nonionic: Spans (sorbitan esters, ↑ HLB) for w/o, Tweens (polysorbates, ↓ HLB) for o/w
Ointments
Used as emollients (make skin more pliable), protective barriers, or vehicles for drugs.
Ointment bases
1. Oleaginous bases: not washable. Petrolatum: occlusive, does not rancid, use wax to ↑ viscosity.
Synthetic esters: e.g. glyceryl monostearate, isopropyl myristate, butyl palmitate, PEG, long chain
2. Absorption bases: anhydrous, water-insoluble, not washable, but can absorb water. Example:
anhydrous lanolin (wool fat), hydrophilic petrolatum (petrolatum, bees wax, stearyl alcohol, cholesterol), e.g. Aquaphor.
3. Emulsion bases: Hydrous wool fat (lanolin): w/o with 25% water, emollient and occlusive. Cold cream: w/o with almond oil, white wax, sodium borate. Vanishing cream: o/w with ↑ water and
humectants (PEG, glycerin). Hydrophilic ointment: o/w with SLS.
4. Water soluble bases: washable and absorb water. PEG ointment: PEG 400 and 4000 by fusion
method. PG and PG-alcohol: forms clear gel with 2% hydroxypropyl cellulose.
Preparation: metal spatula may interact with iodine or mercuric salts. Use levigation or fusion method. Fusion method: used for solids with ↑ melting point. Oil phase melted with highest melting point
materials first. Heat water soluble ingredient separately to above the highest melting point. Mixed the two phases in the appropriate order for o/w or w/o.
Suppositories
Used for local (hemorrhoids, infection) or systemic effect. Systemic effect bypasses the first pass metabolism
Used when oral route is not possible, e.g., infants, nausea, vomiting, GI distress, coma, debilitation.
Types of suppositories:
1. Rectal: cylindrical, tapered bullet like. Adult: 2 g.
2. Vaginal: oval, 5 g, for antiseptics, contraceptives, anti-infective. 3. Urethral: long (6 cm), tapered, local anti-infective.
Suppository bases:
Minimum 30 C narrow, sharp melting point. Oil soluble drug has ↑ mucous absorption from an oil base, and vice versa.
Bases that melt: cocoa butter (theobroma oil), witepsol (saturated fatty acid mixture), wecobee (from
coconut oil); or Bases that dissolve: PEG.
Preparation: the suppository is molded with the fingers after a plastic mass is formed.
1. Hand-rolling: Correct the amount of base needed based on the quantity of the drug and density of the
base.
2. Compression: Mixture is placed into compression device. Pressure is applied and mixture is forced
into lubricated mold cavities. Used with cocoa butter.
3. Fusion (molds): most common. Use mineral oil to lubricate mold. Pour melt continuously to avoid
layering. Avoid for thermolabile drugs and insoluble powders (settle).
Powders
Advantages: compounding flexibility, chemical stability, rapid ingredients dispersion. Disadvantages:
time consuming preparation, inaccurate dosing, unsuitable for bad taste / hygroscopic drugs.
Milling: mechanical process of reducing particle size (comminution). Micrometrics: is the study of
particles.
Advantages of milling: ↑ surface area ↑ dissolution rate and bioavailability (e.g. griseofulvin), ↑
drying of wet masses. ↑ ointment texture / stability / appearance. ↑ uniform distribution of colorants. Particles of same size ↑ mixing, ↓ segregation.
Disadvantages of milling: may change polymorphic form ↓ activity. ↑ heat / adsorption
degradation. Flow problems and segregation. ↑ static charge particle aggregation / ↓ dissolution. ↑ surface area ↑ air adsorption / ↓ wettability.
Comminution techniques: Trituration reducing particle size or mixing with a mortar and pestle. Pulverization by intervention a solvent is added to help pulverization and then evaporated (e.g.
alcohol to camphor). Used with gummy substances that reagglomerate or resist grinding. Levigation add a nonsolvent (levigating agent, e.g., mineral oil) to form a past and help pulverization in mortar and pestle or ointment slab and spatula. Avoid gritty feel of solids.
