SHRI VISHNU COLLEGE OF PHARMACY: BHIMAVARAM
(AUTONOMOUS)
M.PharmII Semester Regular Examinations,
Sub:Pharmaceutical and Cosmetic Product Development (MPH 204T)
Time:3 Hours Max. Marks: 70M
Note: 1. Answer all the 5 Questions
2. Each Question carries 14 Marks
3. Answer any one question from each unit.
1. a) Describe in detail about the preformulation studies with respect to dosage form
necessities and physical and chemical properties.
Pre formulation studies characterize physical and chemical properties of a drug molecule in
order to develop safe, effective and stable dosage form. In pre-formulation studies,
physicochemical properties of drug molecules are characterized either alone or in
combination with excipients.
Physical Properties: 1. Physical form (crystal & amorphous) 2. Particle size, shape, 3.
Polymorphism 4. Flow properties, 5. Solubility profile (pka, pH, Partition Coefficient)
Chemical Properties of Drug Substances: a) Oxidation & Reduction b) Hydrolysis c)
Photolysis d) Racemization e) Polymerization f) Isomerization
b) Explain the role of DSC technique in drug development?
DSC is commonly used in pharmaceuticals to determine purity, detect polymorphism, and
study stability and compatibility. It provides information on thermal events and material
properties through measurements of heat flow versus temperature.
2. a) Appraise the importance of preformulation studies? Summarize the steps involved
in preformulation studies.
Preformulation studies provide a path for formulation development and drug product
development in respect of drug form, adjuvants, composition, physical structure, and
chemistry of drug molecules, facilitating pharmacokinetic and biopharmaceutical properties
evaluation, adjustments, and their implementation to get an appropriate end product.
b) Explain the polymorphism and its influence in the formulation of solid and liquid dosage
forms.
It is the ability of the compound to crystallize as more than one distinct crystalline species with
different internal lattice. Different crystalline forms are called polymorphs but their chemical
composition remain same. Polymorphs are of 2 types • Enatiotropic • Monotropic
Depending upon their relative stability, one of the several polymorphic form will be physically
more stable than others. • Stable polymorph represents the lowest energy state, has highest
melting point and least aqueous solubility. • Metastable form represent the higher energy state,
have lower melting point and high aqueous solubility . • Metastable form converted to the stable
form due to their higher energy state. • Metastable form shows better bioavailability and
therefore preferred in formulations. • Only 10% of the pharmaceuticals are present in their
metastable form. • Solubility (particularly important in suspensions and biopharmaceutically),
melting point, density, crystal shape, optical and electrical properties and vapour pressure are
often very different for each polymorph. • Polymorphism is remarkably common, particularly
within certain structural groups: 63% of barbiturates, 67% of steroids and 40% of sulphonamides
exhibit polymorphism. • The steroid progesterone has five polymorphs, whereas the
sulphonamide sulphabenzamide has four polymorphs and three solvates.
Polymorphs differ from each other with respect to their physical property such as • Solubility •
Melting point • Density • Hardness • Compression characteristics.
3. a) Summarize the experimental determination of solubility of poorly aqueous soluble
drugs.
The most common method for the determination of thermodynamic solubility of a drug is the
shake-flask method. In this method, an excess amount of drug is added to the solubility medium.
The added amount should be enough to make a saturated solution in equilibrium with the solid
phase.
Other methods: Shake-flask method, Miniaturized Shake-flask method, Small scale Shake-flask
method (SSF approach), Miniature devices, Equilibrium 96-well microtiter plate methods,
Column elution method.
b) Categorize various approaches for the solubility enhancement of drugs and explain with
examples.
Approaches for solubility enhancement of drugs:
Physical Modifications: A. Particle size reduction 1. Micronization 3.Sonocrystalisation 2.
Nanosuspension 4.Supercritical fluid process B. Modification of the crystal habit 1. Polymorphs
2. Pseudopolymorphs C. Drug dispersion in carriers 1. Eutectic mixtures 2. Solid dispersions 3.
Solid solutions D. Complexation Use of complexing agents E. Solubilization by surfactants
Microemulsions
II. Chemical Modifications: 1. Change in the pH 2. Use of buffer 3. Derivatization III. Other
methods 1.co-crystallisation 2. co-solvency 3.Hydrotrophy 4.Solubilizing agents 5.Selective
adsorption on insoluble carrier 6.Solvent deposition 7.Using soluble prodrug 8.Functional
polymer technology 9.Precipitation Porous 10.microparticle technology 11.Nanotechnology
approaches
4. a) Explain the significance of pH-solubility profile in dosage form development.
pH = − Log [H+ ] pH scales from 1 to 14 acid pH < 7 neutral = 7 alkali/basic= >7 Importance of
pH in preformulation 1. Injections should be in range of pH 3-9 to prevent tissue damage and
pain at injection site. 2. Oral syrups cannot be formulated too acidic for palatability reasons. 3.
