2. Preformulation
Preformulation may be described as a phase of the research
and development process where the preformulation
scientist characterizes the physical, chemical and
mechanical properties of a new drug substance, in order to
develop stable, safe and effective dosage form.
The word preformulation is composed of two words pre
and formulation. Activities done prior to formulation
development are called as preformulation studies. It
provides the scientific basis for formulation development.
3. Objectives
The preformulation investigations confirm that
there are no significant barriers to the
compound’s development as a marketed drug.
The formulation scientist uses these information's
to develop dosage forms.
4. Significance
Preformulation studies helps to develop the elegant
dosage forms (stable, effective & safe).
It is important to have an understanding of the physical
description of a drug substance before dosage form
development.
It is 1st step in rational development of a dosage form of
a drug substance before dosage form development.
It generates useful information to the formulator to
design an optimum drug delivery system
It helps to establish the kinetic rate profile of new drug
substance with their compatibility with the common
excipients.
5. Classification of preformulation study.
There are two classes of preformulaion study
1. fundamental preformulation,
2. derived preformulation
6. Fundamental preformulation
These are specific to the drug molecule and are dependent on
the chemical structure of the drug molecule. Such as
• Solubility: solubility in different solvents, dissociation
constant (pKa), salt formation, partition or distribution
coefficient (log P or log D), pH solubility profile and
dissolution kinetics,
• Permeability,
• Solid state properties like solid form, crystalinity,
polymorphism, solvated forms and amorphous form
• Solid state stability and solution state stability, wherein
inherent stability, pH – stability profile and photo-stability
are studied.
7. Derived preformulation:
These properties are carried out to learn about the
issues related to development of a particular
dosage form like solid oral, liquid oral or parenteral.
Derived preformulation properties are specific to
the intended dosage form to be developed. For
solid oral dosage form like tablet, include –
• characterization of particle properties like
morphology and particle size
• bulk density
• flow properties and
• compaction behavior
Cont……
8. In case a capsule dosage form is to be developed,
compaction behavior, shall not be required. The
last activity performed in pre-formulation studies
is the compatibility studies, wherein the physical
and chemical stability of the drug molecule is
studied in presence of excipients. Obviously, the
choice of excipients is dictated by the type of
dosage form to be developed.
9. Preliminary evaluation and molecular optimization
Once a pharmaceutically active compound has been identified,
a project team consisting of representatives from the
disciplines indicated in the following figures has
responsibility for assuring that the compound enters the
development process in its optimum molecular form. While
each discipline may have its own criteria for an ‘optimized’
molecule, the physical pharmacist must focus on how the
product will be formulated and administered to patients.
Commonly, stability and/or solubility shortcomings can
adversely affect these aspects of drug performance.
Cont…..
10. When the first quality sample of the new drug becomes
available, probing experiments should be conducted to
determine the magnitude of each suspected problem areas.
If a deficiency is detected, then the project team should
decide on the molecular modifications that would most
likely improve the drugs properties. Salts, prodrugs,
solvates, polymorph or even new analogs may emerge from
this modification effort.
11.
12. Following figure shows how drug formulation goes in to market
stepwise representation is mentioned in it.
13. Major area of preformulation research:
1. Bulk characterization:
Crystallinity & polymorphism
Hygroscopicity
Fine particle characterization
Powder flow properties.
2. Solubility analysis:
Ionization constant Pka
pH solubility profile
Common ion effect-Ksp
Solubilization
Dissolution
Partition co-efficient
Cont……
15. Bulk characterization
When a drug molecule is discovered all the solid
forms are hardly identified. So during bulk
characterization the following characteristics
are studied.
1. Crystallinity & polymorphism
2. Hygroscopicity
3. Fine particle characterization
4. Powder flow properties.
16. Crystallinity & polymorphism
Crystal habit & internal structure of drug can affect
physic-chemical properties which range from flow
ability to chemical stability. Habit means the
description of outer appearance of a crystal. While
internal structure describes the molecular
arrangement within the solid, changes in internal
structure usually alter crystal habit.
Ex. 1: Conversion of sodium salt to its free acid form
produce both a change in internal structure & crystal
habit.
Ex. 2: Conversion of Sod. Benzoate to Benzoic acid.
18. Idea about salts, solvates, hydrates and co-crystals
Figure. 3: General idea about polymorphs, amorphous, solvates,
salts, and co-crystals.