Mixing powders:
Spatulation: using spatula to mix small amounts of powder on paper or pill tile. Not possible for potent
drugs or large quantities. Useful to eutectic mixtures (mixture melting point is lower than each ingredient), such as phenol, camphor, menthol, thymol, aspirin, phenyl salicylate, phenacetin. Inert diluent can be used to minimize contact (MgO, MgCO3, kaolin, starch).
Trituration: used both to comminute and mix. For comminution, use porcelain or ceramic mortar with
Geometric dilution: used for mixing potent drugs with large amount of diluent. First mix equal amounts
of drug and diluent in a mortar by trituration, repeat until diluent is used up.
Sifting: powders are passed through sifters similar to flour sifters, resulting in a light fluffy product. Not
suitable for potent drugs.
Tumbling: mix powders in a large container rotated by motor. Use and packaging of powders:
As bulk powders or divided powders. For bulk powders, a perforated sifter can is used for external dusting or an aerosol container is used for spraying onto skin.
Powders dispensed in bulk: antacids and laxatives (e.g. PEG is mixed with a drink). Douches are
mixed with water and applied vaginally. Dentifrices and dental cleansing powders. Powders for ear, nose, throat, tooth sockets, vagina. Non potent substances.
Divided powders: dispensed usually in folded paper (chartulae). If drug is not potent, approximate
portions by block and divide method (do not weight).
Special problems: volatile substances (camphor, menthol, essential oils) use sealed containers.
Liquids added to divided powders in small amounts. Hygroscopic substances become moist divide, add diluent, double wrap. Eutectic mixtures.
Capsules
Hard gelatin capsules
Storage: contain 15% water, so when ↓ humidity capsules become brittle, when ↑ humidity
capsules become shapeless.
Size: empty capsules are numbered (000 largest / 600 mg, 5 smallest / 30 mg). Large capsules are
for veterinary use. May add lubricant to ↑ flow or wetting agent to ↑ dissolution.
Filling: by the punch method. Powder is placed on paper and the capsule is pressed into powder until
filled.
Soft gelatin capsules
Preparation: from gelatin shells. Glycerin or polyhydric alcohol (sorbitol) is added to make shells more
elastic. Contain preservatives (sorbic acid, parabens).
Uniformity and disintegration
Uniformity is demonstrated by weight variation or content uniformity. Disintegration are usually not requires unless they are enteric coated.
Contents may be designed for sprinkling on food (e.g. Theo-Dur Sprinkle).
Tablets
Advantages of solid dosage forms: accurate dose, easy shipping / handling, less shelf space, no
preservative, no taste masking problems, more stable / longer expiration.
Advantages of liquid dosage forms: more effective (antacids, adsorbents), easier to swallow. Advantages of tablets; precise dose, ↓ content variability, ↓ manufacturing cost, easy packaging and
shipping, easy to identify, easy to swallow, specific release forms, stable, tamperproof.
Disadvantages of tablets: difficult compression, difficult formulation / ↓ bioavailability (poor wetting, ↓
dissolution, ↑ dose).
Ideal tablet: free of defects, strong / durable, stable, predictable drug release.
Tablet design and formulation (excipients)
Diluents: fillers to make up the tablet bulk of ↓ dose drugs. May ↑ cohesion, flow, or direct compression. Examples: kaolin, lactose, mannitol, sugar, starch, microcrystalline cellulose, calcium phosphate. Do not
use calcium salts with tetracycline (↓ absorption).
Binders / adhesives: added dry or liquid to ↑ granulation or direct compression. Examples: cornstarch,
glucose, molasses, natural gum (acacia, may be contaminated), celluloses (methylcellulose, CMC, microcrystalline cellulose), gelatins, provide (PVP). Liquid binders are more effective.
↑↑ too hard, ↓ dissolution. ↓↓ soft crumbling tablets.
Disintegrants: ↑ disintegration on gastric fluid contact (critical for dissolution and bioavailability). They draw water to tablet, swell and burst. Examples: cornstarch, potato starch, sodium starch glycolate, celluloses (sodium CMC), clays (veegum, bentonite), cation exchange resins.
