Transcript Lecture 2 *Influence of pharmaceutical factors, such as physical

Lecture 2
“INFLUENCE OF PHARMACEUTICAL
FACTORS, SUCH AS PHYSICAL STATE, SIMPLE
CHEMICAL MODIFICATION OF MEDICINAL
SUBSTANCE ON THE THERAPEUTIC
EFFICIENCY OF MEDICINES”
The maximal usage of «pharmaceutical factors» is the primary
purpose of pharmaceutical technology for providing of high
quality of medicines that coincides with the strategic task of
biopharmaceutics which consists in the maximal increase
efficiency of medications and decline to the minimum of possible
side action on an organism.
Therapeutic
activity of medicinal
substances caused
by:
•constant
factors
(chemical
structure,
doze);
•variables
factors
(pharmaceutical).
Pharmaceutical factors and their classification
Physical state of medicinal substance
PHARMACEUTIC
AL
Medicinal form
and ways of application
FACTORS
Auxiliary substances (their nature, physical state
and quantity)
Simple chemical updating of medicinal
substance
Technological process
Studying of pharmaceutical factors is obligatory from the point of view of
biopharmaceutics in a view of their essential influence on dynamics of
bioavailability of medicinal substances, stability of medicines during storage
term and many other parameters.
Pharmaceutical factors influence on:
•
activity of substance;
•
substance releasing from the medicinal form;
•
absorption;
•
distribution in organism;
•
elimination.
The physical state of medicinal substances
influences on the stability of medicines during storage,
therapeutic efficiency, speed of absorbtion,
distributions and elimination from the organism.
On the biological action of medicines can influence and
other factors:
•superficial properties of medicinal substance (hydrophilic or
hydrophobic, etc.)
•a degree of cleanliness (a kind and quantity of impurity, a degree of
cleanliness, presence of microorganisms or allergens)
•the nature of solvent
•presence of the environment, which protecting medicines from
influence of acids and alkalis
•quality of packing
•storage term
•degree of crushing and polymorphism of medicinal substances
influences on the pharmacotherapy most essentially
Polymorphs have different stabilities and may spontaneously
convert from a metastable form (unstable form) to the stable
form at a particular temperature. They also exhibit different:
•
melting points,
•
solubilities (which affect the dissolution rate of drug and consequently its
bioavailability in the body),
•
X-ray crystal and diffraction patterns.
Various conditions in the crystallisation process is the main reason
responsible for the development of different polymorphic forms. These
conditions include:
•
solvent effects (the packing of crystal may be different in polar and
nonpolar solvents)
•
certain impurities inhibiting growth pattern and favour the growth of a
metastable polymorphs
•
the level of supersaturation from which material is crystallised (in which
generally the higher the concentration above the solubility, the more likelihood
of metastable formation)
•
temperature at which crystallisation is carried out
•
geometry of covalent bonds (differences leading to conformational
polymorphism)
•
change in stirring conditions
Despite the potential implications, polymorphism is not always well
understood.
So, due to differences in solubility of polymorphs, one polymorph
may be more active therapeutically than another polymorph of same
drug:
• cortisone acetate exists in at least five different polymorphs, four of
which are unstable in water and change to a stable form;
• carbamazepine (used in epilepsy and trigeminal neuralgia) betapolymorph developed from solvent of high dielectric constant ex
aliphatic alcohol, whereas alpha polymorph crystallized from solvents of
low dielectric constant such as carbon tetrachloride;
• estrogen and chloroamphenicol also show polymorphism;
• resorcinol has two forms ( and );
• levomycetin stay in 4 polymorphic forms (А,В,С,D),
but only B-form is an 100 % active;
• phenobarbital has 11 polymorphic forms;
• tetracycline – 4 forms;
• testosterone – 6 forms;
•
prednisolon – 6 forms.
The physical state of medicine influence also on the therapeutic
activity. Depending to this parameter all drugs are divided in 4
groups:
•
•
•
•
dry (powders);
liquid (solutions, suspensions, infusions, drops etc.);
soft (ointments);
gaseous (aerosols).
According to the dispersive classification medicines are
represented as all-round binary disperse system.
The solubility of substances depends on surface properties and
their degree of crushing. Diferency of particles size of medicinal
substances can cause to nonequal absorbtion rate and their
content in biological liquids of the same medicine. So, the clinical
non-equivalence is possible.
All these should be taking into account while preparing of liquid
medicinal forms for grounded a technological operations and
composition of medicines.
