This presentation gives details for the preformulation studies of herbal cosmeceuticals & pharmaceuticals.

1. Preformulation
Studies of
Herbal
Cosmetics
Presented by : Chhavi Singh
M. Pharm 1 year
Enroll. No. 155/MPG/SPS/2020

2. CONTENTS
• Preformulation Studies
• Principles
• Organoleptic Characters
• Physical Description & Bulk Characterization
• Solubility Analysis
• Stability Analysis
• References

3. 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 could provide important information for formulation design or support the need for
molecular modification.
• Every drug has intrinsic chemical and physical properties which has been consider
before development of pharmaceutical formulation.
• This property provides the framework for drugs combination with pharmaceutical
ingredients in the fabrication of dosage form.
• Preformulation study is done to develop the elegant, stable, effective and safe dosage
form by establishing kinetic rate profile, compatibility with the other ingredients and
establish Physicochemical parameter of new drug substances.
PREFORMULATION STUDIES

4. Preformulation studies include :
• Studies of Assessment of physicochemical properties of herbal extracts and their
relevance to the final formulation
• The physical and chemical stability of the herbal extracts
• Compatibility studies of the herbal extracts with potential excipients
GOALS
To establish
The physicochemical parameters of a new drug
Its physical characteristics
Its compatibility with common excipients
Providing a scientific data to support the dosage form design and evaluation of the product
efficacy and stability.

5. PRINCIPLE OF PREFORMULATION STUDIES

6. Organoleptic Characters
• Color: If the color is undesirable or variable,
incorporation of a dye in the final product is
recommended.
• Taste: If taste is considered to be
unpalatable, a less soluble form of the drug
(salt or prodrug) ought to be considered.
• Odor: The substance may exhibit an
inherent odor characteristic of major
functional groups present. Odor greatly
affects the flavor of a preparation or food
stuff.

7. The major areas of Preformulation research
A. PHYSICAL DESCRIPTION & BULK CHARACTERIZATION
• Crystallinity and Polymorphism
• Hygroscopicity
• Fine Particle Characterization
• Thermal Effects
• Powder Flow Properties
• Identification of drug substance
B. SOLUBILITY ANALYSIS
• Ionization Constant- pKa
• pH Solubility Profile
• Common Ion Effect
• Solubilization
• Partition Coefficient
• Dissolution
C. STABILITY ANALYSIS
• Preliminary stability evaluation

8. • Drugs can be used therapeutically as solids, liquids and gases.
• Solid materials are preferred in formulation work because of their ease of
preparation.
• The majority of drug substances in use occur as solid materials.
• Most of them are pure chemical compounds of either:
- Amorphous (higher solubility)
- Crystalline in nature (higher stability)
Crystallinity and Polymorphism
The amorphous or crystalline characters of drugs are of great importance to its
ease of formulation and handling, its chemical stability and its biological
activity.
PHYSICAL DESCRIPTION AND BULK CHARACTERIZATION

9. AMORPHOUS DRUGS
• Amorphous drugs have randomly arranged
atoms or molecules.
• Amorphous forms are typically prepared by
precipitation, lyophilization, or rapid cooling
method.
CRYSTALLINE DRUGS
• Crystals are characterized by repetitious
spacing of constituent atoms or molecules in
a 3-D array.
• Crystalline forms of drugs may be used
because of greater stability than the
corresponding amorphous form.

10. POLYMORPHISM
Polymorphism is the ability of a compound to crystallize as more than one distinct
crystalline species with different internal lattices or crystal packing arrangement even
they are chemically identical depending on the variation in :
a. Temperature
b. Solvent
c. Time
Significance of polymorphism
• Different polymorphs exhibit different solubilities, therapeutic activity and stability.
• Chemical stability and solubility changes due to polymorphism can have an impact on
drug’s activity.