19. Crystalline
Crystals are characterized by repetitious spacing of
constituent atoms or molecule in a dimensional
array. Evaluation of crystal structure,
polymorphism, & solvate form is an important
preformulation activity. The changes in crystal
characteristics can influence bioavailability,
chemical and physical stability, & can have
implication in dosage form process functions. It can
be a significant factor relating to tablet formulation
because of flow and compaction behavior among
other.
e.g. Nacl, CsCl crystal.
20. Crystal morphology
Repetition of atom or molecule in regular three
dimensional arrays (structure) there are six
crystalline systems
1. Cubic
2. Tetragonal
3. Orthorhombic
4. Monoclinic
5. Triclinic
6. Hexagonal.
21.
22. Amorphous / non crystalline
In this forms the solids do not have any fixed
internal structure. They have atoms or molecules
randomly placed as in a liquid. Due to higher
thermodynamic energy of amorphous form than
crystalline form they shows greater dissolution
rates and upon standing amorphous forms tends to
reverts to more stable forms. This thermodynamic
instability is a major disadvantage for developing
amorphous forms.
e.g. Amorphous Novobiocin.
24. Polymorphism(Crystal forms)
When a substance exists in more than one crystalline
form, the various forms are called Polymorphs and
the phenomenon is called polymorphism. e.g .
Chloramphenicol palmitate has three polymorphs A,
B and C. An important factor affect on formulation
is the crystalline or amorphous form of the drug.
Polymorphic form exhibits different physico-
chemical properties including melting point and
solubility. Polymorphic form in drug are relatively
common, it has been estimated that at least 1/3 of all
organic compounds exhibit polymorphism.
25. Types
Polymorphs are two types
1. Enantiotrophic polymorphs,
2. Monotrophic polymorphs
Enantiotrophic polymorphs: Enantiotrophic
polymorphs is the one which can be reversibly
changed into another form by altering the
temperature or pressure.
e.g: Sulfur. Carbon. Nitrogen .Oxygen.
26. Monotrophic polymorphs: The transition take place in only
one direction is called as monotrophic polymorphs. Or is
one which is unstable at all temperature & pressure. Ex:
glyceryl steartes.
The polymorphs differ from each other with respect to their
physical properties, such as solubility, melting point,
density, hardness, dissolution, compression characteristics.
Polymorphs (Drugs and There Polymorphic forms)
Steroids like Progesterone has 5 polymorphs.
Barbiturates like Barbitone have 2, & Pentabarbitone has 3.
A sulphonamide like Sulphabenzamide has 4 polymorphs &
3 solvates. Caffeine has 2 polymorphs
Chlorpropamide has 3 polymorphs.
27. Properties of solvates / hydrates
Generally, the anhydrous form of a drug has greater
aqueous solubility than its hydrates. This is because
the hydrates are already in equilibrium with water
and therefore have less demand for water. e.g.
anhydrous forms of theophyline and ampicillin have
higher aqueous solubility than the hydrates.
Non aqueous solvates have greater aqueous
solubility than the non-solvates. E.g. chloroform
solvates of griseofulvin are more water soluble than
their non-solvate forms.
28. Effects of polymorphs
Effect on Bioavailablity
Different polymorphic forms of a given drug shows
difference in the dissolution rate & solubility. When
absorption of drug is dissolution rate limited, as more
soluble and faster dissolving form may be utilized to improve
the rate and extent of bioavailability.
For example: Chloramphenicol palmitate Comparative blood
level data obtained in human after oral administration of
1.5gm of pure A & pure B forms of Chloramphenicol
palmitate & their mixtures. These data shows that the pure
form B is more soluble so was most bioavailable. Where as
pure form A is less soluble so least bioavailable.
29. Effect on chemical stability
For drugs prone to degradation in the solid state, the
physical form of drug influence the rate of degradation.
Ex. Aztreonam (monobactam antibiotic) Exist in needle
like α and spherical β-crystalline forms. In the presence
of high humidity ( 37 C / 75% RH),the α-form undergoes
β-lactum hydrolysis more readily with a half life of about
6 months Where as the β-form under identical condition
is stable for several years . In as much as two crystal
forms of labile drugs could exhibit widely different solid
state stabilities. So the Preformulation scientist might
have consider changing the crystal form for eliminating a
stability problem.
30. Effect on tableting behaviors
.
In a typical tableting operation flow and compaction
behaviors of the powder mass to be tableted are
important. These properties among other are related
to morphology, tensile strength, and density, of the
powder bed which becomes significantly different for
two polymorphic forms of same drug.