A portion can be added with the diluent and another with the lubricant after granulation double disintegration.
Lubricants / antiadherents / glidants: lubricants ↓ friction between tablet and die upon ejection (talc,
magnesium stearate, calcium stearate). Anti-adherents ↓ sticking, adhesion of granules to the punches or die. Glidants ↓ particle friction ↑ powder / granule flow.
Colors / dyes: disguise off-color drugs, product ID. FDC dyes are applied in solution. Lakes are dyes
absorbed on a hydrous oxide (dry powder).
Flavoring agents: only for chewable or mouth dissolving tablets. Flavor oils or powders are ↑ stable,
water soluble flavor are ↓ stable. Maximum: 0.75%.
Artificial sweeteners: only for chewable or mouth dissolving tablets. May come with diluent (mannitol,
lactose). Other agents; saccharin, aspartame.
Adsorbents: hold fluid in apparently dry state. Example: magnesium oxide, magnesium carbonate,
bentonite.
Tablet types and classes
For oral ingestion:
May be mask taste, color, odor, control release, enteric coating, incorporate another drug, avoid incompatibility, ↑ appearance.
Compressed: from powders, crystals or granules with or without excipients. No coating.
Multiple compressed: layered compress tablet granules around previously compressed granules,
then repeat. Compression coated / dry coated made by feeding previously compressed tablet to a machine that compresses an shell around it separate incompatible drugs, provide repeat action / prolonged action.
Repeat-action: multiple compressed tablet where the outer shell rapidly disintegrates in the stomach.
Example: Repetabs, Extentabs. The components of the inner layer are insoluble in the stomach but soluble in the intestine.
Delayed action / enteric coated: delays drug release to prevent stomach destruction, prevent stomach
irritation, or better stomach absorption. Enteric: intact in stomach, release in intestine (e.g. Ecotrin).
Sugar / chocolate-coated: to protect drug from air / humidity, mask taste / odor. Process includes seal
coating (waterproofing), subcoating, syrup coating (for smoothing, coloring), polishing. Disadvantage: time consuming, require expertise, bulky coats.
Film coated: compressed tablets coated with water soluble or insoluble polymer (HPMC, povidone, PEG).
Film is colored, ↑ durable, ↓ chipping, ↓ bulky (3% wt ↑), ↓ time consuming than sugar coating. May contain film former, plasticizer, surfactant, opacifier, sweetner, color, flavor, glossant, volatile solvent.
Air-suspension coated: fed into vertical cylinder and supported by air column (Wurster process) where
the coating solution is applied.
Chewable: disintegrate rapidly when showed or dissolved. Contains flavored and colored mannitol.
Used for children, multivitamins, antacids, antibiotics.
Used in oral cavity
Buccal / sublingual: allow absorption through oral mucosa after dissolution. Avoid gastric destruction or
intestinal ↓ absorption. Examples: sublingual nitroglycerin, buccal progesterone.
Troches / lozenges / dental cones: dissolves slowly in the mouth and provide local effect.
Used to prepare solutions:
Effervescent: made by compressing granular effervescent salts (citric acid, tartaric acid, sodium
bicarbonate) that release CO2 when contacting water. Example: alkalinizing analgesics (Alka-Seltzer, ↑ dissolution, absorption).
Other tablets to prepare solution: dispensing tabs, hypodermic tabs, tab triturates.
Processing problems
Capping: separation of the top or bottom crown from main body of tab. Lamination: separation of tab
into two or ↑ layers. Usually due to air entrapment.
Picking: removal of the surface material by a punch. Sticking: adhesion of material to the die wall. Due
to excess moisture or melting ingredient.
Tablet evaluation and control
General appearance: size, shape, color, odor, taste, surface, texture, physical flaws, consistency,
marking legibility.
