DOSAGE FORM DESIGN CONSIDERATIONS Flashcards

1
Q

study on the: formulation, manufacture, stability, and
effectiveness of pharmaceutical dosage forms

A

Pharmaceutics

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2
Q

-Selective use of these non-medicinal agents

A
  • Pharmaceutical ingredients or excipients
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3
Q

Uses of Pharmaceutical ingredients or excipients

A

Solubilize
Thicken
Stabilize
Flavor
Suspend
Dilute
Preserve
Efficacious
Emulsify
Color
Appealing closure forms

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4
Q

Requirements of a proper design & formulation
of dosage form

A

a. Consideration of drug substances: Physical, chemical and biological
characteristics
b. Compatible with one another - stable, efficacious, attractive, easy to
administer, and safe
c. Manufactured under appropriate measures of quality control and packaged in
containers to make the product stable
d. Labeled to promote the correct use and stored under conditions to maximize
shell life

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5
Q

To protect the drug substance from the
destructive influences of atmospheric
oxygen or humidity.

A

Coated tablets

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6
Q

To protect the drug substance from the
destructive influence of gastric acid after oral
administration.

A

Enteric-coated

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7
Q

To conceal the bitter, salty or offensive taste
or odor of a drug substance.

A

Capsules,
Flavored syrups

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8
Q

To provide liquid preparations of substances
that are either insoluble or unstable in the
desired vehicle.

A

(Suspension)

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9
Q

To provide clear liquid dosage forms of
substances.

A

Syrups, Solutions

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10
Q

To provide rate-controlled drug action.

A

Controlled-release tablets

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11
Q

To provide optimal drug action from topical
administration sites.

A

Ointments, Creams,
Transdermal patches

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12
Q

To provide for insertion of a drug into one of
the body’s orifices

A

Suppositories

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13
Q

To provide placement of drugs directly in the
bloodstream or body tissues

A

Injections

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14
Q

To provide for optimal drug action through
inhalation therapy

A

Inhalants, Inhalation
aerosols

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15
Q

the framework for product
development.

A

Determine desired product type

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16
Q

Develop and examine initial formulations of the product:

A

a. desired features: drug release profile bioavailability

clinical effectiveness

b. pilot plant studies and production scale-up.

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17
Q

a formulation that best meets the goals of the product

A

Master Formula

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18
Q

Factors to consider before formulation of a medicinal agent in
one or more dosage forms:

A

a. Therapeutic matters (nature of the illness)
b. manner it is treated (locally or through systemic action)
c. age and anticipated condition of the patient.

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19
Q

Before the formulation of a drug substance into a dosage form, it is
essential that:

A
  • It is chemically and physically characterized
  • It defines the nature of the drug substance

This information provides the framework for the drug’s combination
with pharmaceutical ingredients in the preparation of the dosage
form

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20
Q

Considerations for physical characteristics:

A
  • Particle size
  • Crystalline structure
  • Melting point solubility.
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21
Q

Determination of chemical properties

A

-Structure form
- Reactivity

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22
Q

Evaluation of the purity of the chemical substance for:

A
  • Identification and for evaluation of its chemical, physical, and biological properties
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23
Q

Three ways liquid drugs be given in solid form

A
  • Sealed in soft gelatin capsule
  • Developed into a solid ester or salt form suitable for tablets or drug
    capsules
  • Mixed with a solid or melted semisolid material
  • melted mixture is poured into hard gelatin capsules to harden &
    capsules sealed
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24
Q

It gives an indication of particle size and size range of the raw material
along with the crystal structure.
Provide information in formulation processing attributable to
changes in particle or crystal characteristics of the drug.
* Example: spherical and oval powders flow more easily than needle-shaped
powders and make processing easier