31. Effect on physical stability
One form of the polymorphic form is thermodynamically
stable at given tempt. & pressure. The other form converts
to the stable form that time. This transformation may be
rapid or slow. The stable polymorph exhibit highest melting
point, the lowest solubility and maximum physical and
chemical stability under safe condition to justify its use for
reason of better dissolution or ease of tableting.
Polymorphic transformation can occur during grinding,
granulation, drying, and compressing operation. Ex.
Digoxine, Spironolacton, and estradiol are reported to
undergo, polymorphic transformation during the size
reduction.
32. Analytical methods for characterization of solid forms
Method Material required per
sample
Microscopy
Hot stage microscopy
Differential Scanning Calorimetry (DSC)
Differential Thermal Analysis (DTA)
Thermogravimetric Analysis
Infrared Spectroscopy
X-ray Powder Diffraction
Scanning Electron Microscopy
Dissolution / Solubility Analysis
1 mg
1 mg
2 – 5 mg
2 – 5 mg
10 mg
2 – 20 mg
500 mg
2 mg
mg to gm
33. Hygroscopicity
Many pharmaceutical materials have a tendency to adsorb
atmospheric moisture (especially water-soluble salt forms).eg. CaO,
NaCl, Sucrose. They are called hygroscopic materials and this
phenomenon is known as hygroscopicity. Most pharmaceutical
compounds lose or gain water from the atmosphere depending on the
relative humidity (RH). Materials unaffected by RH are termed as non
hygroscopic. Pharmaceutical air conditioning is usually set bellow
50%RH and very hygroscopic products that are moisture sensitive are
made and stored below 40% RH. Tablets and capsules must be
hydrophilic to facilitate wetting, deaggregation and dissolution during
drug delivery. As a paradox, they must have limited hygroscopisity to
ensure good chemical and physical stability under all reasonable
climatic condition.
Deliquescent materials: They absorb sufficient amount of moisture and
dissolve completely in it. (e.g. anhydrous calcium chloride).
34. Why do we care about
Hygroscopicity?
Amorphous compounds may take up water and re-crystallize & or
degrade. Anhydrous material may hydrate and become less soluble.
The weight change with sorption may cause errors in potency.
The volume changes associated with water gain and loss may
compromise dosage form integrity.
Changing the solid state form in the dosage form requires regulatory
approval.
Different forms may have different compaction, flow and charging
characteristics.
Prevention of Hygroscopicity
Good packaging ( air tight glass bottles)
Use of foil blisters
Use of desiccants.
35. Significance of hygroscopicity test
1. To decide special handling procedure (with respect to
time).
2. To decide
the storage condition i.e. at low humidity
environment.
special packaging – e.g. with desiccant.
3. Moisture level in a powder sample may affect the flow
ability and compactibility which, are important factors
during tableting and capsule filling.
4. After adsorption of moisture, if hydrates are formed then
solubility of that powder may change affecting the
dissolution characteristics of the material.
5. Moisture may degrade some materials. So humidity of a
material must be controlled.
36. Fine particle characterization
Bulk flow, formulation homogeneity and surface area
controlled processes such as dissolution and chemical
reactivity are directly affected by size, shape, and surface
morphology of drug particles. In general new drug candidate
should be tested during preformulation with the particle size
as is practical to facilitate preparation of homogeneous
samples and maximize the surface area for actions. A light
microscope with a calibrated grid usually provides size and
shape characterization for drug particles. Brauner, Emmet,
and Teller (BET) Nitrogen adsorption is a more precise
measurement for surface area determination and also surface
morphology may be observed by scanning electron
microscopy (SEM).
37. Powder flow properties
Pharmaceutical powders may be classified as a free-flowing or
cohesive (non free flowing). Most flow properties are significantly
affected by changes in particle size, density, shape, electrostatic
charge and adsorbed moisture which may arise from processing or
formulation. As a result, a free flowing drug candidate may become
cohesive during development, thus necessitating an entirely new
formulation strategy. Preformulation powder flow investigation should
quantitatively assess the pharmaceutical consequences of each
process movement and provide direction for the formulation
development project team such as granulation or densification via
slugging, the need for special auger feed equipment or a test system
for evaluating the improvements in flow brought about by
formulation. Free-flowing properties may be characterized by a simple
flow rate apparatus and cohesive powders may be characterized by
tensile testing or evaluated in a shear cell.