Hardness / friability resistance: Hardness affects dissolution / disintegration. Slow dissolved tabs are
harder, vice versa. Hardness tester measure force required to break tab. Friabilators measure weight loss when tabs roll and fall (<1%). Chewable / effervescent tabs are highly friable, require special packaging.
Weight variation: USP standards apply to tabs containing >50 mg drug where drug is > 50% of total
weight.
Content uniformity: USP standards apply if drug <50 mg.
Disintegration: USP test is conducted in vitro. Disintegration time: nitroglycerin (2 min), aspirin (5 min),
most other drugs (<30 min), buccal tabs (4hr), enteric coated (none in 1 hr is simulated gastric fluid, within 2 hr in simulated intestinal fluid).
Dissolution: standards in USP. Increased emphasis on dissolution replaced disintegration for many
drugs.
Aerosols
Pressurized dosage forms that deliver drugs topically or systemically with the aid of liquefied or propelled gas (propellant).
Valve allows pressurized product to be expelled continuously or intermittently when the actuator is
pressed. Dip tube conveys the formulation for the container’s bottom to the valve.
Metered dose inhalers (MDIs): aerosol systems for systemic or pulmonary delivery. They contain fine
drug mist solution or dispersion. 1 Actuation = 1 dose.
Propellants: compressed gases (CO2, N2, NO), ↓ pressure with time due to ↑ head space. Liquefiable gases: saturated hydrocarbons, hydrofluorocarbons, dimethyl ether, chlorofluorocarbons (CFC). CFC
are banned now.
Advantages: push-button dispensing convenience, stability of closed container (protects from light,
moisture, air, microbes), ↓ tampering, wide product range. Disadvantage: propellants are environmental hazard.
Controlled release dosage forms
They release drug slowly. Also known as delayed-release, action, prolonged-action, sustained-release, prolonged-sustained-release, timed-sustained-release, slow-sustained-release, extended-action, extended-release.
Advantages: ↑ compliance, ↓ total drug used, ↓ local or systemic SE, ↓ drug accumulation / potentiation /
loss of activity with prolonged use, ↑ treatment efficiency, rapid condition control, ↑ bioavailability, ↓ level fluctuation, ↓ cost.
Coated beads or granules:
Examples: Theo-Dur Sprinke, Spansules, Sequels,.
Produce drug level similar to multiple dosing.
Non-aqueous (e.g. alcohol) drug solution is coated onto small inert beads or granules (starch/sugar). Beads may be made of drug if dose is ↑. Some granules take no further coating to give immediate release. Otherwise, coats of a lipid (e.g. beeswax) or cellulosic (e.g. ethylcellulose) material are applied. Thickness is varied by varying # of coats to provide SR.
Microencapsulation
Example: Bayer time-release aspirin.
Solids, liquids or gases are encased in microscopic capsules.
Coacervation: most common method of encapsulation. A hydrophilic substance is added to a colloidal
drug dispersion and causes layering and formation of microcapsules.
Film forming substances for coating (natural or synthetic) include shellacs, waxes, gelatin, starches,
cellulose acetate phthalate, ethylcellulose. After the coating dissolves, the drug is immediately available.
Matrix tablets:
Examples: Gradumet, Lontabs, Dospan, Slow-K
Use hydrophilic polymers (methyl cellulose, HPMC), insoluble plastics (polyethylene, polyvinyl acetate, polymethacrylate), fatty compounds (waxes, glyceryl tristearate).
The immediate dose is coated as a top layer.
Osmotic systems:
Example: Oros system (Alza)
Oral osmotic pump composed of a core tablet and semipermeable coating that has a small hole (0.4 mm) produced by laser beam for drug exit. The system requires only osmotic pressure to be effective and is independent of pH.
Drug release rate is controlled by changing surface area, membrane nature, or hole diameter.
Ion-exchange resins:
Example: biphenamine (amphetamine and dextroamphetamine), lonamin (phentermine), Pennkinetic
system.
Ion exchange resins are complexed with drugs by passage of a cationic drug solution through a column that contains the resin. The drug is complexed to the resin by replacement of hydrogen atoms. Then the resin-drug complex is washed and tableted.
