preformulation Flashcards
what is formulation
the process of developing a drug candidate
into a drug product.
what is preformulation
an investigation of physical and chemical
properties of a drug substance alone and when combined with excipients.
what is the objective of preformulation
- To establish the physical chemical properties of the new drug entity
- To determine the drug kinetics and stability.
- To establish the drug compatibility with common excipients
how can the information that is gained in the preformulation process be useful?
development of a dosage form that is bioavailable, stable and can be mass produced.
what are the charaterizations of API
- Organoleptic properties
- Solubility, dissolution rate and partitioning.
- Bulk properties
- Stability and compatibility studies.
give some examples on bulk properties
Particle size
Crystallinity and polymorphism (solid state
properties)
Hygroscopicity
Density Flow and compression properties
how should the prefomulation process start?
should generally begin with the
description of the drug substance.
Color, odor and taste of the new drug must be recorded.
how can the organoleptic properties effect the formulation stages?
– If taste is considered to be unpalatable, a less soluble form of the drug (salt or prodrug) could be considered.
– Unacceptable odor or taste may force the formulator to use flavoring agents or coat the final product.
– Unsightly or variable color may force the formulator to use coloring agents or coat the final product.
– If the material is irritating to the skin or causing
sneezing, appropriate procedures for material
handling and personnel protection can be
developed.
what is the saturation solubility?
the maximum concentration of a solution
which may be prepared at a given temperature.
why is the solubility important?
the manufacturing of injectable solutions or other solution dosage forms and the therapeutic
outcome: no drug will reach its ultimate therapeutic target without first being in solution.
note It has been estimated that historically, up to 40% drug candidates have been abandoned because of poor aqueous solubility.
what are the different solubility classes?
Class I High Solubility High Permeability like metoprolol
class II low Solubility High Permeability like ketoconazole
class III high Solubility low Permeability like cimetidine
class IV low Solubility low Permeability hydrochlorothiazide
what is the Importance of solubility for oral dosage forms?
The bioavailability of an orally-administered drug depends primarily on its solubility in the GI tract and its permeability across cell membranes (i.e.absorption).
In order to be absorbed a drug must be present in the GI fluids in a dissolved form.
how to determine solubility?
by the solubility test
- Excess of API in 100 mL of solvent at constant temperature (e.g.37 °C) is agitated for a sufficient length of time (in a closed appropriate container).
- Samples are withdrawn as a function of time and clarified by filtration or centrifugation and assayed using a detection techniques (e.g. HPLC or UV).
- A plateau concentration, corresponding to the saturation solubility, is found.
what factors should the solubility test include?
pH, temperature, ionic strength and buffer concentrations.
Therefore, preformulation solubility studies usually involve also pH-solubility profile, pKa determination and temperature dependence
what is the prefered bioavailability ?
above 10 mg mL-1
what are the deferent mechanisms to enhance solubility ?
• Micellar solubilization/ addition of surfactants
• Cyclodextrin complexation
• Use of co-solvent systems
• pH adjustment (acidic/basic drugs)
what is the dissolution rate
the rate at which the material dissolves
how is the dissolution determined
by solubility: drugs with low solubility tend to have low dissolution rate and vice versa.
how is the dissolution determined
by solubility: drugs with low solubility tend to have low dissolution rate and vice versa.
what is the dissolution rate equation? (noyes- whitney)
dC/dt= (DA(Cs-C))/h*V
dC/dt—– dissolution rate
D= diffusion coefficient
A= surface area
Cs= saturation of solute in solution at a given time
C= concentration of solute in a solution at a given time
h= thickness of the diffusion layer
v= viscosity
How to determine dissolution rate of a drug?
Compressing the drug (API) into a compact disk and testing its dissolution
in an appropriate dissolution apparatus.
Such dissolution apparatus is different from those used for testing final
dosage forms (i.e. tablets or capsules – studied later on in the course).
what is partitioning?
an indication of lipophilicity which
affects permeability.
what is the partitioning coefficient law?
p=Co/Cw
log p <1 = low permeability
log p = 1-2 relatively permeable
log p >2 highly permeable
how do we determine partitioning?
The most common method for determining partition and
distribution coefficients is the shake flask method.
in this technique:
The drug is shaken between octanol and water layers.
Then aliquots from the two phases are taken and
analyzed for the drug content.
The values of the partition coefficient obtained from this
type of experiments is affected by temperature, pH and
buffer ions.
what is the importance of particle size?
Physical stability of suspensions and emulsions.
Flow properties (e.g. for solid dosage forms).
Dissolution rate.
what are the main methods to determine the particle size?
Sieve method
Microscopy
Laser diffractometers.
what are the main methods to determine the particle size?
Sieve method
Microscopy
Laser diffractometers.
the solid particles are made of what ?
molecules, atoms or ions that
are held in close proximity to each othe
the solid particles are made of what ?
molecules, atoms or ions that
are held in close proximity to each othe
what are the two main sates of a solid?
crystalline and amorphous
what is the crystalline form ?
a form in which the units (i.e. molecules, ions
or atoms) are packed in a defined order, and this order repeats over
and over again throughout the particle of solid.
what are the different lattice forms?
