preformulation

1. PREFORMULATION
Presented b
Miadur rahman
+8801671952533
1

2. 1.Concept of preformulation
2.Steps in preformulation process
3. Organoleptic Properties of Drugs
4. Purity
5. .Melting point
6.Stability
7.Excipient compatibility
8.Solubility
9.Polymorphism
10.pH & pKa
11. Salt Formation
12. Partition coefficient
references
Contents

3. PREFORMULATION
It can be defined as an investigation of physical
and chemical properties of a drug substance -
alone and or when combined with excipients.
The overall objective of preformulation testing is
to generate information useful to the formulator
in developing stable and safe dosage forms with
good bioavailability.

4. THE CONCEPT OF PREFORMULATION
Almost all drugs are marketed as tablets, capsules or
both. Prior to the development of these major
dosage forms, it is essential that certain
fundamental, physical and chemical properties of
the drug molecule and other properties of the drug
powder are determined. This information decides
many of the subsequent events and approaches in
formulation development.
This first learning phase is known as
preformulation.

5.  During the early development of a new drug substance, the
synthetic chemist, alone or in cooperation with specialists in
other disciplines (including preformulation), may record some
data which can be appropriately considered as preformulation
data.
 This early data collection may include such information as
- Gross particle size,
- Melting point,
- Infrared analysis,
- Thin-layer chromatographic purity,
- And other characteristics .
 These data are useful in guiding, and becoming part of, the
main body of preformulation work.

6. 1. Stability
a. Solid State
(1) Temperature
(2) Light
(3) Humidity
b. Solution
(1) Solvent
(2) pH
(3) Light
2.Physico-chemical Properties
a. Molecular Structure and Weight
b. Color
c. Odor
d. Particle size, Shape, and Crystallinity
e. Melting Point
f. Thermal Analysis Profile
(1) DTA
(2) DSC
(3) TGA
g. Hygroscopicity Potential
h. Absorbance Spectra
(1) UV
(2) IR
i. Solubility
(1) Water and Other Solvents
(2) pH-Solubility Profile
(3)Salt Forms
(4) Co solvents
(5) Complexation
(6) Prodrug
j. partition coefficient
k. polymorphism potential
3. Physico-mechanical Properties
a. Bulk and Tapped Density
b. Compressibility
4. In Vitro Availability Properties
a. Dissolution of Drug Crystal Per sec
b. Dissolution of Pure Drug Pellet
c. Dissolution Analysis of Pure Drug
5. Other Studies
a. Plasma Protein Binding
b. Effect of Compatible Excipient on Dissolution
c. Kinetic Studies of Solution Degradation
Steps in Preformulation Process Pharmaceutical Research

7. Preformulation is the first step in the rational development of
dosage form of a drug substance/ why do preformulation
testing?
Below some important reasons are mentioned as to why
preformulation testing is important in drug development.
i. To aid in the candidate drug selection
ii. To aid in the product design
iii. To aid in the product design
iv. To decrease the time required to introduce the product into
market
v. For overall safety and efficacy of the product

8. Organoleptic Properties of Drugs
• Organoleptic properties:
–Color
–Odor
–Taste

9. Color
• Identification of color is an important factor of
preformulation studies.
• Addition of colorant improves drug adherence.
• Color Intensity also relates to the presence of
chromophores.

10. Odor & Taste
• Odor
– The substance may exhibit an inherent odor
characteristic of major functional groups
– Odor greatly affects the flavor of the preparation
• Taste
– Taste is very important for patients compliance
– Taste may be suppressed by using appropriate
flavors and excipients or by coating the final
product.

11. Purity

12. Purity
• Designed to estimate the levels of all known &
significant impurities & contaminants in the
drug substance under evaluation.
• Purity test is performed in an analytical
research & development group.
• Occasionally, an impurity can affect stability.

13. Purity
• Thin layer chromatography is a wide ranging
applicability & is an excellent tool for
characterizing the purity.
• HPLC & gas chromatography are also useful.
• More quantitative information can be obtained
by using quantitative differential scanning
colorimetry.

14. Particle Size

15. Particle Size
• Various Chemical & physical properties of
drug substances are affected by their particle
size distribution and shapes.
• The effect is not only on physical properties
but also on it’s chemical properties.
• It also influence the flow and the mixing
efficacy of granules and powders.
• Fine materials are relatively more open to
attack from atmospheric humidity, oxygen.

16. Particle Size
• Various Chemical & physical properties of
drug substances are affected by their particle
size distribution and shapes.
• The effect is not only on physical properties
but also on it’s chemical properties.
• It also influence the flow and the mixing
efficacy of granules and powders.
• Fine materials are relatively more open to
attack from atmospheric humidity, oxygen.

