Pharmaceutical preformulation

1. Pharmaceutical pre-formulation
Fakhrul Ahsan, Ph.D.
Office: Room # 214
fakhrul.ahsan@ttuhsc.edu
I have used the above book, Pharmaceutical dosage forms: Tablets Volume 1 by
Lieberman et al. I may have used sentences directly the book. A large number of
pictures used in this note are from various websites, which I did not cite to avoid
clutters.

2. Learning objectives
1. Understand pharmaceutical formulations and pre-formulations
2. Appreciate the roles of various physicochemical parameters in
dosage form development.
3. Define and understand the following parameters:
 Solubility
 PKa
 Partition coefficient
 Dissolution
 Polymorphism
 Drug stability
 Particle size, shape and surface area
 Flow properties
 Compression properties
 Compatibility with excipients
 Hygroscopicity

3. Dosage forms
 Tablets
 Capsules
 Hard gelatin
 Soft gelatin
 Microcapsules
 Solutions
 Suppositories
 Injections
 Creams
 Ointments
 Eye drops
 Ear drops
 Nose drops
 Inhalers
 Sprays
 Transdermal
patches
 Emulsion
 Suspension
 Implants
 Lotions
 Inserts
 Powders
 Gels
 Pastes
 Granules

4. Pharmaceutical formulations
 A recipe or formula for a dosage form that
includes the following information
 Name and quantities ingredients
 Sequence of mixing the ingredients
 Processing steps
 A recipe for preparation of a drug product is
called formulation.
 A Pharmaceutical formulation contains
 One or more active ingredient (Drug)
 Many additives called excipients

5. Pharmaceutical pre-formulation
 Study the physical and chemical properties of a
drug substance alone and in combination with
excipients.
 The first step in the rational development of
dosage forms of a drug substance.
 Help develop stable and bioavailable dosage
forms that can be produced in large amount.
 You start pre-formulation after biological
screening and when you decide for moving
forward to clinical trials

6. Pre-formulation parameters
 Organoleptic Properties
 Purity
 Drug stability
 Particle size, shape and
surface area
 Solubility
 pH-solubility profile
 Solubilization
 Dissolution
 Partition coefficients
 Ionization constant
 Permeation across biological
membrane
 Crystal properties and
polymorphism
 Stability in the presence of
excipients
 Density
 Hygroscopicity
 Flowability
 Compactibility
 Wettability
 Potential hazards associated
with handling

7. Organoleptic properties
 These parameters can be perceived
by sense organ:
 Color
 Odor
 Taste
 Drug substances, in general, have characteristics color,
odor and taste.
 In pre-formulation step, you determine the organoleptic
properties.
 In case of unacceptable tastes and odors, you add
flavors and excipients
 You can add dyes to alleviate the unsightly and variable
color.

8. How do we test the taste?
 Electronic tongue
 A sensor device that can recognize, identify, and
discriminate tastes and flavors of various liquids
http://www.electronictongue.com/stand.html

9. Purity
 The presence of unwanted substances is not
desirable.
 Common impurities are
 Metals:
 Even a few parts per million may cause deleterious
effects on the dosage form.
 Synthetic intermediates:
 Maybe toxic or may not have therapeutic effects
 Slight impurity may affect the appearance of the
drug substance

10. Solubility
 The concentration of a solute in
a saturated solution at a certain
temperature.
 Solubility affects
 Bioavailability,
 Drug release rate
 Therapeutic efficacy.
 Determination of solubility
 Prepare a solution of the
material in a solvent by
adding an excess of the
material
 Shake the solution until an
equilibrium is established
 Quantitate the drug using an
analytical method

11. Solubilization
 The process that increases the solubility
 You can increase the solubility by adding a third
substance to the aqueous solution of a drug.
 Common solubilizers
 Organic solvents
 Surfactants
 Complexing agents.
 Need for solubilization
 If a drug has a solubility of 5 g/L, the dose is 500
mg, how much water would you need to solubilize a
single dose of the drug?
 We will need 100,000 liter water to solubilize this
drug
 Or we have to use other agents to solubilize the
drug.
The water volume of a pool 60 ft. long, 30 ft. wide and that slopes in depth from 3 ft. to 10 ft. is as
follows: 30 x 60 x ((10 + 3)/2) = 11,700 cubic ft. of water 11,700 x 7.5 = 87,750 gallons. =332,170 liters