More alkali may attack the glass container. 4. If drug is susceptible to degradation in acidic pH,
then its delayed release formulation is to be prepared. 5. The pH of formulation must not
sensitize the site of application. e.g. pH for buccal application should in the range of 6.6 to 6.8. 6.
GIT shows a variety of pH [pH 6.6 (buccal), pH 1.2 (stomach), pH 6.8 duodenum, pH 7-8 (small
intestine)] throughout its length from oral cavity to colon. The dosage form should be stable at
the pH of the intended or target site of absorption.
Ionization constant (pKa) Strong acids, e.g., HCl, are ionized at all pH values, whereas the
ionization of weak acids is dependent on pH. Why are we more concerned about weak acid or
base? Because, most of the drugs are either weak acid or base or its salt. It is very important to
know the extent to which the molecule is ionized at a certain pH, since properties such as
solubility, stability, drug absorption and activity are affected by this parameter. The Ionization
constant (pKa) provides this information.
The relationship of pH, pKa and solubility
pH= pKa + Log (S − Su)/ Su ….. For weak acids
pH= pKa + Log Su/ (S − Su) ….. For weak Bases
b) Appraise how use of cosolvents, surfactants and complexing agents contribute for the
enhancement of drug solubility.
Co-solvency: Cosolvents are prepared by mixing miscible or partially miscible solvents. Weak
electrolytes and nonpolar molecules have poor water solubility and it can be improved by
altering polarity of the solvent. It is well-known that the addition of an organic cosolvent to
water can dramatically change the solubility of drugs. Cosolvent system works by reducing the
interfacial tension between the aqueous solution and hydrophobic solute. Aquous solvent -
Etahnol, sorbitol, glycerin, propylene glycol. Non aquous solvent - glycerol dimethyl ketal,
glycerol formal, glycofurol, dimethyl acetamide. SOME PERANTRALPRODUCT THAT
CONTAIN COSOLVENT 1.Diazepam - 10% ethanol + propylene glycol 2.Digoxin - 10%
ethanol + propylene glycol
Micellar Solubilisation
Solubilisation can be defined as ‘‘the preparation of a thermodynamically stable isotropic
solution of a substance normally insoluble or very slightly soluble in a given solvent by the
introduction of an additional amphiphilic component or components.’’ At surfactant
concentrations above the cmc the solubility increases linearly with the concentration of
surfactant, indicating that solubilisation is related to micellization. The location of a solubilised
molecule in a micelle is determined primarily by the chemical structure of the solubilizate.
Solubilisation can occur at a number of different sites in a micelle:
1. On the surface, at the micelle–solvent interface
2. Between the hydrophilic head groups
3. In the palisades layer, i.e., between the hydrophilic groups and the first few carbon atoms of
the hydrophobic groups that comprises the outer regions of the micelle core
4. In the micelle inner core.Selection of proper solubilising agent:
Surfactants having HLB values higher than 15 are best solubilising agents. Final selection of the
solubilising agent should be based on phase solubility studies (explained by Guttman et al).
5. a) Persuade how drugs are stabilized against chemical decomposition? Explain with
detailed examples.
Stabilization by Modification of Molecular Structure of Drug Substance 2 • Stabilization by
Complex Formation 3 • Stabilization by Formation of Inclusion Complex with Cyclodextrin
Other Methods for Stabilization of Drug Substances against Degradation 4 Addition of
Stabilizers Such as Antioxidants and Stabilization through the Use of Packaging 5 Stabilization
by Incorporation into Liposome, Micelles or Emulsion.
b) Define shelf life and describe a method to determine the shelf life of a formulation.
Shelf life is defined as the time necessary for the drug to decay to 90% of its original
concentration. product will remain stable when stored under recommended storage conditions.
Thus, an expiration date is the date beyond which it is predicted that the product may no longer
retain fitness for use.
Stability testing is necessary to determine a drug's shelf life and recommended storage
conditions. It involves evaluating a drug's chemical, physical, and microbial properties under
different temperatures and humidity levels over time. The process used to determine drug shelf
life is called “stability testing.” This process is performed in a cleanroom and used to determine
when a drug ceases to be potent or stable (predictable in the results it produces).
6. a) Explain in detail the criteria for interpretation of kinetic data.
Any report of a kinetic investigation should specify how many complete independent
experiments were carried out, and must include estimation of the precision of parameters
obtained. For oligomeric enzyme it should be clear whether the values are relative to one subunit
or for one molecule.
b) Generalize how the kinetic principles are used in the stability testing of formulations.
