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.
Topicals / systemic: drug delivery through skin / mucosa / rectum, final formulation in phase III.
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

f 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 preapproval 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 (120×120 = 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.

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
Nonpolar molecules: perfect symmetry and dipole moment = zero. Example: carbon tetrachloride.

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 are shear thinning but they
do not recover viscosity after shear is removed, i.e., structural recovery is slow 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.

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