12. pH-solubility profiles
 Solubility of acidic and
basic compounds depend
on the pH of the medium
 The solubility of a
compound is the sum of
the solubility of ionized
and unionized forms
 An acidic compound is
more soluble in a basic
solvent
 A basic compound is more
soluble in an acidic
solvent.
pH
Log
solubility
µmol/L)
Amphoteric drug
Basic drug
Acidic
drug

13. Ionization constant
 The equilibrium constant for the reaction in which a
weak acid or base is in equilibrium with its
conjugate base or acid in aqueous solution.
 Kb is the ionization constant of a base
 Ka is the ionization constant of an acid
 pKa = -log Ka
 The smaller the pKa, the stronger the acid,
 The Henderson-Hasselbalch equation can estimate
the ionized and un-ionized drug concentration at a
particular pH.
 For acidic compounds:
 pH = pKa + log ([ionized drug]/[un-ionized drug])
 For basic compounds:
 pH = pKa + log ([un-ionized drug]/[ionized drug])

14. Ionization constant
 Drug stability
 Drug instability may result from the gain or loss of a
proton by a substrate molecule
 An electronic rearrangement may reduce or increase the
reactivity of the molecule
 Drug activity
 Weakly acidic or basic drugs may exist in ionized or non-
ionized form or in a mixture of both.
 Drug absorption
 Absorption of a many of drugs depends on the ionization
constants.
 Non-ionized form of an acidic or basic drugs are soluble in
lipids and better absorbed via the lipoidal biological
membrane.
 Completely ionized drugs are absorbed poorly.

15. Let’s take the poll
►Solubility is an organoleptic property (T/F).
►Solubility of an acidic drug increases with the
increase in pH of the solution (T/F).
►Ionized form of a drug is likely to be better
absorbed from the GI tract.
►To solubilize a drug, we prepare a drug solution
using as much water as we need (T/F).

16. Dissolution
 The act of dissolving a
drug in a solvent or
biological fluid
 The rate of dissolution is
the rate at which a solid
dissolves into a solvent
 You can assess the extent
of absorption (In vitro) of
drugs from dosage forms
such as tablets and
capsules
 Low dissolution means
(usually) poor absorption
 Dissolution is the rate
limiting step for
absorption of poorly
soluble drug.
 Used as a surrogate for
bioavailability

17. Dissolution assay
 You place tablets or capsules
in a stainless steel wire
basket
 You rotate the basket at a
fixed speed
 Put the basket in the
dissolution medium contained
in a cylindrical vessel.
 Collect sample periodically
and analyze for drug content.
 Plot the amount of drug
against time.
http://www.youtube.com/watch?v=Eqz0X3y3vjs

18. Particle size, shape and surface
area
 A particle is any unit of matter having
defined physical diameter.
 Particle size should be controlled for
oral, parenteral and topical
formulations.
 Bioavailability of a drug substance
depends on particle size
 Flow properties for solid formulations
depends on particle size.
►Dissolution video

19. Particle size, shape and surface
area
 Decrease in particle size,
increases the surface area.
 Increased surface area,
increases solubility, dissolution
and bioavailability.
 Particle shapes affect the flow,
surface area and packing
properties of a powder.
Intact Chopped

20. Crystal properties and
polymorphism
 Polymorphism occurs
when a drug substance
exists in more than one
crystalline form with
different space lattice
arrangements.
 Properties that may vary
due to polymorphisms are
 Physical properties
(melting point)
 Solubility
 Rate of dissolution

21. Polymorphism affects bioavailability
and stability
 A more soluble and fast-dissolving
polymorph is preferred over poorly
soluble and slowly dissolving form
 Usually, only one polymorphic form is
thermodynamically stable at a given
temperature and pressure.
 The less stable forms converts to the
stable form with time
 Stable polymorph exhibits the highest
melting point, the lowest solubility, and
the maximum chemical stability.