A

MICROSCOPIC EXAMINATION

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25
Determines the: purity of the substance compatibility of various substances before inclusion in the dosage form
MELTING POINT DEPRESSION
25
depressed melting point
Impure substance
26
sharp melting point
Pure substance:
27
*Phase diagrams constructed determine:
- existence and extent of the presence of solid and liquid phases in binary, ternary and other mixtures
28
substances can exist in more than one crystalline form
POLYMORPHISM
29
usually exhibit different physicochemical properties (including melting pt and solubility)
Polymorphic forms
30
* Evaluation of: a. Crystal structure (Techniques: microscopy, IR spectroscopy, thermal analysis, x-ray diffraction) b. Polymorphism c. Solvate form * Changes in crystal characteristics can influence bioavailability and chemical and physical stability can cause implications in dosage forms process functions
Polymorphic forms POLYMORPHISM
31
is defined as the maximum concentration of a substance that can be completely dissolved in a given solvent at a certain temperature and pressure level
Drug solubility
32
Determined by equilibrium solubility method
- excess amount of drug + solvent = shaken at constant temp. over a prolonged period of time until equilibrium is obtained
33
for therapeutic efficacy.
A drug must possesses aqueous solubility
34
incomplete/erratic absorption
Insoluble compounds
35
The smaller the particle size
the greater the solubility
36
If a drug product is formulated into a liquid product:
adjustment of pH of solvent to enhance solubility
37
require extremes in pH outside of accepted physiologic limits or that may cause stability problems with formulation ingredients.
Weak acidic or basic drugs
38
Adjustment of pH usually has
little effect on the solubility of substances other than electrolytes.
39
The use of cosolvents or other techniques such as complexation, micronization, or solid dispersion
may improve aqueous solubility
40
Time it takes for the drug to dissolve in the fluids at the absorption site (rate-limiting step in absorption).
DISSOLUTION RATE
41
Increased Dissolution rate of drugs
by decreasing the particle size
42
Dissolution rate of drugs Increased by
increasing the solubility of the diffusion layer
43
use a highly water-soluble salt of the parent substance.
For a higher dissolution rate
44
can affect the onset, intensity, and duration of response and control the overall bioavailability of the drug from the dosage form
Dissolution rate
45
2 methods in determining dissolution rates of chemical compounds
1. Constant surface method 2. Particulate dissolution
46
- Intrinsic dissolution rate of the agent - Characteristic of compound & solvent under fixed experimental conditions - Value is expressed as: mg dissolved/min/cm2
Constant surface method
47
- Weighed amount of powdered sample + dissolution medium in constant agitation system - to study the influence of particle size, surface area, and excipients upon the active agent
Particulate dissolution
48
Describes the Relationship of diffusion and dissolution of the active drug in the dosage form and when administered in the body
Fick’s law (law of diffusion)
49
Relates to a steady-state flow
1st law
50
Relates to a change in conc. of drug with time, at any distance, or a non- steady state of flow
2nd law
51
* Everted intestinal sac - determines degree & rate of passage of drug through the membrane sac by passive & active transport * Early assessment of passage of drug molecules across biologic membranes * To produce a biologic response - drug molecule must first cross a biologic membrane * The biologic membrane (lipid barrier) - permits absorption of lipid soluble substance by passive diffusion * Molecules’ lipophilic character – measured by the oil-water coefficient
MEMBRANE PERMEABILITY
52
Interrelationship at the absorption site & absorption characteristics of various drugs:
* Dissociation constant * lipid solubility * pH
53
Indication of absorption expectations:
* Data from basic physicochemical studies: pKa, solubility & dissolution rate
54
Selection of appropriate extraction solvents, drug stability, use of salting-out additives and environmental concerns.
PARTITION COEFFICIENT
55
is a measure of a molecule’s lipophilic character; that is, its preference for the hydrophilic or lipophilic phase. If a solute is added to a mixture of 2 immiscible liquids, it will distribute between the 2 phases and reach an equilibrium at a constant temperature.
The oil-water partition coefficient
56
strong effect on formulation & pharmacokinetic parameters of the drug
Extent of ionization of drug
57
is determined by potentiometric titration
Dissociation constant (pKa)
58
for the pharmacist important:
-predicting precipitation in admixtures -calculating solubility of drugs at certain pH values
59
-Extent a product retains within specified limits and through its period of storage and use
STABILITY
60
Stability studies conducted in the preformulation phase:
Stability studies conducted in the preformulation phase:
61
-important for preformulation. * Presence of impurities can lead to erroneous conclusions in some evaluation parameters
physical and chemical stability of pure drug substances
62