17. MELTING POINT
Defined as the temperature at which the solid and liquid phases are in equilibrium .
the melting point of a drug can be measured using three techniques:-
1) Capillary melting
2) Hot stage microscopy
3) Differential scanning calorimetric or thermal analysis.
Capillary melting :-
Capillary melting gives information about the melting range but it is different to assign
an accurate melting point.
Hot stage microscopy:-
This the visual observation of melting under a microscope equipped with a heated and
lagged sample stage. The heating rate is controllable and up to three transitions can be
registered. These values are more accurate .
Differential scanning calorimetric and thermal analysis :-
Differential thermal analysis (DTA) measures the temperature difference between the
sample and a reference as a function of temperature or time when heating at a constant
rate .

18. Stability
To design dosage form it is necessary to know the inherent
stability of the drug. This includes the solid state stability of
the drug, stability of the drug in presence with excipients and
stability in solution including gastric fluids. How degrading
factors like hydrolysis, oxidation, photolysis etc. affect the
drug must also be investigated.
a)Solid State:
1. Temperature
2. Light
3. Humidity
b)Solution :
1. Solvent
2. pH
3. Light

19. Excipient compatibility:
In the dosage form a drug is intimately
related to one or more excipients. These
excipients may affect the stability of the drug
making them incompatible. So excipient
compatibility testing is important to select the
appropriate excipient. This can be done by
chromatography and DTA.

20. Test Method/function/characterization
Spectroscopy Simple UV assay
Solubility
Aqueous
pKa
Salts
Solvents
Partition coefficient
Dissolution
Phase solubility, purity
Intrinsic solubility, pH effects
Solubility control, salt formation
Solubility, hygroscopicity, stability
Vehicles, extraction
Lipophilicity, structure activity
Biopharmaceutics
Melting point DSC, polymorphism, hydrates, solvates
Assay development UV, TLC, HPLC
Stability (in solution and solid state) Thermal, hydrolysis, oxidation, photolysis, metal
ions, pH
Microscopy Morphology, particle size
Powder flow
Bulk density
Angle of repose
Tablet and capsule formulation
Compression properties Tablet and capsule formation
Excipient compatibility Excipient choice

21. Solubility
Any solid drug must dissolve in the gastric fluid before absorption and action. So
the absorption, distribution, action, excretion etc. will only take place when it
dissolves in the relevant biological fluid. Thus determination of solubility is very
important.

22. Aqueous solubility:
The solubility of the drug in aqueous solvent is important for two reasons-
• whether liquid dosage form can be prepared for oral and parenteral
administration.
• Whether the bioavailability will be affected due to low solubility
Kaplan’s suggestion:
the aqueous solubility of a compound over pH 1-7 at 37⁰C is
• Below 0.1% (<1 mg/mL) then potential bioavailability problem is likely to occur.
• Between 0.1-1% (1 mg/mL – 10 mg/mL) then bioavailability problem may occur.
• Above 1% (>10 mg/mL) then bioavailability problem is not expected.

23. Intrinsic solubility (C0):
The solubility of a compound (a acid or base) in the solvent of
same nature is the compound’s intrinsic solubility.
The intrinsic solubility should be measured at two
temperatures-
I. 4⁰C to ensure physical and chemical stability.
II. 37⁰C for biopharmaceutical evaluation

24. Solubility in other solvents:
Determination of solubility of a drug in other solvents and solvents mixture is necessary –
In the development of liquid formulations when water itself doesn’t impart sufficient
solubility or stability.
 In the development of assay methods.
Some solvents used in preformulation studies:
Solubility Analysis:
i. Analytical method
ii. Synthetic method

25. Polymorphism
Polymorphs are crystalline substances which are chemically same but differ in
the physical properties due to different molecular arrangement. Such differing
factors include density, melting point, solubility etc. the phenomena of existing as
different polymorphs is termed polymorphism.
During crystallization few things can happen-
• If the crystallization conditions are kept constant throughout then the original
crystal structure should be obtained.
• But if the crystallization conditions are changed then leading to polymorphism.

26. Polymorphism can be classified into 2 types:
 Enantiotropic
 Monotropic
During Preformulation it is important to
1. Identify the polymorph that is stable at room temperature.
2. Determine whether polymorphic transitions are possible within
the temperature range and during processing.
Examples:
 Chloramphenicol exist in A,B & C forms, of these B form is more
stable & most
preferable.
 Riboflavin has I,II & III forms, the III form shows 20 times more
water solubility than form I.

27.  Effect of polymorphism on chemical stability:
Different polymorph will have different stability. This can be advantageous as
possible use of suitable polymorph may resolve stability issue. But this becomes
disadvantageous when polymorphs with less stability arise during processing.
A more specific example is Aztreonam, an antibiotic that exists in needle-like form
(α form) and dense spherical form (β form).
 Effect of polymorphism on physical stability:
At a given condition metastable polymorphs may form. Metastable polymorphism
show adequate stability and solubility which make useful them in drug design.