22. Assessing of polymorphism
 Hot-stage microscopy
 Single-crystal X-ray
 X-ray powder diffraction
 Thermal analysis

23. Partition and distribution
coefficients
 Measures drug's lipophilicity and determines
drug’s ability to cross cell membranes.
 The ratio of concentration of a compound in the
two phases of a mixture of two immiscible
solvents at equilibrium
Po/w = (Coil/Cwater)equilibrium
 The rate of drug transfer for passively absorbed
drugs is directly related to the lipophilicity of the
molecule.

24. Partition coefficient (LogP)
 The ratio of concentrations of a unionized
compound between an aqueous and organic
solvent
 You can measure the partition coefficient of
ionizable solutes by adjusting the pH so that
compound remains predominantly in the un-
ionized form in the solvent.

25. Distribution coefficient (LogD)
 Log D is the ratio of the sum of the
concentrations of both ionized and
un-ionized form in octanol and
water
 You can measure the distribution
coefficient by adjusting pH with a
buffer that will remain unaffected
due to incorporation of the
compound

26. Determination of partition
coefficients
 Commonly determined using
an oil phase of octanol or
chloroform and water.
 When P is greater than 1,
drug is classified as lipophilic,
when it is less than 1, drug is
hydrophilic

27. Permeation across a biological membrane
 Drug permeability
 The rate of drug transport
across a biological membrane
is called drug permeability.
 Permeability provide
information regarding
absorption characteristics of
a drug.
 You can use cell or isolated
organs for the permeability
study
 Place drug in one side of the
membrane and stir the fluid
 Collect samples periodically
and analyze for the drug
content.
Drug permeation

28. Let’s take the poll
 Decrease in particle size , increases the surface
area and thus increase the drug absorption (T/F).
 Dissolution is the rate limiting step for absorption
of highly soluble drug (T/F).
 Drugs with a higher partition coefficient (Po/w>1) is
likely to be hydrophilic (T/F).
 Two polymorphs of a drug may have different
solubility (T/F).

29. Drug stability
 You have to investigate if a drug undergoes
degradation or loses its efficacy due to any
chemical or physical changes
 Stability dictates what excipients to be used,
storage condition, packaging and shelf-life of a
drug.
 Drug degradation may reduce the quantity of the
therapeutic agent in the dosage form.
 Toxic products may form during the decomposition
process.
 The physical appearance of the dosage may
change due to aging

30. Stability in the GI fluid
Drugs that degrade in the GIT is not
suitable for oral administration
Formulation should protect the drug from
degradation in the GIT
Orally unstable drugs are administered by
other routes of administration including
nasal, parenteral or pulmonary route.

31. Routes of drug degradation
 Hydrolysis or solvolysis
 Decomposes in the presence of solvents
 Oxidation
 React with atmospheric oxygen under the ambient
condition
 Photolysis
 Degrades in normal sunlight or room light

32. Routes of drug instability
 Dehydration
 Removal of water from the
molecule changes the
structure or physical
properties of the molecule.
 Isomerization
 Drugs convert into their
optical or geometrical
isomers. e.g. epinephrine

33. Hygroscopicity
 Hygroscopic substances
 Absorb moistures from the air
 Deliquescent substances
 Absorb moisture from the air to the extent that they
liquefy partially or wholly
 Efflorescent substances
 Substances become powdery and liberate their water of
crystallization
 Drugs that possess any of these physical properties may
not be suitable for solid dosage forms.

34. Wettability
The tendency of a drug to get wet when it
comes in contact with the solvent
Influence the drug granulation process,
penetration of dissolution fluids into tablets
and granules, solubility and dispersibility
Sodium dodecyl sulfate (SDS) increases
wettability

35. Let’s take the poll
 The presence of water causes solvolysis (T/F).
 In dehydration, drugs absorb molecules of water
from the atmosphere (T/F).
 Deliquescent substances become powdery by
releasing the water of crystallization (T/F).