Release is dependent on ionic environment in GI and resin properties (↓ pH ↑ release).
Complex formation:
Example: hydroxypropyl-beta-cyclodextrin forms a chemical complex slowly dissolves depending on pH.
Hydrocolloid systems:
Example: Valrelease (SR diazepam) includes hydrodynamically balanced system (HBS). HBS
contains a matrix that is ↓ dense than gastric acid, so it remains buoyant. Multiple hydrocolloid layers swell when contacting gastric acid and slowly erode releasing the drug.
4. Biopharmaceutics and Drug Delivery Systems
Drug transport and absorption
Transport across cell membranes
Cell membrane: is a semipermeable structure composed of lipids and proteins. Proteins, protein bound drugs and macromolecules do not cross cell membranes easily. Nonpolar lipid soluble and smaller molecular weight drugs diffuse through cell membranes faster.
Passive diffusion / partitioning: passive diffusion is dominant within the cytoplasm or in interstitial fluid (Fick’s law). Passive transport across cell membranes involves successive partitioning of solute between aqueous and lipid phase as well as diffusion within phases. Nonionized drugs are more lipid soluble and partition better across cell membranes.
Carrier-mediated transport: Active transport: drug moves against concentration gradient, requires energy, carrier may be selective for drugs that resemble natural substrates, system may saturate at concentrations, process may be competitive. Facilitated diffusion: carrier mediated transport that occurs with a concentration gradient and does not require energy.
Paracellular transport: drug transport across tight junction between cells or channels. It involves diffusion and convective (bulk) flow of water and dissolved molecules
Vesicular transport: the process of engulfing particles by a cell. Only mechanism that does not require water solubility for absorption. Pinocytosis: engulfment of small solute or fluid volumes. Phagocytosis: engulfment of large particles or macromolecules by macrophages.
Endo/Exo-cytosis: movement of macromolecules in and out of the cell.
Transport proteins: (e.g. P-glycoprotein) are embedded in the lipid bilayer of cell membranes. These are ATP energy dependent pumps. Work closely with cytochrome P450 3A4 to intracellullar drug concentration. Substrates: cyclosporin, nifedipine, digoxin.
Routes of drug administration
Parenteral: IV Bolus is directly injected to the blood stream, very quick action / SE. IV infusion:
constant input rate maintains constant plasma concentration. Intra-arterial: to achieve concentration in specific tissue before systemic drug absorption, mostly diagnostic and chemotherapy. IM: rate of
absorption depends on muscle vascularity, drug lipid solubility / matrix. SC: vasculature slow
absorption. Intra-articular: into the joint. Intrathecal: into the spinal cord. Intradermal: into the dermis. Enteral: Buccal / sublingual: allows nonpolar lipid soluble drug absorption, bypassing first pass
metabolism. Peroral: most common, convenient, safe. Disadvantages: inconsistent / incomplete
absorption (gastric emptying, intestinal motility), GI enzyme digestion, acid pH decomposition, GI irritation, first pass metabolism. Absorption is usually by passive diffusion. Duodenum is the main absorption site (villi / microvilli surface area). Residence time (period of contact) is needed for absorption. Double peak: cimetidine or acetaminophen as immediate release on empty stomach produce two peak plasma level. Rectal: drug in solution (enama) or suppository is placed in the rectum. Drugs absorbed in the lower 2/3 bypass the liver first pass metabolism.
Respiratory: Intranasal: as spray or drops for local (decongestant, steroid) or systemic effect. Pulmonary: inhaled perorally (nebulizer, MDE) into pulmonary tree. Particles > 60 um deposit on trachea. Particles > 20 um do not reach bronchioles. Particles 2-6 um reach alveolar ducts. Particles 1-2 um retained in the alveoli. Particles < 0.6 um exhaled, not deposited.
Transdermal (percutaneous): suitable for small lipid soluble molecules (clonidine, nitroglycerin, fentanyl, scopolamine, testosterone, estradiol).
Local activity: topical antibiotics, anti-infectives, antifungals, loacal anesthetics. Minimum systemic absorption.