-Chemically, drug substances with different susceptibilities toward chemical instability:
alcohols, phenols, aldehydes, ketones, esters, ethers, acids, salts, alkaloids, glycosides and others.
63
Most frequently encountered destructive process:
-HYDROLYSIS (solvolysis process) -OXIDATION
64
- Drug molecules interact with water molecule to yield breakdown product. Example: Aspirin or ASA, combines with water molecules and hydrolyzes into a molecule of salicylic acid and acetic acid
Hydrolysis (solvolysis process)
65
Susceptible to the hydrolytic process:
esters, substituted amides, lactones, and lactams
66
- loss of electrons from an atom or molecule; - loss of hydrogen (dehydrogenation) from a molecule - involves free radicals (molecules or atoms containing one or more unpaired electrons). - Destructive to: aldehydes, alcohols, phenols, sugars, alkaloids & unsaturated fats & oils
OXIDATION
67
Five types of stability
1. CHEMICAL 2. PHYSICAL 3. MICROBIOLOGIC 4. THERAPEUTIC 5. TOXICOLOGIC
68
–active ingredient retains chemical integrity and labeled potency within the specified limits. - important for selecting: *storage conditions (temperature, light, humidity) *proper container for dispensing *anticipating interactions when mixing drugs & dosage forms - must know reaction order & rate
CHEMICAL
69
original physical properties, appearance, palatability uniformity, dissolution and suspendability are retained.
PHYSICAL
70
–sterility/resistance to microbial growth
MICROBIOLOGIC
71
therapeutic effect remains unchanged
THERAPEUTIC
72
no significant increase in toxicity occurs.
TOXICOLOGIC
73
- description of the drug concentration with respect to time.
RATE REACTIONS
74
- estimate the shelf life of a product that has been stored or to be stored under a different set of conditions.
Q10 METHOD
75
*Water reduced or eliminated from the system. *Water-liable drugs - waterproof protective coating applied in the tablet. *In liquid formulation - water replaced by substitute liquids. *Suspending them in nonaqueous vehicle *For injectable products – anhydrous vegetable oils may be used as solvent
Drugs subjected to hydrolysis
76
anhydrous vegetable oils may be used as solvent for
injectable products
77
Aqueous preparation is desired - supplied in dry form for reconstitution before dispensing
For unstable antibiotic drugs
78
storage under refrigeration
For unstable preparations
79
– major determinant in stability
pH
80
optimum stability
pH 5 & 6
81
increases stability
buffering agents
82
* prepared in dry state *packaged in sealed containers with air replaced by inert gas (Nitrogen, carbon dioxide).
Oxygen sensitive drugs
83
In Aqueous Preparations: Ex: Na2SO3, NaHSO3, H3PO3, ascorbic acid
add antioxidants (for stability):
84
Inoleaginous/unctous prepns: Ex: alpha tocopherol, butylhydroxyanisole & ascorbyl parmitate
* add antioxidants (for stability):
85
* add antioxidants (for stability):
- In Aqueous Preparations: Ex: Na2SO3, NaHSO3, H3PO3, ascorbic acid - In oleaginous/unctous prepns: Ex: alpha tocopherol, butylhydroxyanisole & ascorbyl parmitate
86
source of difficulty in preparing stable solutions of oxidizable drugs
Trace metals in drug, solvent, container or stopper
87
Trace metals in drug, solvent, container or stopper - Eliminated by:
*purification of source of contaminant *complexing or binding metal by using specialized agents (chelating agents- Ca disodium edetate & EDTA)
88
- catalyst to oxidation reactions - preparations were packaged in light resistant or opaque containers
Light
89
easily oxidizable drugs may be stabilized in formulation by considering
* selective exclusion from the system of: oxygen oxidizing agents trace metals light heat other chemical catalysis * add to create and maintain a favorable pH: antioxidants chelating agents buffering agents
90
- reaction between two or more identical molecules with resultant formation of new & generally larger molecule (Ex: Formaldhyde)
Polymerization
91
Process where one or more active chemical groups removed:
* Chemical decarboxylation * Deamination
92
Decomposition of Carboxylic acid (RCOOH) & release of CO2
Decarboxylation
93
- Removal of nitrogen containing group from organic amine (Ex. Insulin)
Deamination
94
Importance of Drug Stability * In Pre-clinical testing and in clinical (human) trials
- for a true and accurate assessment of the drug/drug prod evaluated
95
Importance of Drug Stability * Marketed drug product
- for the safety and effectiveness when distributed and during the entire course of its shelf-life and use
96
Product stability assessed before marketing: * Formulation * Influence of:
- pharmaceutic ingredients present - container & closure
97
Product stability assessed before marketing:
* Formulation * Influence of: - pharmaceutic ingredients present - container & closure * Manufacturing & processing conditions * Packaging components & conditions of warehousing/storage * Conditions of shipping, temp., light & humidity * Shelf life & patient utilization
98
Stability testing considerations
* Product containers, closures, and other packaging features * Parenteral and other sterile prods must meet sterility test standards - to ensure protection against microbial contamination
99
Drug instability detected
* Change in: a. physical appearance, b. color, c. odor, d. taste, or e. texture of the formulation