Pharmaceutics- general area of study concerned with the formulation manufacture,

stability, and effective of pharmaceutical dosage form.

Proper design and formulation of a dosage form
-requires consideration of physical chemical, and biologic characteristics of all drug
substances and pharmaceutical ingredients.

Drug and pharmaceutical materials must be compatible to practice a product that is
1. stable
2. efficacious
3. attractive
4. easy to administer
5. safe

The need for dosage forms
potent nature and low dosage
-precludes any expectation that the general public could safely obtain the
appropriate dose of a drug from the bulk material.

Reasons for the need for dosage forms
1.) to protect the dosage substances from the destructive influences of atmosphere
oxygen or humidity (coaled tablets, sealed ampule)
2.) to protect the drug from gastric acid after oral administration (enteric-coated
drugs)
3.) to conceal bitter salty or offensive taste or odor of the drug (capsules, coaled
tablets, flavored syrups)
4.) to provide liquid preparations of substances either unstable or insoluble
(suspension)
5.) to provide clear dosage forms of substances (syrups, solution)
6.) to provide rate controlled drug action (various controlled-released tablets,
capsules, and suspensions)
7.) to provide optimal drug action from topical administration sites
8.) to provide for insertion of drug into one of the body orifices(rectal or vaginal)
9.) to provide for placement of drugs directly into bloodstream or body
tissues(injections)
10.) to provide optimal drug action through inhalation therapy(inhalants and inhalation
aerosols)
General Considerations in Dosage Form Design
Master Formula-formulation that best meets the goals for the product
Before a medicinal agent us formulated into one or more dosage forms, among other
factors considered are such therapeutic matters as the nature of the illness, the manner
in which it is treated (locally or through systemic action), and the age and anticipated
condition.
Tablets and capsules-most desirable and convenient in oral and systemic use and self
administration medication
For infants and children younger than 5 years old, pharmaceutical liquids are
preferred for oral administration
Chewable tablets- formulated for people who have difficulty in swallowing
Capsules more easily swallowed than tablets
Medications for elderly 1. Oral liquids 2. Drugs which are easily identified

Pre-formulation Studies
Early stages of formulation
Collection of basic information on the physical and chemical characteristics of
drugs
Collected information provides FRAMEWORK for the drugs combination with
pharmaceutical ingredients in the fabrication of a dosage form

Physical Description
Chemical Properties-Structure, form and reactivity
Physical Properties- Physical description, particle size, crystalline, melting pt.,
and solubility
Biologic properties-relate its ability to get to a site of action and elicit a biologic
response
o Solids-usually used
o Liquids-much lesser extent than solid(b/c of volatility)
o Gases- even less frequent
Heat of Vaporization
Amount of heat absorbed when 1g liquid evaporates
The use of vapor is important in operation of implantable pumps delivering
medications as well as in AEROSOL Dosage forms
Used in inhalants
Used to determine time of usefulness
Melting Point Depression
Phenomenon commonly used to determine the purity of a drug substance and
compatibility of various substance before inclusion in the same dosage form
If not pure=change in melting point
Phase rule
Phase diagram-often constructed to provide a visual picture of solid and liquid
phases in binary, ternary, and other mixtures.



Particle size
-affects certain physical and chemical properties of drugs substances.
-Affects sedimentation rates and flow characteristics
-significantly influences the oral absorption profiles of certain drugs.
-satisfactory content uniformity depends to a large degree to particle size and
EQUAL DISTRIBUTION of active ingredient throughout formulation.

Polymorphism
-compounds may occur in non-crystalline (or amorphous) or crystal forms
-evaluation of crystal structure, polymorphism, solvate form is an important
preformulation activity.



Various Techniques used to determine crystals
1. hot stage microscopy
2. thermal analysis
3. infrared spectroscopy
4. x-ray diffraction

Solubility
important physiochemical property
a drug must possess some aqeous solubility for therapeutic efficacy
frequent modification of drug into salt or ester forms is frequently used to increase
solubility
determined by the equilibrium solubility method
chemical analysis of drug content in solution- determine degree of solubility.
Smaller particle size increases solubility
pH is adjusted to enhance solubility (electrolytes)

Dissolution
rate which a drug becomes available to the organism
time it takes for the drug to dissolve in the fluids at the absorption site
rate limiting step in absorption
affect overall bio availability of the drug from the dosage form
increased or decreased by particle size
use of highly water soluble salt of the parent substance
-most effective means of obtaining higher dissolution rate

Determined by 2 methods:

1. constant surface method- intrinsic dissolution rate
2. particulate dissolution- suspension of an agent is added to a fixed amount of solvent
without exact control of surface area

Intrinsic dissolution rate- characteristic of each solid compound and a given solvent in a
fixed experimental condition

Membrane permeability
passage of drug molecules across biologic membranes
a drug must cross biologic membrane to elicit a biologic response
biologic membrane-acts a lipid barrier to most drugs and permits the absorption of
lipid soluble substances by passive diffusion.
Partition Coefficient
Inherent in this procedure is the selection of appropriate extraction solvents,
drug stability, use of salting-out additives, and environmental concerns
Octanol-partition coefficient is commonly used in formulation development
pKa or Dissociation Constants
Extent of dissociation or ionization of drug substances
Extent of ionization: important effect on the formulation and
pharmacokinetic parameters of the drug
Extent of ionization also has a strong effect on absorption, distribution, and
elimination
pKa: usually determined by potentiometric titration
Drug and drug product stability
Evaluation of the physical and chemical stability of the pure drug substance
Drug stability: mechanisms of degradations
Chemical instability of medical agents may take many forms because the
drugs in use today are such diverse chemical constitution.
Hydrolysis and Oxidation: most frequently encountered destructive
processes (chemically)
Hydrolysis: solvolysis process in which (drug) molecules interact with water
molecules to yield breakdown products
Hydrolysis most important single cause of drug decomposition: this is due
to the great number of medicinal agents are esters or contain such other
groupings as substituted amides, lactones, and lactams, which are susceptible
to the hydrolytic process
Oxidation: loss of electrons from atom or molecule. Each electron is accepted
by other molecule, the recipient
Oxidation is synonymous to the loss of hydrogen (dehydrogenation) from a
molecule
Free chemical radicals: molecules or atoms containing one or more unpaired
electrons such as O2 and free OH; these chemicals tend to take electrons
from other chemicals, thus oxidizing the donor
Many of the oxidative changes in pharmaceutical preparations have the
character of autoxidation: autoxidation occur spontaneously under the
initial influence of atmospheric oxygen and proceed SLOWLY and then more
RAPIDLY
Autoxidation: a type of chain reaction commencing with the union of oxygen
with the drug molecule and continuing with a free radical of this oxidized
molecule participating in the destruction of other drug molecules and so
forth
Decomposition may be prevented in other liquid drugs by suspending them
in a nonaqueous vehicle rather than dissolving them in an aqueous solvent
Antioxidants: reacts with one or more compounds in the drug to prevent
progress of the chain reaction, thus diverting the oxidative process and
preserving the stability of the drug
Antioxidants act by being the molecule oxidized rather than the drug being
protected
For easily oxidizable drugs, the formulation pharmacist may stabilize the
preparation by the selective exclusion from the system of oxygen, oxidizing
agents, trace metals, light, heat and other chemical catalysts
Antioxidants, chelating agents, and buffering agents may be added to create
and maintain a favorable pH
Kinetics and shelf life
Stability is the extent to which a product retains within specified limits and
throughout its period of storage and use the same properties and
characteristics that it possessed at the time of its manufacture
Half-life: the time taken for the radioactivity of a specified isotope to fall to half
its original value
Five Types of Stability
Chemical: each active ingredient retains its chemical integrity and labeled
potency within the specified limits.
Physical: the original physical properties including appearance, palatability,
uniformity, dissolution and suspendability are retained.
Microbiology: sterility or resistance to microbial growth is retained according
to the specified requirements. Antimicrobial agents retain effectiveness
within specified limits.
Therapeutic: The therapeutic effect remains unchanged.
Toxicologic: no significant increase in toxicity occurs.
Reaction rate
Description of the drug concentration with respect to the time
Order: the exponent of the individual concentration term in the rate
expression
Overall order: Sum of the order of the exponents of the concentration terms
of the rate expression
Zero order and first order: most commonly encountered in pharmacy
Q10 method of shelf life estimation
Lets the pharmacist estimate shelf life for a product that has been stored or is
going to be stored under different set of conditions
Q10 = e
(Ea/R)(1/T + 10) (1/T)

Pharmaceutical Ingredients and Excipients (table siya so check nyo nalang)

Harmonization of Standards
Pharmaceutical industry is multinational
Standards for each drug substance and excipient used in pharmaceuticals are
contained in pharmacopeias. For new agents, in an application for regulatory
approval by the governing authority
4 pharmacopeias w the largest international use are
o USP-NF
o British pharmacopeia
o European pharmacopeia
o Japanese Pharmacopeia
The goal of harmonization is an ongoing effort by corporate representatives and
international regulatory authorities