11. Hygroscopicity
• Many drugs, particularly water-soluble salts, have a
tendency to adsorb atmospheric moisture.
• Changes in moisture level can greatly influence
many parameters such as ; chemical stability,
flowability, and compatibility.
• Adsorption and equilibrium of moisture content can
depend upon ; atmospheric humidity, temp,
surface area, exposure, and the mechanism for
moisture uptake.
Analytic methods for monitoring the moisture level
are :
• Gravimetric Method
• Karl Fischer titration
• Gas chromatography

12. Fine Particle Characterization
• Size, shape & surface morphology of drug particles affect the flow property,
dissolution & chemical reactivity of drugs. The effect is not only on the physical
properties of solid drugs but also, in some instances, on their biopharmaceutical
behavior.
Significance of Particle Size:
• Particle size of drugs may affect formulation and product efficacy.
• Certain physical and chemical properties of drug substances are affected by the
particle size distribution including; drug dissolution rate, content uniformity, texture,
stability, flow characteristics, and sedimentation rates.
• Satisfactory content uniformity in solid dosage forms depends to a large degree on
particle size and the equal distribution of the active ingredient throughout the
formulation.

13. Methods To Evaluate Particle Size & Distribution:
Sieving or screening:
• Disadvantage: It requires a relatively large sample size.
• Advantage: Simplicity in technique and equipment requirements.
Optical microscopy:
• It is the first step in the determination of particle size and shape for substance.
• Quantitative evaluations need min. 300 particles (tedious and time consuming).
Sedimentation:
• It utilizes the relationship between rate of fall of particles and their size.
Stream scanning:
• Technique utilizes a fluid suspension of particles which pass the sensing zone where
individual particles are sized, counted & tabulated.
• Sensing units are based on ; light scattering transmission, as well as conductance.
• The popular unit in the pharmaceutical industry for this purpose is the Coulter Counter.

14. SURFACE MORPHOLOGY
• Observed by Scanning Electron Microscopy (SEM), which serves to confirm the physical
observations related to surface area.
• Surface morphology of drug can provide greater area for various surface reactions
such as; degradation, dissolution, or hygroscopicity.
• Surface roughness leads to poor powder flow characteristics of powders due to friction
and cohesiveness.

15. Thermal Effects
Differential scanning calorimetry and Differential thermal analysis [DSC & DTA]
• Measure the heat loss or gain resulting from physical or chemical changes within a
sample as function of temperature.
Thermo gravimetric analysis (TGA)
• Measure changes in sample weight as a function of time (isothermal) or function of
time (isothermal) or temperature.
• De-solvation and decomposition processes are frequently monitored by TGA.
Applications of TGA:
• Purity, polymorphism, solvation, degradation, and excipient compatibility.
• To investigate and predict any physicochemical interactions between components in
the formulation.
• Used for selection of chemically compatible excipients.

16. X-RAY DIFFRACTION
• It is an important technique for establishing the batch-to batch reproducibility of a
crystalline form.
• Each diffraction pattern is characteristic of a specific crystalline lattice for a given
compound.
Applications
• Quantitative ratios of two polymorphs and their percentages of crystallinity may be
determined.
• Mixtures of different crystalline forms can be analyzed using normalized intensities at
specific angles, which are unique for each crystalline form.

17. Powder Flow Properties
• Flow properties are significantly affected by: Changes in particle size, density,
shape, and adsorbed moisture, which may arise from processing or formulation.
• The powder flow properties can be characterized by the following methods:
- Angle of Repose
- Compressibility
Angle of repose
• It is the maximum angle between the surface of a pile of powder and horizontal
plane.
Tan θ= h/r
• The rougher and more irregular the surface of the particles, the higher will be the
angle of repose.
• Lower values indicate better flow characteristics.

18. The acceptance criteria for angle of
repose are:
Compressibility
Characterized by Carr’s compressibility index.
Carr’s compressibility index
The acceptance criteria for Carr’s index are:

19. SOLUBILITY ANALYSIS
• The solubility of drug is an important physicochemical property because it affects
the bioavailability of the drug, the rate of drug release into the dissolution
medium, and consequently, the therapeutic efficacy of the pharmaceutical
product.
• Solubility is usually determined in a variety of commonly used solvents and some
oils if the molecule is lipophilic.
• The solubility of a material is usually determined by the equilibrium solubility
method, which employs a saturated solution of the material, obtained by stirring
an excess of material in the solvent for a prolonged period until equilibrium is
achieved.
General rules –
• Polar solutes dissolve in polar solvents
• Non-polar solutes dissolve in non-polar solvents

20. Solubility can be determined as:

21. Ionization constant
• For a compound containing basic or acidic functional groups, solubility at a given pH is
influenced by the compound’s ionization characteristics.
• The solubility of a compound in aqueous media is greater in the ionized state than in the
neutral state. Thus, solubility of ionizable compounds is dependent on the pH of the
solution.
• Considerations for an ionizable compound include the impact of ionization on stability
and permeability.
• The Henderson-Hasselbalch equation provides an estimate of 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])
• pKa of a compound is thus a measure of drug un-ionized at a certain pH.

