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PHARDOSE LEC  Specific for glass:

 Light-transmission test
CHAPTER 3: CURRENT GOOD MANUFACTURING AND  Specific for plastics:
COMPOUNDING PRACTICES  Light-transmission test
 Vapor transmission test
 Toxicity studies
 Specific for aerosols:
Compounding
 Valve
 Preparation of components into a drug  Actuator
product:  Metered-dose
 As the result of a practitioner’s  Particle size
prescription drug order  Spray characteristics
 For the purpose of, or as an  Leak testing
incident to, research, teaching, or  Specific for parenterals:
chemical analysis  Sterility
 Includes the preparation of limited amounts  Permeation test
of drugs or devices
According to USP
Manufacturing
 Container
 Production, preparation, propagation,  Holds the article and may/may not
conversion, or processing of a drug or be in direct contact with the article
device, either directly or indirectly, by  Immediate container
extraction from substances of natural origin  In direct contact with the article
or independently by means of chemical or  Closure
biological synthesis  Part of the container
 Includes:
Classification of containers according to their ability
 Packaging or repackaging
to protect their contents from external conditions:
 Labeling or relabeling
 Well-closed container
CGMP
 Protects the contents from
 Current Good Manufacturing Practices extraneous solids
 Protects the contents from loss
under ordinary conditions of
handling, shipment, storage, and
Labeling of Pharmaceuticals distribution
 Tight container
Labeling is essential for:  Protects the contents from
contamination by extraneous
 Product stability (storage conditions)
liquids, solids, or vapors
 Efficacious use
 Protects the contents from loss,
efflorescence, deliquescence, or
evaporation
Packaging of Pharmaceuticals  Hermetic container
 Impervious/resistant to air or any
Tests performed depending on the intended use and other gas under the ordinary or
type of container: customary conditions of handling,
shipment, storage, and distribution
 Physicochemical tests  Those sterile are generally used to
 Drug compatibility hold preparations intended for
 Drug stability injection or parenteral
 Leaching and/or migration tests administration

Lacorte, Aries S. 3D-PH | PHAR 3


 Single-dose container Light-resistant containers
 Quantity of drug contained is
intended as a single dose and  To protect pharmaceuticals from
when opened cannot be resealed photochemical deterioration
with assurance that sterility has  Amber glass or light-resistant opaque
been maintained plastics
 Maximum volume: 1000 mL  UV absorbers may be added to plastic to
 Without antimicrobial/preservative decrease the transmission of short UV rays
ingredient  Must meet the USP standards which define
 Fusion-sealed ampules, pre-filled the acceptable limits of light transmission at
syringes, cartridges any wavelength of light between 290 and
 Multiple-dose container 450 nm
 Hermetic container that permits  Penetration of light to containers
withdrawal of successive portions  Amber glass: 5%
of the contents without changing  Flint glass: 2%
the strength or endangering the  Plastic: 50%
quality or purity of the remaining
portion Classification of glass
 Maximum volume: 30 mL
Type Description Use
 “Vials”
I Highly resistant, Parenterals
 Contain more than a single unit or
borosilicate glass
dose of the medication
II Treated soda-lime glass Parenterals
TABLETS, CAPSULES, AND ORAL LIQUIDS III Soda-lime glass Parenterals
MAY BE PACKAGED IN SINGLE-UNIT OR NP General purpose soda-lime Non-
MULTIPLE-UNIT CONTAINERS glass parenterals

Single-unit packages Classification of plastics

 Advantages: Type Description Remarks


 Positive identification of each 1 Polyethylene  Safe for food
dosage unit and reduction of Terephthalate
medication errors (PET)
 Reduced contamination of the 2 High Density  Safe for food
drug to its protective wrapping Polyethylene
 Reduced dispensing time (HDPE)
 Greater ease of inventory control 3 Polyvinyl chloride  Very hard
in the pharmacy or nursing station (PVC)  Used in furnitures
 Elimination of waste through 4 Low Density  Safe for food
better medication management Polyethylene
with less discarded medication (LDPE)
 Packaging materials may be combinations 5 Polypropylene  Safe for food
of paper, foil, plastics, or cellophane 6 Polystyrene  Leach with food
 Solid dosage forms: (“Styrofoam”)  Looks like clam
 Clear plastic or aluminum blister 7 Other  Contains BPA,
wells which mimics and
 Most popular method of single- disrupts hormones
unit packaging (estrogens)
 Oral liquids  Looks like glass
 Paper, plastic, foil cups, or pre-
packaged in glass containers (with
threaded/crimpled aluminum caps)