Importance of stability: to verify that no changes have been introduced in the formulation or
manufacturing process that can adversely affect the stability of the product. To determine shelf
life and storage conditions. To provide a database. To protect the reputation of the manufacturer.
legal requirement to provide data. assurance to patient that drug is safe. Testing.
stability testing methods: 1. Real time stability testing 2. Accelerated stability testing 3. Retained
sample stability testing 4. Cyclic temperature stress testing.
Performed for longer duration of the test period in order to allow significant product degradation
under recommended storage conditions. • depends upon the stability of the product which should
be long enough to indicate clearly that no measurable degradation occurs. Data collected at
appropriate frequency To distinguish instability from day to day Stability of reference material
include the stability of reagent as well as consistency of performance 1. Real time stability
testing
Accelerated stability testing • A product is stressed at several high temp. & the amount of heat
input required to cause product failure is determined. • This is done to subject the product to a
condition that accelerates degradation. • This information is then projected to predict shelf life or
used to compare the relative stability of alternative formulations. Samples subjected to stress
Refrigerated Assayed simultaneously
The concept of accelerated stability testing is based upon the Arrhenius equation Where, K =
constant (0.00831 kJ/mol), T=absolute temperature (K) 𝑙𝑛 𝐾 = 𝑙𝑛 𝐴 + ∆𝐸 𝑅𝑇
degradation rate/s, A = frequency factor/s, ∆E = activation energy (kJ/mol), R = universal gas
ICH Guidelines: TITLE Q1A Stability testing of New Drug Substances and Products (Second
Revision) Q1B Stability testing : Photo stability testing of New Drug Substances and Products
Q1C Stability testing of New Dosage Form Q1D Bracketing and Matrixing Designs for stability
testing of Drug Substances and Products Q1E Evaluation of stability data Q1F Stability data
package for Registration Applications in Climatic Zones III and IV Q5C Stability testing of
Biotechnological/Biological Products GUIDELINE FOR STABILITY TESTING
7. a) Assess the characteristics to be considered in the choice of packaging components for
different dosage forms.
Packaging must meet the following Requirements: [ideal requirements] Protect the preparation
from environmental conditions. Non-reactive with the product and so does not alter the
identity of the product, Does not impart tastes or odors to the product, Nontoxic, FDA approved,
Protect the dosage form from damage or breakage, Meet tamper-resistance requirements,
wherever applicable. Adaptable to commonly employed high-speed packaging equipments.
Criteria for the Selection of package type and package material: Stability- Compatibility with
the contents- Strength of container and the degree of protection required. Moisture-proofness-
Resistance to corrosion by Acids or Alkalis- Resistance to grease. Protection against salt-
Resistance to microorganisms. Resistance to insects and rodents. Resistance to differences in
temperature. Protection against light, fire and pilferage-Odor retention and transmission-
Aesthetic effect, Cost, Machine suitability of packaging and the filling method.
b) Classify various types of glass containers used for the packaging of pharmaceuticals with an
emphasis on their evaluation.
TYPES OF GLASS Type I: Borosilicate Glass Type II – Treated Soda-Lime Glass Type III –
Regular Soda-Lime Glass Type NP – General Purpose Soda-Lime Glass
Type I: Borosilicate Glass Highly resistant glass: A substantial part of the alkali & earth cations
are replaced by boron and/or aluminum & zinc. It is more chemically inert than the soda-lime
glass (which contains either none or an insignificant amount of these cations). It is used to
contain strong acids & alkalies as well as all types of solvents. The addition of approx 6% boron
to form type I glass reduces the leaching action.
Type II: Treated Soda-Lime Glass When glassware is stored for several months, especially in a
damp atmosphere or with extreme temperature variations, the wetting of the surface by
condensed moisture (condensation) results in salts being dissolved out of the glass. This is called
“blooming” or “weathering” & it gives the appearance of fine crystals on the glass. Type II
containers are made of commercial soda-lime glass that has been de-alkalized or treated to
remove surface alkali.
“weathering” of empty bottles. Some manufactures expose the glass to an atmosphere
containing water vapor & acidic gases. This results in a reaction between gases & surface alkali,
which makes it resistant to attack by water. The alkali removed from the glass appears on the
surface as a sulfate bloom, which is removed when the containers are washed before filling.
Thus sulfur treatment neutralizes the alkaline oxides on the surface & thus rendering the glass
more chemically resistant. Type III – Regular Soda-Lime Glass Containers are untreated & made
up of commercial soda-lime glass of average or betterthan-average chemical resistance. Type NP
– General Purpose Soda-Lime Glass Containers made up of soda-lime glass are supplied for
non-parenteral products, those intended for oral or topical use.
8. a) Discuss the techniques to be adopted during transportation in case of regular and cold
chain pharmaceutical products.
The cold chain involves the transportation of temperature-sensitive products along a supply chain
through thermal and refrigerated packaging methods and the logistical planning to protect the
integrity of these shipments.
b) Compare and contrast different types of plastic containers and closures used for
packaging of pharmaceuticals.