Biopharmaceutical principles
Physicochemical properties
Drug dissolution: bioavailability rate limiting step for drugs with limited solubility. Diffusion is described by Noyes Whitney equation (similar to Fick’s law).
Drug solubility in a saturated solution is a static equilibrium property. Dissolution rate is a dynamic property with a rate.
Particle size / surface area: inversely related. surface area dissolution rate. For some hydrophobic drugs, particle size aggregation to surface free energy. To prevent aggregate formation, small particles are molecularly dispersed in PEG, PVP (povidone), dextrose. Examples: Griseofluvin molecular dissolution in water soluble carrier (PEG 400) bioavailability.
Partition coefficient: ratio of solubility at equilibrium in nonaqueous solvent (n-octanol) to that in aqueous solvent (water). Hydrophilic drugs ( water solubility) dissolution.
Ionization: ionized form is more polar and more water soluble. Based on Henerson-Hasselbalch equation.
Salt formation: type of salt affects dissolution, bioavailability, duration of action, stability, irritation, toxicity. Soluble salt may be stable than nonionized form (e.g. sodium aspirin vs. aspirin).
Effervescent forms: contains acid drug and sodium bicarobnate, tartaric acid, citric acid. Water is added prior to use. Excess sodium bicarbonate forms an alkaline solution in which the drug dissolves. CO2 is formed by the decomposition of carbonic acid. For weak acids, potassium and sodium salts are more soluble than polyvalent cation salts. For weak bases, common water soluble salts include hydrochloride, sulfate, citrate, gluconate.
Polymorphism: ability to exist in > 1 crystalline form. Polymorphs have different physical properties. Amorphous non-crystalline forms have dissolution.
Chirality: drug exists as optically active stereoisomers or enantiomers different PK / PD. Most chiral drugs are used as racemic mixtures. Example: ibuprofen has R and S enantiomers, only S is active. Hydrates: drug may exist in hydrated, solvated form and anhydrous form. Anhydrous ampicillin dissolves faster than hydrated ampicillin.
Complex formation: Chelates are complexes involving a ring-like structure and a metal. Natural chelates: hemoglobin, cyanocobalamin, insulin). Tetracycline forms a chelate with polyvalent metal ions water solubility absorption. Many drugs adsorb strongly on charcoal or clay (kaolin, bentonite) by forming complexes. Theophylline + ethylene diamine water soluble complex (aminophylline). Many drugs are complexed with cyclodextrins to solubility. Large drug complexes (drug-protein) do not cross cell membranes easily free drug must first dissociate for absorption or glomerular filtration.
Delivery system formulation
Complex formulation bioavailability issues. For oral solid dosage forms, dissolution is the rate limiting step. For CR or SR, release from the delivery system is the rate limiting step.
Solutions: are homogeneous mixtures of solutes dispersed molecularly in a dissolving medium. Aqueous solution is the most bioavailable and consistent form (no dissolution). Oral solutions are used as reference preparations for solid oral forms. Elixir (drug dissolved in hydroalcoholic solution) has bioavailability. Alcohol solubility. However, drug may ppt when elixir is diluted in the GI with food, but absorption is still rapid because of surface area. A viscous drug solution (syrup) may mixing, dilution and GI gastric emptying.
Suspensions: bioavailability from suspension is similar to solutions due to surface area. Suspending agents: hydrophilic colloids (celluloses, acacia, xantham gum). viscosity may have issues as syrups above.
Capsules: Hard gelatin caps are simple (contain powders) and preferred new drugs early clinical trials. Soft gelatin caps contain nonaqueous solution, suspension or powder. It may have bioavailability if water miscible vehicle is used (e.g. lanoxicaps), and vice versa. Aging and storage may affect gelatin shell moisture content and bioavailability.
Compressed tablets: ratio of excipients : drug possiblity of excipients affecting bioavailability. Lubricants are usually hydrophobic, water-insoluble drug surface wetting dissolution and bioavailability. Surfactants dissolution and bioavailability.