Lacorte, Aries S. 3D-PH | PHAR 3


Problems encountered in the use of plastics in  Between 8o and 15oC (46o and
packaging 59oF)
 Room Temperature
 Permeability  Between 20o and 25oC (68o and
 Atmospheric oxygen and moisture 77oF)
vapor  Between 15o and 30oC (59o and
 Leaching 86oF)
 Constituents of the container go  Warm
with the article  Between 30o and 40oC (86o and
 Occurs when liquid or semi-solid 104oF)
dosage forms are packaged in  Excessive Heat
plastic  Above 40oC (104oF)
 Influenced by: temperature,
solubilizing effects of liquid Protection from Freezing
contents, excessive agitation
 Remedy: plasticizers, stabilizers,  Protects the product from:
antioxidants  Freezing
 Sorption  Risk of breakage of the container
 Article goes with the constituents  Loss of strength or potency
of the container  Destructive alteration of the
 Considerations: absorption, dosage form
adsorption
 Influenced by: chemical structure
of article, physicochemical
properties of polymer
 Light-transmission
 Alteration of the container upon storage

Child-resistant/Adult-senior Use Packaging

 Child-resistant container
 Significantly difficult for children
under 5 years of age to open or to
obtain a harmful amount of its
contents
 Not difficult for normal adults to
use properly
 Child-proof closures
 Shown to have significant potential
for causing accidental poisoning in
youngsters
 Aspirin products, certain
household chemicals

Storage of Pharmaceuticals

Terms employed for the desired storage conditions:

 Cold
 Between 2o and 8oC (36o and 46oF)
 Refrigerator
 Cool

Lacorte, Aries S. 3D-PH | PHAR 3


PHARDOSE LEC  To provide rate-controlled drug
action
CHAPTER 4: PHARMACEUTICAL AND FORMULATION  Ointments, Creams, Transdermal Patches
CONSIDERATIONS  To provide optimal drug action
from topical administration sites
 Suppositories
 To provide for insertion of a drug
Pharmaceutics
into one of the body’s orifices
 Study on the formulation, manufacture,  Injections
stability, and effectiveness of  To provide placement of drugs
pharmaceutical dosage forms directly in the bloodstream or body
tissues
Requirements of a proper design and formulation of  Inhalants, Aerosols
dosage forms  To provide for optimal drug action
through inhalation therapy
 Consideration of drug substances
 Physical, chemical, biological General Considerations in Dosage Form Design
characteristics
 Must be compatible with one  Determine desired product type
another (stable, efficacious,  Framework for product
attractive, easy-to-administer, development
safe)  Develop and examine initial formulations of
 Manufactured under appropriate the product
measures of quality control and  Drug release profile bioavailability
packaged in containers  Clinical effectiveness
 Labeled to promote correct use  Pilot plant studies
and stored under conditions to  Production scale-up
maximize shelf-life  Master formula
 Formulation that best meets the
The Need for Dosage Forms goals of the product

 Coated tablets Factors to consider before formulation of a


 To protect the drug substance medicinal agent in one or more dosage forms
from the destructive influences of
atmospheric oxygen or humidity  Therapeutic matters
 Enteric-coated tablets  Nature of illness
 To protect the drug substance  Route of administration
from the destructive influence of  Local or systemic
gastric acid after oral  Age
administration  Anticipated condition of the patient
 Capsules, Syrups
Three ways for the liquid drug be given in solid form:
 To conceal the bitter, salty, or
offensive taste or odor of a drug  Sealed in soft gelatin capsule
substance  Developed into a solid ester or salt form
 Suspensions suitable for tablets/capsules
 To provide liquid preparations of  Mixed with a solid or melted semi-solid
substances that are either materials (melted mixture is poured into
insoluble or unstable in the desired hard gelatin capsules)
vehicle
 Solutions, Syrups Pharmaceutical Ingredients
 To provide clear liquid dosage
forms of substances  Excipients
 Controlled-release tablets