PLASTIC CONTAINERS: Advantages: 1. Ease of manufacturing 2. Available in various types
of quality 3. Freedom of design to which they lend themselves 4. Extremely resistant to breakage
TABLE: Polymers used for the production of Plastics: COMMONLY USED POLYMERS LESS
COMMONLY USED POLYMERS Polyethylene Polymethyl methacrylate Polypropylene
Polyethylene terephthalate Polyvinyl chloride (PVC) Polytrifluoroethylene Polystyrene
Aminoformaldehydes Polyamides Dosage Form – Plastic Interactions / Limitations of Plastic
Materials: 1. Permeation 2. Leaching 3. Sorption 4. Chemical modification 5. Alteration on the
properties of plastics or product
9. a) Define and explain the building blocks for the formulation of shampoo?
Building blocks for the formulation of shampoo:- 1) Principal surfactant (anionic type) Non ionic
surfactant has sufficient cleansing property but have low foaming power. Cationic are toxic. So
anionic are preferred. 2) Secondary surfactant (anionic or ampholytic detergent) They modify
detergent and surfactant properties of principal surfactant. 3) Antidandruff agents (selenium,
cadmium sulfide, ZPTO) 4) Conditioning agent (lanolin, oil, herbal extract, egg, amino acids) 5)
Pearlescent agents (substituted 4 methyl coumarins) 6) Sequestrants (EDTA) Added because Ca,
Mg salts are present in hard water. Soaps cause dullness by deposition of Ca, Mg soaps on hair
shaft. This prevented by EDTA. 7) Thickening agents (alginates, PVA, MC) 8) Colors, perfumes
and preservatives
b) Discuss the ideal properties of skin care products. Extend formulation and evaluation of
cleansing creams.
The cream should have a medium-to-high percentage oil phase and be easily spreadable, should
not “rub in” and should not irritate the skin. In addition, if it can leave a residual emollient film
on the skin, so much the better [99]. Surfactants in skin cleansers interact with the skin in several
manners.To have a high solid suspension in a stable viscous form and therefore gelling agents or
thickening polymers have to be incorporated. To prevent it from drying out it also becomes
necessary to add humectants to the system. Finally, colours (if desired), and preservatives (if
necessary), are also added.
Herbal ingredients used in oral care: Myrrh, pine resin, baptisia, Echinacea, essential oils –
cinnamon oil, clove oil, eucalyptus oil, peppermint oil etc.
10. a) Summarize in detail about foundation creams.
. Cosmetics can be classified for skin or body care or as decorative. Decorative cosmetics are
used for application and coverage of skin defects, resulting in improved appearance as well as
psychological effects such as increased self-confidence. One form of decorative cosmetics is
foundation, which serves to cover uneven facial skin surfaces, scars, acne, and pores. Foundation
is often equipped with sun protection factor (SPF) serving as a second layer of protection from
ultraviolet (UV) rays on the face. Skin contains its own natural protective system against the
effects of sunlight, but this is often ineffective to withstand excessive sun exposure; therefore,
additional shielding may be required to protect against UV light [1,2]. Foundation usually
contains broad-spectrum physical and chemical sunscreens such as titanium dioxide, zinc oxide,
octyl methoxycinnamate, or oxybenzone – to prevent UV radiation (UVR) exposure. However,
these components have been reported to cause skin irritation, photosensitivity, and contact
dermatitis by interaction with cutaneous molecules on chronic use [3]. Therefore, natural
compounds such as polyphenols may be more optimal photo protectants. Flavonoids as
antioxidants with strong activities can bind metal ions and prevent the harmful effects resulting
from exposure to UV rays [4]. Phenolic compounds, especially flavonoid groups, have potential
as sunscreens as the chromophores can absorb UV rays, thereby reducing intensity on the skin.
One compound that can be used for these purposes is epigallocatechin gallate (EGCG). EGCG is
an effective antioxidant primarily found within green tea leaves, in which its content can protect
the skin from UVR. The SPF value of 200 µg/mL green tea leaf extract measured in vitro using a
UV–visible spectrophotometer was 18.10±0.05 [5]. Elevated SPF values can be caused by high
levels of polyphenols and flavonoids in green tea. The high antioxidant activity of EGCG as a
sunscreen could be beneficial for skin health, especially of the face. Nevertheless, there remains
no research concerning EGCG SPF values and its use in cosmetics, especially foundation.
b) Report the preparation, formulation and evaluation of depilatories.
The following ingredients are needed to make the hair cream: thioglycolic acid, cetyl alcohol,
turmeric powder, neem, tulsi extract, ginger and papaya powder, liquid paraffin and the required
amount of orange oil. The pH, viscosity, spreadability and homogeneity of the depilatory cream
composition were evaluated.