Modified release dosage forms: products that alter the rate or timing of drug release. More stringent quality control is used. Dose dumping, abrupt drug release, is a problem. Allows in dosing frequency. They provide more flat consistent plasma concentration that avoids toxicity and lack of efficacy. A loading dose may be used. Delayed release control the timing of release, e.g. enteric coating.
Transdermals: have occlusive backing film to prevent TEWL to hydration and permeation. Concentration gradient is maintained by a drug reservoir.
Targeted drug delivery: place the drug at or near the receptor (e.g. specific cell such as tumor, organ, tissue). Systems include macromolecular drug carriers (proteins), liposomes, nanoparticles, monoclonal antibodies.
Inserts and implants: drug is impregnated into a biodegradable material and released slowly. Inserted into vaginal, buccal cavity, skin. Example: l-norgestrol implant is inserted in the upper arm for 5-year contraception.
6. Basic Pharmacokinetics
Introduction
Rates and orders of reactions
Reaction rate: velocity of the reaction
Reaction order: way in which the drug (reactant) affects the rate
Zero order reaction: drug concentration changes with time at a constant rate. Rate constant = Ko
(concentration / time; mg/ml/hr). Linear correlation of concentration vs. time with slope=Ko and intercept = Co.
First order reaction: change of concentration with time is the product of the rate constant and
concentration of the remaining drug. Drug concentration decreases by a fixed percent in each time unit. Linear correlation of log concentration with time. Rate constant )K) = 1/hour. Half life t1/2=0.693/k.
Models and compartments
Model: mathematical description to express quantitative relations in a biological system. Compartment: group of tissues with similar blood flow and drug affinity.
Drug distribution
Drugs distribute quickly to tissues with ↑ blood flow
Drug cross capillaries by passive diffusion and hydrostatic pressure. Drugs easily cross the capillaries of the kidney glomerulus.
Brain capillaries are surrounded by glial cells forming a thick lipid membrane (BBB) ↓ diffusion of polar and ionic hydrophilic drugs.
Tissue accumulation due to drug/tissue physicochemical or affinity.
Tetracycline accumulate in bone (calcium Complexation).
Plasma protein binding: results in a big complex can’t cross membranes. Albumin: major plasma
protein for drug binding. Alpha1-glycoprotein: binds basic drugs (e.g. propranolol) in the plasma. ↑ bound drugs (e.g. phenytoin) can be displaced by other ↑ bound drug ↑ free unbound drug in effect / toxicity.
One-compartment model
Intravenous bolus injection
Very rapid drug entry. Rate of absorption is negligible.
Entire body is one compartment all tissue equilibrate rapidly.
Drug elimination: first order kinetics. Elimination rate constant = renal excretion rate constant +
metabolism (biotransformation) rate constant
Some controlled release oral drugs have zero absorption rate constant.
Apparent volume of distribution (Vd): hypothetical volume of body fluid in which drug is dissolved. Vd
is needed to estimate amount of drug in the body (Db) relative to concentration in plasma (Cp).
Cp = Db / Vd
More drug distribution into tissues ↓ Cp ↑ Vd
Single oral dose
Rapid absorption then elimination, both with first order kinetics.
Time to reach max concentration (tmax) depends only on absorption and elimination rate constants but not on Vd or Db.
AUC: calculated using trapezoidal rule by integrating the plasma drug concentration over time. AUC
depends on Do, Vd, elimination K but not absorption K.
Lag time: at the beginning of systemic drug absorption, e.g. due to delay in gastric emptying.
Intravenous infusion
Absorption: zero order. Elimination: first order (when infusion stops)
Steady state concentration (Css): target plateau drug concentration where fraction of drug absorbed =
fraction of drug eliminated.
Loading dose (DL): initial IV bolus dose to produce Css as rapidly as possible. Start IV infusion at the
same time.
DL: amount of drug that, when dissolved in the apparent Vd, produces the desired Dss. Reaching 07% of
Css without DL takes ~ t1/2. Time to reach Css depends on the drug elimination half life.
