QUALITY EVALUATION ON PROMETHAZINE TABLETS MARKETED IN NEPAL

i
QUALITY EVALUATION OF PROMETHAZINE HCl TABLETS
MARKETED IN NEPAL
Submitted By:
Angkrit Sapkota (symbol no. 17170042)
Hikmat Chand (symbol no. 17170052)
Kiran Shrestha (symbol no. 17170054)
Neeraj Ojha (symbol no. 17170059)
Niraj Shrivastav (symbol no. 17170060)
Yuvraj Kalathoki (symbol no. 17170053)
2020

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QUALITY EVALUATION OF PROMETHAZINE HCl TABLETS MARKETED IN NEPAL
A Thesis submitted to CiST College in partial fulfillment of the degree of
Bachelor of Pharmaceutical Sciences
Submitted to:
Department of Pharmacy, CiST College
Sangam chowk, New Baneshwor, Kathmandu
Affiliated to Pokhara University
Submitted By:
Angkrit Sapkota (symbol no. 17170042)
Hikmat Chand (symbol no. 17170052)
Kiran Shrestha (symbol no. 17170054)
Neeraj Ojha (symbol no. 17170059)
Niraj Shrivastav (symbol no. 17170060)
Yuvraj Kalathoki (symbol no. 17170053)
2020

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THESIS APPROVAL
The Thesis entitled “Quality evaluation of promethazine HCl tablets marketed in Nepal”
submitted by Angkrit Sapkota, Hikmat Chand, Kiran Shrestha, Neeraj Ojha, Niraj Shrivastav and
Yuvraj Kalathoki in a partial fulfillment of the requirements for the degree of Bachelor of
Pharmaceutical Sciences is approved by
Dr. Shila Gurung Date
Pokhara University
Lekhnath, Pokhara
(External)
Dr. Shiva Bahadur Karkee Date
Head of Pharmacy Department
CiST College
Sangam chowk, New Baneshwor
(Examiner)
Sajan Maharjan Date
Lecturer
(Supervisor)

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DECLARATION
The results presented in this project work entitled “Quality evaluation of promethazine HCl
tablets marketed in Nepal” has been entirely carried out under the guidance and supervision of
Mr. Sajan Maharjan, Lecturer, CiST College.
We hereby declare that this work is original and has not been submitted in part or full to any
other institutions for the award of any other degree or diploma or qualification.
Name: Angkrit Sapkota
Symbol no.: 17170042
PU Reg. No: 2016-1-17-0082
Name: Hikmat Chand
PU Reg. No: 2016-1-17-0092
Name: Kiran Shrestha
Symbol No.: 17170054
PU Reg. No: 2016-1-17-0094
Name: Neeraj Ojha
PU Reg. No: 2016-1-17-0099
Name: Niraj Shrivastav
PU Reg. No: 2016-1-17-0100
Name: Yuvraj Kalathoki
PU Reg. No: 2016-1-17-0093

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CERTIFICATE
This is to certify that the Thesis entitled “Quality evaluation of promethazine HCl tablets
marketed in Nepal” submitted by Angkrit Sapkota, Hikmat Chand, Kiran Shrestha, Neeraj Ojha,
Niraj Shrivastav and Yuvraj Kalathoki in the partial fulfillment of Bachelor of Pharmaceutical
Sciences was carried out under my guidance and supervision during all stages of planning,
execution and analysis.
The results of this work have not been previously submitted to any institution to acquire any
other academic degree or diploma.
SajanMaharjan Date