Lacorte, Aries S. 3D-PH | PHAR 3


Lacorte, Aries S. 3D-PH | PHAR 3
Lacorte, Aries S. 3D-PH | PHAR 3
Lacorte, Aries S. 3D-PH | PHAR 3
Lacorte, Aries S. 3D-PH | PHAR 3
Lacorte, Aries S. 3D-PH | PHAR 3
PREFORMULATION STUDIES  Substances that can exist in more
than one crystalline form
Physical Description  Different physicochemical
properties
 Physical Description  Important: Crystal structure, polymorphism,
 Particle size and solvate form
 Crystalline structure  Microscopy
 Melting point  Infrared (IR) spectroscopy
 Solubility  Thermal analysis
 Chemical properties  X-ray diffraction
 Structure
 Purity
 Identification and evaluation for
chemical, physical, and biologic Solubility
properties
 Drug must possess aqueous solubility for
Microscopy examination therapeutic efficacy
 Determined by equilibrium solubility
 Particle size method
 Particle size can affect:  An excess of the drug is placed in a
 Dissolution rate solvent and shaken at a constant
 Bioavailability temperature over a long period
 Content uniformity until equilibrium is obtained
 Stability
 Taste Solubility and Particle Size
 Texture
 Flow properties  Small particle size, increased solubility,
 Absorption greater surface area
 Sedimentation rate
Solubility and pH
Melting Point Depression
 Critical: Solubility and stability
 Purity and compatibility  Liquid products
 Pure substance: Sharp melting  Adjustment of pH of the solvent
point facilitates solubility
 Impure substance: Depressed  Weak acidic/basic drugs: May
melting point require extremes in pH that are
outside physiologic limits or that
Heat of Vaporization may cause stability problems

 Important for: Nasal inhalants, Aerosols, Dissolution Rate


Volatile drugs, Implantable pumps
 Important: Time of the drug to dissolve
Phase Rule  Can be increased by
 Decreasing the particle size of the
 Phase diagrams drug
 Existence and extent of the  Use of highly water-soluble salt of
presence of solid and liquid phases the parent substance
in binary, ternary, and other  Two methods in determining dissolution
mixtures rates:
 Important: Melting point 1. Constant surface method
 Intrinsic dissolution rate
Polymorphism

 Polymorphs

Lacorte, Aries S. 3D-PH | PHAR 3


 Characteristic of the Dissociation Constants (pKa)
compound and solvent
under fixed conditions  Drug ionization: Strong effect on
2. Particulate dissolution formulation and pharmacokinetic
 Weighed amount of parameters of the drug
powdered samples and  Determined by potentiometric titration
dissolution medium  Predicting precipitation in
 To study the influence of admixtures
particle size, surface area,  Calculating solubility of drugs at
excipients on the active certain pH
agent
 Fick’s laws of diffusion
 Describes the relationship of
diffusion and dissolution of the
active drug in the dosage form and Hydrates and Solvates
when administered in the body
 1st law: Relates to a steady-state  Hydrates: Substance + water
flow  Solvates: Substance + solvent
 2nd law: Related to a change in
concentration of drug with time or HYDRATES AND SOLVATES MUST BE
non-steady-state flow PACKAGED IN TIGHT CONTAINERS

Membrane Permeability  Hygroscopic powders: Tend to absorb


moisture from air
 Everted intestinal sac
 Deliquescent powders: Absorb moisture
 Determines degree and rate of
from air and may liquefy
passage of drug through the
 Efflorescent powders: May give up water of
membrane sac by passive and
crystallization and may become damp or
active transport
pasty
 Early assessment of passage of drug
molecules across biologic membranes Organic Salt Considerations
 To produce a biologic response:
Drug molecule must first cross a  Salts increase aqueous solubility of weak
biologic membrane acidic/basic drugs
 Biologic membrane (lipid barrier):  When dissolved:
Permits absorption of lipid-soluble  Ionized potion
substance by passive diffusion  Unionized portion: exerts effect
 Molecule’s lipophilic character:
Measured by oil-water coefficient Organic Ester Considerations
(Partition coefficient)
 Data that provides indication of absorption  Ester: “Base” form of the drug
 pKa  Acetate esters
 solubility  Succinate esters
 dissolution rate  Considerations:
 Solubility
Partition Coefficient  Stability
 Resistance to degradation upon
 Measures molecule’s lipophilic character administration
 Selection of appropriate:  Prodrug
 Extraction solvents
 Drug stability Potency-Designated API
 Salting-out additives
 Environmental conditions  Antibiotics, endocrine products,
biotechnology-derived products, biologics

