Preformulation is a group of studies that focus on the physicochemical properties of a new drug candidate that could affect the drug performance and the development of a dosage form. ... This property provides the framework for drugs combination with pharmaceutical ingredients in the fabrication of dosage form.

1. Md. Saiful Islam
BPharm, MPharm (PCP)
North South University
Fb Group: Pharmacy Universe
Pre-formulation

2. - Drug molecules are rarely
administered alone.
- They are administered as dosage
forms or formulations.
- Formulation development can be
involved at various stages like animal
studies, first time in human studies,
clinical trials and commercialization of
the product.
What is Preformulation?

3. What is Preformulation?
• Before any formulation development is initiated, the drug molecule is
characterized for certain fundamental physical, chemical properties
and physico-technical properties.
• A thorough understanding of these properties allows science based
development of formulations, by enabling identification of challenges
during formulation development.
• These activities, done prior to initiation of formulation development
are called as pre-formulation studies.
• Pre-formulation can be considered as the learning phase about the
molecule.

4. Points studied in preformulaion works
1) Physical description:
- Most drug substances in use are solid materials and exists
either in crystalline or amorphous form. Physical description of
solid substances includes particle size, crystalline structure,
melting point, solubility etc.
- Liquid drug substances need some special attention in
formulating a dosage form. As many of the liquid drugs are
volatile and evaporates even at low temperature, these require to
keep in a sealed container to prevent evaporation
- Another problem with liquid drug is that without chemical
modification it can't be formulated in tablet form, the most
preferred form of oral medication

5. Physical……
Following approaches are used to formulate the liquid drug in solid
dosage form :
- The liquid substance is sealed in a soft gelatin capsule (e.g.,
Vitamin A, D & E etc.)
- The liquid drug may be converted into solid ester or salt form which
is suitable for tablet or capsule
- The liquid drug may be mixed with a solid or melted semisolid
material like high molecular weight polyethylene glycol. Then the
mixture is poured into hard gelatin capsules and sealed
Formulation and stability difficulties arise less frequently with solid
dosage form than with liquid dosage form. For that reason, many new
drugs first reach the market as tablets or dry filled capsules.

6. 2) Microscopic examination:
- It gives an indication of particle size & the size range of the raw
material along with the crystal structure
- Photomicrographs of drug substances might help to solve any
problem, arising during formulation processing due to change in the
particle or crystal characteristics of the drug
- Spherical and oval powders flow more easily than needle shaped
powder and make processing easier

7. 3) Melting point depression:
- The impure substance will exhibit a change in melting point. This
phenomenon is commonly used to determine the purity of a drug
substance & in some cases, the compatibility of various substances
before inclusion in the same dosage form
4) The phase diagram:
- A phase diagram, which is a temperature-composition diagram &
represents the melting point as a function of composition of two or
three component system, often constructed to provide a visual
picture of the existence and extent of the presence of solid & liquid
phases in mixtures

8. 5) Particle size:
- Particle size of drug substances affects certain physical & chemical
properties including dissolution rate, bioavailability, content
uniformity, taste, texture, color & stability
- In addition, flow properties & sedimentation rates are also related to
particle size
6) Polymorphism:
- Evaluation of crystal form , polymorphysm and solvate form is an
important preformulation study
- A drug substance may exist in different polymorphic form. Each
polymorphic form exhibits different physicochemical properties
including melting point and solubility
- Compounds may also occur in noncrystalline or amorphous form

9. Polymorphism…….
- A drug substance takes more energy to escape from crystalline form
compared to amorphous powder
- Changes in crystal characteristics may influence bioavailability,
physical and chemical stability and can influence the processing
function
- Hot stage microscopy, thermal analysis, IR spectroscopy, X-ray
diffraction are the widely used techniques for the determination of
crystal properties

10. 7) Solubility:
- Solubility is the indicative of maximum concentration that can be
dissolved in the solvent to form a saturated solution. Thus it is
expressed as grams of solute dissolving in volume of solvent.
- Solubility, specially aqueous solubility is an important
physicochemical property of a drug substance
- For therapeutic efficacy, a drug must be in solution at first to enter
into the systemic circulation

11. Solubility….
If the solubility of the drug substance is less than the
desired -
- Chemical modification of the drug into salt or ester is done to
increase the solubility
- In many cases, co-solvents are used or complexation,micronization
or solid dispersion technique might use to overcome the solubility
problem
- A small increase in solubility can be brought about by reducing the
particle size
- In case of liquid dosage form, the PH adjustment of the solvent may
enhance solubility. But it has a little effect. Sometimes it may cause
stability problem with formulation ingredients.