Surface properties are depends on:
•technological process of medicines
obtaining;
•kind of medium;
•crystallization velocity;
•temperature of process;
•increasing of pressure;
•type of impurities etc.
Properties of the active pharmaceutical igredients (API)
important
to dissolution include:
The solubility of the API in the dissolution
medium, which is usually an aqueous buffer
solution (may contain surfactants as well)
Whether the API is hydrophilic or hydrophobic
(ease of surface wetting)
The particle size of the API
Whether the API is crystalline or amorphous in
the drug product
If there are polymorphs, which polymorph is
present
If a salt form is used
Properties of the drug product important to
dissolution include:
Semi-permeable membrane
Osmotic core containing drug
Water
Delivery orifice
Drug solution
Whether the product is designed to immediately
release the API, to delay release, or to release the
drug over time.
API properties
Analytics
In-Vitro Drug Release
Formulation
Design
Formulation
API properties
Analytics
Dissolution: An interplay of three groups of factors
•As a formulation design aid (since formulation can profoundly affect
dissolution behaviour)
•As a quality control measure immediately after production for batch
release
•As a quality control measure to check performance during the shelf life
•To predict performance under various dosing conditions („biorelevant“
methods)
•To verify that the quality of a product is not adversely affected when
there is a change in excipients or manufacturing method (can
sometimes be used instead of a pharmacokinetic study)
•To obtain approval for a multisource drug product („generic“ version of
an existing drug product) – in certain cases a pharmacokinetic study is
not required.
Dissolution as a quality control measure for batch release, and
to ensure continued quality during the shelf-life.
•Here it is important to have a well-designed dissolution test that can detect
batches with poor quality without rejecting batches of adequate quality.
•The USP and, recently, the International Pharmacopeia, make
recommendations for specific drug products
Standard dissolution method for highly soluble APIs
–Paddle Apparatus
–500 mL
–SIFsp/IP Phosphate Buffer pH 6.8 (corresponds to one of the three pH
values stipulated by the FDA in its biowaiver guidance)
–75 Rpm
–37 °C (corresponds to the temperature of the Gastro-Intestinal (GI) fluids;
for transdermal products a lower temperature, usually 32°C is used, since
this is closer to skin temperature)
–Sampling at 30 min.
–Specification: >85 % release within 30 min.
Therapeutical activity of medicinal substances depends on:
Optical properties
Degree of ionization
Contain in molecul
crystalline
water
Among optical isomers there is no chemical
distinction, but each of them revolves the
plane of polarization ray in certain direction.
In spite of the fact that the chemical analysis
fully confirms the presence of the same
substance in medicine with different isomers,
they will not be therapeutically equivalent.
Depending on concentration of hydrogen
ions the medicinal substances can be in the
ionized or unionized form. pH index
influences also on the solubility, coefficient of
distributing
of
medicinal
substances,
membrane potential and superficial activity.
The waterless medicinal substances and
crystallohydrate has a different solubility that
causes change of their pharmacological
action. For example, the waterless forms of
caffeine, ampicillin, teophylline dissolve
quickly, as compared to their crystallohydrate
and consequently is quickly sucked.
The clinical researches of application a simple chemical
modification of medicines showed a differect results:
For example: Chinin-base
Chinin sulphate  solubility is 1 : 800
Chinin chloride  solubility is 1 : 34
Chinin bromide  solubility is 1 : 16
Tthese substances has a different pharmacokinetic (because a
solubility is differ) but the activity is saved.
For example:
While glucose mix in medicinal form with following substances:
•Alkaline
substances

the
activity
of
euphylline,
hexamethylentetramine, caffeine-sodium benzoate etc. dereased
because the pH is changed;
•Cardiac glycosides  hydrolysis is carring out;
•Essenciale for injections  “muddy” is forming.
Simple chemical modification of medicines
Simple chemical
modification
The same substance is represented as a different type of
chemical compound (salt, base, esther, complex etc.), but
the pharmacological activity is stable
While replacing one substance by other we should be recalculate their amount in molecular
mass or unit of action:
For example:
Replacing of medicines
Medicinal substance
Base form
Potassium bromide ()
Sodium bromide ()
Codein phosphate ()
Codein ()
Caffeine sodium benzoate ()
Caffeine ()
Liquid phenol ( )
Crystalline phenol ()
On the basis of biopharmaceutics researches proved
that arbitrary replacement some ion in the molecule of
medicinal substance, coming from cleanly technological or
economic indicators is unpossible
.