28. • Polymorphism may also affect physical stability of the dosage form. Steps like
granulation may cause solvate formation whereas drying may cause solvate to transform
into anhydrous or amorphous forms. These conversions may be undesirable and the
formulator must assure integrity of the desired polymorph by proper handling.
• A specific example is carbochromen hydrochloride tablets in high humid crackings are
observed due to conversion of anhydrous form into hydrate.
 Effect of polymorphism on bioavailability:
A classic example of the importance of polymorphism in bioavilability can be illustrated
with chloramphenicol palmitate suspension.
o So it is obvious that the stable form
will have less dissolution and
bioavilability than the metastable form.

29. Powder Flow Properties
Flow properties can be affected by change in particles size, shape and density.
Carr’s Index Determination Determination of powder flow properties:

30. Ionization constant
75 % drugs are weak bases, 20 % drugs are weak acids and
5 % drugs are nonionic and amphoteric form
Ionization constant usually important in the absorption of
weakly acidic and basic drug because . It is used to…
Calculate the change of solubility with ph
Manipulate the pH to increase solubility
Select suitable salt form of the drug if needed.

31. The Henderson-Hasselbalch equation describes the
relationship between pH, pKa,

32. • For base PH = Pka + log [unionised] / [ionised]
• The ionization constant (dissociation constant)
is also important in the determination of
absorption into biological membrane

33. SALT
FORMATION

34. • If a weak acidic or basic drug have insufficient solubility then
its solubility can be improved by suitable salt formation
• Salt are always more soluble then the corresponding acid or
base under all ph condition
• Some of the common counter ions used in salt formation
For acidic drug For basic drug
potassium Hydrochloride
sodium Sulphate
calcium phosphate
zinc citrate

35. • Example: diclofenac sodium, hare the counter
part is sodium so it’s a acidic drug
Parent drug Salt form of drug
Promethagine Promethagine hydrochloride
salbutamol Salbutamol sulphate
Diclofenac Diclofenac sodium

37. Partition coefficient indicates how a drug will distribute itself
between two immiscible liquid
It gives the idea about relative hydrophilicity and lipophilicity
If a drug is added in two immiscible liquids than it will distribute
itself between the two phases in such a way so that the ratio of the
concentrations of the drug in the two layers is a constant at constant
temperature. This constant is known as distribution coefficient or
partition coefficient

38. • If the concentration in solvent A is C1 and the concentration
in solvent B is C2 where A and B are immiscible then
partition coefficient-
• In Pharmacy, the concentration of the organic phase is
written in the numerator and the concentration of the
aqueous phase is written in the denominator. Thus-

39. Partition coefficient or distribution coefficient is also expressed as log P. it
gives us idea about-
• The lipophilicity and the hydrophilicity of the drug. The larger the value
of P the greater is the lipophilicity of drug.
• How quickly or slowly absorption and bio-membrane transportation will
occur.
• Blood and body fluids are normally aqueous in nature where the
biological membranes are lipid in nature. Therefore drugs with high P
values will have greater affinity towards the membrane and bio-
membrane transportation will be favored. But bio-membrane
transportation will be slower for drugs with smaller P values.

40. Conclusion
• Preformulation studies have a significant part
to play in anticipating formulation problems
and identifying logical path in both liquid and
solid dosage form technology.
• The most appropriate salt development and
Stability studies in solution will indicate the
feasibility of parental or other liquid dosage
form and can identify methods of stabilization.

41. References:
1.Leon Lachman, Herbert A lieberman,The theory and practice of industrial
pharmacy 2009.
2.G. Banker and C.T. Rhodes, Modern Pharmaceutics, Marcel Dekker, Inc.,
2000.
3.H. Brittain, Physical Characterization of Pharmaceutical Solids, Marcel
Dekker, Inc., 1995.
4. H. Brittain, Polymorphism in Pharmaceutical Solids, Marcel Dekker, Inc.,
1999.
5.S.R. Byrn, R.R. Pfeiffer and J.G. Stowell, Solid State Chemistry of Drugs,
Second Edition, SSCI, Inc.,1999.
6.M. Gibson, Pharmaceutical Preformulation and Formulation, HIS Health
Group, Englewood, CO, 2001.
7.D.J.W. Grant and T. Higuchi, Solubility Behavior of Organic Compounds, John
Wiley & Sons, Inc., 1990.
8.L.J. Ravin and G.W. Radebaugh, “Preformulation”, Chapter 75 in Remington’s
Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton,
Pennsylvania, 1990.
9.S. Yalkowsky, Solubility and Solubilization in Aqueous Media, American
Chemical Society, Washington D.C. 1999.
10. Aulton’s pharmaceutics. The design and manufacture of medicines.2009.
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