Appearance and Palatability
Most drug substances in use today are unpalatable and unattractive in their natural
state
Their preparations present them to the patient as colorful, flavorful formulations
attractive to the sight, smell and taste
These qualities have virtually eliminated the natural reluctance of many patients
to take medications because of disagreeable taste and odor
The proper combination of flavor, fragrance, and color in a pharmaceutical
product contributes to its acceptance
An electronic tongue is used to aid in providing a global taste fingerprint during
formulation development.
o It provides info on bitterness levels and the stability of flavors

Flavoring pharmaceuticals
The flavoring of pharmaceuticals applies to liquids intended for oral
administration
The 10,000 taste buds, roof of the mouth, cheeks and throat have 60 to 100
receptor cell each
These receptors interact w molecules dissolved in the saliva and produce a
positive or negative taste sensation
The addition of these flavorings can mask the disagreeable taste
Capsules or coated tablets are easily swallowed w no contact between the drug
and taste buds
However, chewable tablets are usually sweetened and flavored to improve
acceptance
The medicinal chemist and the formulation pharmacist are well acquainted w the
taste and characteristics of certain types of drugs and try to mask their unwanted
taste
Low molecular weight salts are salty
High molecular weight salts are bitter
In organic compounds, an increase in hydroxyl groups (-OH) seems to increase
sweetness of the compound
Sucrose is sweeter than glucose
Organic esters, alcohols and aldehydes are pleasant to the taste and since many of
them are volatile, they also contribute to the odor thus the flavor of the
preparation in w/c they are used
Nitrogen containing compounds esp plant alkaloids are extremely bitter (quinine)
Some nitrogen containing compounds like aspartame are extremely sweet
D-glucose sweet
L-glucose salty
Saccharin very sweet
N-methyl-saccharin tasteless
Fruits or citrus flavors are used to combat sour or acid tasting drugs
The age of the patient should also be considered in selecting flavoring agents
Flavors can degrade as a result of exposure to light, temp, oxygen, water etc
Different types of flavors:
o Natural flavor
o Artificial flavor
o Spice aromatic vegetable substance
Commercial flavor designations (ABC is a flavor name, example: Cherry)
o Natural ABC flavor all components derived from ABC
o ABC flavor, natural atleast one component and artificially derived from
ABC
o ABC flavor, WONP all components natural. Atleast one component
derived from ABC
o Natural flavor, ABC type -all components natural, no components derived
from ABC
o ABC flavor, artificial all components are artificial
o Conceptual flavors may contain artificial flavors. No reference point
Keep in mind that it is possible to add flavors, but once it is added, it is too late to
remove it
o Water soluble flavors generally start at 0.2% for artificial and 1-2% for
natural
o Oil soluble flavors start at 0.1% in finished product for artificial and
0.2% for natural
o Powdered flavors start at 0.1% in finished product for artificial flavors
and 0.75% for natural

Coloring pharmaceuticals
Coloring agents are used for esthetics
Certified additives are classified according to their approved use
o FD%C color additives used in food, drugs and cosmetics
o D&C color additives, some of which are approved for use in drugs, some
in cosmetics
o External D&C color additives use is constricted to external parts of the
body, not including the lips or any body surface covered by mucous
membrane
In 1970, FD&C Red No 2 drew attention because Russia reported that this color
also known as Amaranth, caused cancer in rats
FD&C Red No 4 only used in externally applied drugs and cosmetics

Preservatives
In addition to the stabilization of pharmaceutical products against chemical and
physical degradation, certain liquid and semisolid preps must be preserved
Preservative Selection
The preservative prevents the growth of the type of microorganisms considered
the most likely contaminants of the preparation
Soluble enough in water to achieve adequate concentrations
Capable of penetrating the microorganism and destroying its integrity
The required concentration of the preservative does not affect the safety or
comfort of the patient
It has adequate stability and will not be reduced in concentration by chemical
decomposition or volatilization
Completely compatible with all other formulative ingredients
Does not adversely affect the container or closure

General preservative consideration
Microorganisms include molds, yeasts and bacteria, with bacterial generally
favoring a slightly alkaline medium and the others an acid medium
To be effective, a preservative agent must be dissolved in sufficient concentration
in the aqueous phase of a preparation
The preservative selected must be largely dissociated at the PH of the formulation
being prepared
Acidic preservatives like benzoic, boric and sorbic acid are more undissociated
and thus more effective as the medium is made more acid
Alkaline preservatives are more effective in alkaline media than acid or neutral
media