22. Uses of these equations
• To determine pka.
• To predict solubility at any pH provided
that Co & pKa are known.
• To facilitate the selection of suitable salt
forming compounds.
• It predicts the solubility & pH properties of
the salts.
Methods for determination of pKa
a. Potentiometric method
b. Spectrophotometric method
c. Solubility method
d. Conductometric method

23. pH solubility profile
• It is a set of solubility values at specified pH values. The values given in a
pH profile refer to solubility as a function of pH for all species of the
compound (ionizable and neutral) in solution.
• Necessary to delineate solubility in complex situations where multiple
ionizable species are present.
METHODS TO DETERMINE SOLUBILITY
a. SHAKE-FLASK METHOD
b. POTENTIOMETRIC TITRATION METHOD
c. TURBIDIMETRIC METHOD

24. Partition coefficient
• Measure of a drug's lipophilicity and an indication of its ability to cross cell membranes.
• Defined as the ratio of un-ionized drug distributed between the organic and aqueous
phases at equilibrium.
Po/w = (Coil/C water) equilibrium
P > 1 Lipophilic drug.
P < 1 Hydrophilic drug.
• For drug delivery, the lipophilic/hydrophilic balance has been shown to be a contributing
factor for the rate and extent of drug absorption.
• It provides a means of characterizing the lipophilic/hydrophilic nature of the drug.
• Commonly determined using an oil phase of octanol or chloroform and water.
Applications of Partition Coefficient
• Measure of Lipophilic character of molecules.
• Recovery of antibiotics from fermentation broth.
• Extraction of drug from biological fluid for therapeutic monitoring.
• Absorption of drug from dosage forms.
• Study of distribution of flavoring oil between oil & water in emulsion.

25. Dissolution
Dissolution rate data, when combined with the solubility, partition coefficient,
and pKa results, provide some insight into the potential in-vivo absorption
characteristics of drug entity.
The dissolution rate of drug substances may be affected by:
• Chemical form: The acid, base, and different salt forms may give significant
differences.
• Crystal form: Polymorphs will differ in dissolution rates; solvates usually exhibit
a higher dissolution rate in aqueous media.
• Particle size: Reduction of particle size produces a greater surface area.
• Surface properties of the drug: High surface energy of a micronized powder
may result in poor wetability and agglomerates.

26. STABILITY ANALYSIS
Development of a drug substance into a suitable dosage form
requires the Preformulation stability studies of drug under the following
categories :
i. Stability study in toxicology formulation
ii. Stability study in solution state
iii. Stability study in solid state
Stability study in toxicology formulation
A new drug is administered to animals through oral route either by:
I. Mixing the drug in the feed
II. In the form of solution
III. In the form of suspension in aqueous vehicle

27. Solution Stability
• Stability of a new drug may depend on:
• pH
• Ionic strength
• Co-solvent
• Light
• Temperature
Solid state stability
•Identification of stable storage conditions for drug
in the solid state and identification of compatible
excipients for a formulation.
Drug-excipient stability profile
•Hypothetical dosage forms are prepared with
various excipients and are exposed to various
conditions to study the interactions of drug and
excipients.

28. • fatima-180922054341.pdf
• https://www.researchgate.net/publication/320373570_Preformulation_studies
• https://ijpsr.com/bft-article/a-review-on-pharmaceutical-preformulation-studies-in-
formulation-and-development-of-new-drug-molecules/
• https://www.researchgate.net/publication/319980566_PREFORMULATION_STUDIES
• https://www.researchgate.net/publication/330193840_AN_OVERVIEW_ON_PREFORMULATI
ON_STUDIES
• https://www.researchgate.net/publication/286453649_Preformulation_Studies_of_Pharmac
eutical_New_Drug_Molecule_Products_An_Overview
REFERENCES

29. Thank you !!