Cubic as in sodium chloride
Tetragonal as in urea
Hexagonal as in iodoform
Rhombic as in iodine
Monoclinic as in sucrose
Triclinic as in boric acid
what does the crystalline form define?
the melting point
what is polymorphism?
is the property of having more than one crystalline form.
give an example on polymorphism
is carbon than can exist both as diamond and
graphite.
notes
lower melting point means dissolving more easily
all compounds wants to transsion to the most stable form (highest melting point)
high melting point = strong lattice = hard to remove molecules = low
dissolution rate
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what are the properties of the most stable polymorphic form?
be the stable form (rather than metastable forms).
be easy to be processed into a dosage form
give good bioavailability
what are the properties of the most stable polymorphic form?
be the stable form (rather than metastable forms).
be easy to be processed into a dosage form
give good bioavailability
what charaterizations are given to the different drugs polymorphs
- identification of the different polymorphs;
- quantitative analysis of the physicochemical properties of the
different polymorphs (examples: solubility, dissolution rate,
flowability, compressibility etc.).
how can we identify different polymorphs using XRPD?
It is a technique in in which the pattern produced by the diffraction of X
rays through the closely spaced lattice of atoms in a crystal is recorded
and then analyzed. Each form shows a characteristic diffraction pattern.
the amorphos gives a noise pattern
how can we identify different polymorphs using DSC
It allows to differentiate polymorphs on the bases of their
melting point and heat of fusion (i.e. heat required to change a
substance from the solid to the liquid state).
DSC also allows to identify which form is stable and which is
metastable.
what are solvates?
Solvents might get trapped in the crystalline lattice, also referred to as pseudopolymorphs.
what are hydrates?
Solvates, where the incorporated solvent is water
monohydrate will have
one molecule of water for each molecule of the material. It is
possible to have different levels of hydrates; some drugs can exist
as mono, di and trihydrate
what are the different properties for solavtes?
Hydrates have very different properties from the anhydrous
form, in the same way as different polymorphs have different
properties from each other.
The most usual situation is for the anhydrous to have a faster
dissolution rate than the hydrate.
As the solvated and nonsolvated exhibit differences in
dissolution rates, they may exhibit differences in bioavailability,
particularly in the case of poorly soluble drugs.
give an example for solvates
Ampicillin solubility in water:
Anhydrate form sparingly soluble
>Trihydrate form slightly soluble
Higher solubility of the anhydrate
form in the GI fluids compared to
the trihydrate form.
Higher concentration of
dissolved drug available for
absorption
Higher bioavailailability
what is an amorphous?
Amorphous solids have atoms or molecules randomly
placed as in a liquid.
what is the TG for the amorphous states ?
Amorphous solids do not have a melting point.
Amorphous forms have a characteristic temperature (called
glass transition temperature or Tg) at which there is a major
change in properties.
If the sample is stored below the Tg the amorphous form will
be brittle and described as the glassy state.
If the sample is stored above the Tg it becomes rubbery.
what is the TG for the amorphous states ?
Amorphous solids do not have a melting point.
Amorphous forms have a characteristic temperature (called
glass transition temperature or Tg) at which there is a major
change in properties.
If the sample is stored below the Tg the amorphous form will
be brittle and described as the glassy state.
If the sample is stored above the Tg it becomes rubbery.
note
amorphous have higher solibilty but isnt thermodynamically stable
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how can we prepare an amorphous?
Large molecular weight species (e,g. polymers) often cannot
form crystals, therefore they tend to be present as amorphous
forms.
For low molecular weight materials, the amorphous form may
be produced if during the preparation, the solidification process
is fast. In this case the molecules might not have time to align
into crystals.
Alternatively, an amorphous form may formed by grinding (i.e.
milling) of solid crystals.
what is a crystal habit?
is the description of the outer appearance of
a crystalline solid, in other word the crystal habit is the external
shape of the crystal.
what are the different crystal habits
equant
acicular
flake
plate
lath
columnar
A single internal structure (i.e. lattice) for a compound can
have several different habits.
Changes in the internal structure usually gives different habits.
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what properties are influenced by crystal habits and how can we determine a crystal habit
Cristal habit can influence properties of the drug, such as
powder flow, compressibility, specific surface area, dissolution
rate, etc.
crystal habits are usually described by
their shapes under a microscope
what is hygroscopicity?
Many drug substances, especially water soluble salts forms,
have the tendency to absorb atmospheric moisture.
Deliquescent material absorb sufficient water to dissolve
completely (MgCl2)
Also, many drugs and pharmaceutical excipients absorb
moisture to form hydrates.
what factors affect hygroscopicity?
humidity
temperature,
surface area of the solid
extent of exposure
how can we test hygroscopicity?
- Placing samples of the bulk drug in open containers with a thin powder
bed to assure maximum atmospheric exposure. - These samples are then exposed to a range of controlled relative
humidity environments. - Moisture uptake is then monitored at different time points.
- Percentage-of-weight gain(due to moisture uptake) data are plotted
against time.
what are the different stabilitiy studies?
Accelerated stability studies (stress testing): The drug substance
(API) is subjected to harsh conditions, in order to have a quick idea
about its stability and excipient compatibility. These test studies
include both solution and solid-state experiments
.
Drug/ excipient compatibility studies: A number of excipients of
each category (diluent, binder, lubricant) are combined with the
API and exposed to harsh storage conditions.
Storage conditions:
Elevated temperature: 40, 50 and 60 °C with dry conditions.
Humidity: 75% RH.
Light: 400 and 900 foot candle for 4 and 2 weeks,
respectively