IV infusion: ideal for drugs with narrow therapeutic window (controls Cp).
Intermittent intravenous infusion
Drug is infused for short periods to prevent accumulation and toxicity. Used for aminoglycosides (e.g. gentamicin).
Multiple doses
Drug is given intermittently in multiple-dose regimen for continuous or prolonged therapeutic activity to treat chronic disease.
Give new dose before previous dose completely eliminated Cp accumulation ↑ to Css. At steady state: Cp fluctuations between a max and a min (C∞min-max).
Superposition principle: assumes that previous drug doses have no effect on subsequent doses total
Cp = cumulative residual Cp from each previous dose.
Dosing rate = dose size (Do) / dose interval (e.g. X mg/hr).
Same dosing rate same average Css but may be different (C∞min-max).
Some AB multiple rapid IV bolus injections.
Oral immediate release drug products (multiple doses) rapid absorption, slow elimination.
Maintenance dose (DM): after loading dose to maintain Cp at Css. If DM dosing interaval = elimination
Multi-compartment models
Drug distributes into different tissue groups at different rates. Tissues with ↑ blood flow equilibrate rapidly with the drug.
Two-compartment model (IV bolus): First, rapid distribution into highly perfused tissue (central compartment) rapid decline in Cp (distribution phase). Both are first-order processes. Then, slow
distribution into peripheral tissues (tissue compartment) slow decline in Cp after equilibration (elimination phase). Vd = Vd at steady state + central + tissue compartment volumes.
Two-compartment model (oral): two-compartment ONLY if absorption is rapid but distribution is slow. Models with additional compartments: example of a third compartment: deep tissue space. If frequent
interval dosing third compartment accumulation.
Elimination rate constant: two constants; one for elimination from central compartment, the other for
elimination after complete distribution.
Nonlinear pharmacokinetics
Also known as capacity-limited, dose-dependent, or saturation PK. Result from the saturation of an enzyme of carrier-mediated system. Do not follow first-order kinetics as the dose ↑.
AUC or drug excreted in urine are not proportional to dose Elimination t1/2 may ↑ at ↑ doses.
Michaelis-Menten equation: describe velocity of enzyme reactions in nonlinear PK. It described rate of
change of Cp after IV bolus. If Cp is ↑ the equation is a zero-order rate of elimination. If Cp is ↓↓ first-order.
Note that first-order PK = linear PK
Clearance
Total body clearance (Cl
T)
ClT = drug elimination rate / Cp = K x Vd
ClT and Vd are independent variables. T1/2 is a dependent variable.
A constant volume of the Vd is cleared from the body per unit time. First order PK: ClT = renal clearance + non-renal (hepatic) clearance
↓ ClT ↑ t1/2. ↑ Vd ↑ t1/2
Renal drug excretion
Major route of elimination for: polar drugs, water-soluble drugs, drugs with ↓ MWt (<500), drugs that are biotransformed slowly.
Glomerular filtration: passive process that filters small molecules. Drugs that are bound to plasma
proteins are too big to be filtered. Creatinine and inulin undergo only glomerular filtration (not tubular secretion or reabsorption) used to measure glomercular filtration rate (GFR).
Tubular reabsorption: passive process that follow Fick’s first law of diffusion to reabsorb lipid-soluble
and non-ionized weak electrolytes drugs back to the systemic circulation. If ionized or water-soluble excreted in the urine. Diuretic ↑ urine flow ↓ time for reabsorption ↑ drug excretion.
Active tubular secretion: carrier-mediated active transport system that requires energy. Two systems:
for weak acids and weak bases. Competitive nature: e.g. probenecid (weak acid) compete for the same system as penicillin ↓ penicillin excretion. Another example: p-aminohippurate. Measure using
effective renal blood flow (ERBF).
Renal clearance (Cl
R)
It is the volume of drug in the plasma remove by the kidney per unit time. ClR = rate of drug excretion / Cp = ml/minute.
Clearance ratio: relates drug clearance to inulin clearance (GFR). If = 1 filtration only. If < 1