12. Drugs solubility is determined by the equilibrium solubility
method, in which –
- an excess of the drug is placed in a solvent shaken at a constant
temperature for a long period until equilibrium is obtained.
- undissolved drug is separated and drug content in solution is
chemically analyzed to determine the degree of solubility
Solubility…….

13. 8) Dissolution:
- The time required for the drug to dissolve in the body fluid at the
absorption site is dissolution rate
- Dissolution is the rate limiting step of absorption
- It can also affect the onset, intensity & duration of action and control
the overall bioavailability of the drug from the dosage form
The dissolution rate may be increased by the following ways:
- by decreasing the drugs particle size
- by making a highly soluble salt of parent substance
Preformulation study should include the effects of excipients on the
dissolution characteristics of drug substance

14. 9) Membrane permeability:
- To produce biologic response, a drug substance should cross a
biological membrane at first
- The biologic membrane act as a lipid barrier for drug molecules and
permits the absorption of lipid soluble substances by passive
diffusion.
- Lipid insoluble drugs can cross the biologic membrane with
considerable difficulty

15. Modern preformulation studies include an early assessment of
passage of drug molecules across biological membranes
The commonly used method, to evaluate both passive & active
transport, is-
- A piece of intestine is removed from an intact animal , everted and
filled with a solution of drug substance
- The degree & rate of passage of drug through the membrane sac is
determined
Membrane permeability…….

16. 10) Partition co-efficient:
- To predict the absorption of any drug, it is desirable to know its
partition coefficient or distribution coefficient, which gives the idea of
the concentration of unionized drug likely to pass through the
biological membranes.
- Since we know biological membranes are consisting of lipoidal
bilayers, which are impermeable to most of the drugs and favor the
permeation of unionized portion of the drug.

17. Partition co-efficient…..
- Therefore, to study the effect of partitioning, a number of organic
solvents with a portion of aqueous medium were tried like
chloroform, ether, isopropyl myristate, n-octanol etc. These solvents
depict the lipid nature of the biological membranes. Amongst all the
solvents, n-octanol simulated best with the body lipids.
- The drugs with good partition coefficient values show greater
absorption as they penetrate the complex lipids of the biological
membranes.

18. 11) Pka / dissociation constant:
• Mostly the drug molecules are weak acidic or weak basic in nature,
which in turn depends on the degree of ionization that gives the ratio
of extent of ionized and unionized form of the drug thereby ultimately
determines the solubility and dissolution of the drug.
• The total solubility of any drug moiety is the sum of ionized
concentration and unionized concentration.
• The unionized concentration is thermodynamic parameter
influenced by temperature and pressure, however the ionized
concentration determines the aqueous solubility of the drug and is
dependent on the pH of the solution.

19. Pka ……
• The ionization constant (dissociation constant) is expressed as pKa.
It is determined by potentiometric titration.
• pKa is defined as pH at which drug is half ionized that is, the ratio of
concentration of ionized Vs unionized is 1
• pKa helps in determining the site of absorption of the drug i.e.
whether the drug will be absorbed in stomach (pH-1), lumen of the
intestine (pH 6.6) or blood plasma (pH 7.4), thereby gives the idea
for selective dosage form design and the route of administration.

20. Pka ……
- The extent of dissociation or ionization of drug substance is the
important physicochemical characteristic.
- In many cases, it is highly dependent on the pH of the medium
containing the drug
- In formulation, often the solvent pH is adjusted to obtain a certain
level of ionization of drug for its solubility and stability
- For the practicing pharmacist, it is important to predict the
precipitation in admixtures and to calculate the solubility of drugs at
certain pH value

21. Now students are able to answer the following questions:
1. What is pre-formulation study? What is its importance?
2. What do physical descriptions of molecule during pre-formulation
study include?
3. How can you formulate a liquid drug in solid dosage form?
4. What is done in microscopic examination of molecule during pre-
formulation study ?
5. What do you mean by melting point depression? How does the
melting point depression of a drug molecule in a formulation is
checked?
6. What parameters of a drug molecule are influenced by particle
size?
7. What would be the considerations in pre-formulation stage if the
drug is crystalline or non-crystalline?

22. Questions……
8. Define solubility. What is the equilibrium solubility method?
9. How can you optimize the solubility of a drug molecule if it is less
than the desired?
10. What is the importance of dissolution testing in pre-formulation
stage?
11.Why the lipid solubility character of a drug molecule is important?
How can the lipid solubility be checked at pre-formulation stage?
12. What is partition co-efficient? Why it is important?
13. What is pKa or dissociation constant? What is the importance of
pKa measurement of a drug molecule?