Lacorte, Aries S. 3D-PH | PHAR 3


 Expressed in:  Chemical
 Units of activity  Active ingredient retains chemical
 Micrograms per milligram (ug/mg) integrity and labeled potency
within the specified limits
Complex Organic Molecules  Important: storage conditions,
proper container, interactions
 Proteins  Must know reaction order and rate
 Unstable molecules and may  Physical
require special handling  Original physical properties
 Potent and used in low  Appearance
concentrations  Uniformity
 Factors:  Dissolution
 pH: Pain at injection site is of  Suspendability
importance  Microbiologic
 Chelating agents: To bind trace  Sterility/resistance to microbial
metals and minimize rates of growth
degradation  Therapeutic
 Antioxidants: Oxidation, which is a  Therapeutic effects remain
factor of degradation unchanged
 Preservatives: Important for  Toxicologic
multiple-dose vials  No significant increase in toxicity
 Stablizers: Polyols occurs
 Tonicity-adjusting agents:
Dextrose, NaCl for isotonicity

Mechanisms of degradation

STABILITY STUDIES  Hydrolysis (solvolysis process)


 Drug molecules interact with water
Stability molecule to yield breakdown
product
 Extent of product retains within specified
 Susceptible: substituted amides,
limits and through its period of storage and
lactones, lactams
use
 Oxidation
Importance of Drug Stability  Loss of electrons from an atom or
molecules
 Preclinical and clinical trials  Involves free radicals (molecules or
 For true and accurate assessment atoms containing one or more
of the drug/drug product unpaired electrons)
evaluated  Susceptible: aldehydes, alcohols,
 Marketed drug product phenols, sugars, alkaloids,
 For the safety and effectiveness unsaturated fats and oils
when distributed and during the  Polymerization
entire course of its shelf-life and  Reaction between two or more
use identical molecules with resultant
formation of new and generally
Stability studies conducted in the preformulation larger molecule
phase:  Formaldehyde
 Decarboxylation
 Solid-state of the drug alone  Decomposition of RCOOH and
 Solution phase release of CO2
 Drug with the expected excipients  Deamination
Five types of stability

Lacorte, Aries S. 3D-PH | PHAR 3


 Removal of nitrogen-containing Q10 Method
group from organic amine
 Insulin  Estimation of shelf-life of the product that
has been stored under different set of
Enhancing Stability conditions

 Added to create and maintain favorable pH Stability Testing Considerations


 Antioxidants
 Chelating agents  Product containers, closures, and other
 Buffering agents packaging features
 Drugs subjected to hydrolysis  Parenteral and other sterile products must
 Water-liable drugs (REMEDY: meet sterility test standards
Waterproof protective coating)
 Liquid formulation (REMEDY: Two types of stability testing
Water is replaced by substitute
 Accelerated Stability Testing
liquids or suspending in non-
 Use of exaggerated conditions of
aqueous vehicle)
temperature, humidity, light
 Injections (REMEDY: Anhydrous
 40oC, 75% RH for 6 months
vegetable oils as solvent)
 Short-term accelerated studies:
 Oxygen-sensitive drugs
Determines most stable of the
 REMEDY: Dry form
proposed formulations for a drug
 REMEDY: Sotre in sealed
product (30oC, 60% RH)
containers with air replaced by
 Stress testing: Temperature
inert gas (Nitrogen, CO2)
elevations in 10o increments higher
 REMEDY: Antioxidants
than used in accelerated studies
Antioxidants for oxygen- Antioxidants for oxygen- until chemical or physical
sensitive aqueous sensitive oleaginous degradation occurs
preparations preparations  Long-term Stability Testing
 Product is subjected to different
Na2SO3 Alpha-tocopherol
zones (temperature and humidity)
NaHSO3 Butylhydroxyanisole
nationally and internationally
H3PO2 Ascorbyl palmitate
 Predicted from the data generated
Ascorbic acid
from continuing stability studies
 25oC, 60% RH for 12 months
 Unstable antibiotics
 REMEDY: Dry form
MANUFACTURED PRODUCTS HAVE
 Unstable preparations
SHELF-LIFE OF 2 OR MORE YEARS
 REMEDY: Store in refrigerator
 Trace metals
 Source of difficulty in preparation
 REMEDY: purification of source of
contaminant, use of chelating
agents (EDTA)
 Light
 Catalyst to oxidation reactions
 REMEDY: Light-resistant or opaque
containers

Rate Reactions

 Description of the drug concentration with


respect to time

Lacorte, Aries S. 3D-PH | PHAR 3