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ACKNOWLEDGEMENTS
we would like to express our special appreciation and thanks to our research supervisor
Mr. Sajan Maharjan, lecturer and coordinator of pharmacy department, CiST college.
Without his assistance and dedicated involvement in every step throughout the process,
this paper would have never been accomplished. We would like to thank you for your
support, understanding and for your brilliant comment and suggestions, thanks to you.
A special thanks to our principal Mr. Naveen Shrestha and department of pharmacy,
Pokhara university for granting us this golden opportunity to be part of this research.
Furthermore, we would like to acknowledge with much appreciation the crucial role of
the academic staff in pharmacy department, technical staff and academic staff of CiST
college who gave us permission to use all required equipment and the necessary
materials to complete the tasks.
We extended to express our heartfelt thanks to Dr. Shiva Bahadur Karkee, HOD of
pharmacy department, CiST college who has invested his full effort in guiding our group
in achieving the goal.
We also appreciate the guidance given by other supervisors as well as the team
especially in our project presentation that has improved our presentation skills to their
comment and advices.
Finally, we thank our colleagues whose friendship, intellectual inspiration and fruitful
discussions helped us whenever it was needed.

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ABSTRACT
The purpose of this Quality Evaluation of promethazine HCl tablets was to evaluate the
quality standards of different marketed brands of promethazine tablets which are
commercially available in Nepalese market with various price ranges, collected from
DDA registered pharmacy retail shops of Kathmandu valley, Nepal. We choose five
different brands and coded them from P1 to P5. The brands were tested for various
quality parameters like weight variation, hardness, diameter, thickness, disintegration
time, assay as per IP and in-vitro dissolution studies as per USP. Packaging and
labeling specifications were not uniform in every brands. All the tested brands
conformed to the official tests for drug content and disintegration. The weight variation
was within the specified limit (except for Brand P2). All samples disintegrated within 4.1
to 7.05 minutes. The percentage content of active ingredient of all brands of
promethazine tablets showed values within the pharmacopeial specifications (92.5 % -
107.5 %). The dissolution profiles showed 3 brands (P3, P4 and P5) attained 75%(Q)
dissolution and complied with USP monograph whereas 2 brands (P1 and P2) don’t
comply with limit. Based on this research results it is suggested that coating may affect
the quality of light sensitive drugs.
Keywords: assay, disintegration, dissolution, promethazine, quality evaluation.

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Table of Contents
1.INTRODUCTION ....................................................................................................................... 1
1.1 Background ...................................................................................................................... 1
1.2. Substandard drugs ................................................................................................................ 2
1.2.1. Reason for substandard drugs ....................................................................................... 3
1.2.2. Problems in substandard drugs ..................................................................................... 4
1.2.3. Ways to improve drug quality....................................................................................... 5
1.3. Light sensitive drugs ............................................................................................................ 6
1.4. Packaging ............................................................................................................................. 7
1.4.1. Types of packaging....................................................................................................... 8
1.4.2. Packaging requirements for light sensitive drugs ......................................................... 8
1.5. UV Spectroscopy.................................................................................................................. 9
1.5.1. Principle of UV Spectroscopy ...................................................................................... 9
1.5.2. Instrumentation and working of UV Spectroscopy .................................................... 10
1.6. Tablets ................................................................................................................................ 11
1.6.1 Types of Tablets........................................................................................................... 11
1.6.2. Common Tablet Defects ............................................................................................. 13
1.7. Excipients used in tablet manufacturing ............................................................................ 15
1.8. Tablet Coating.................................................................................................................... 16
1.8.1. Types of coating.......................................................................................................... 16
1.8.2. Objectives of coating .................................................................................................. 17
1.9. Drug review........................................................................................................................ 17
1.9.1. Histamine and anti-histamine ..................................................................................... 18
1.9.2. Pharmacokinetics ........................................................................................................ 19
1.9.3. Pharmacodynamics .................................................................................................... 20
1.9.4. Medicinal uses............................................................................................................. 21
1.10. Drug categorization.......................................................................................................... 21
2. Problem statement..................................................................................................................... 23
3. Literature review and research gaps.......................................................................................... 24
4. Objective of study..................................................................................................................... 26
4.1. General objective................................................................................................................ 26

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4.2. Specific objectives.............................................................................................................. 26
5. Research design and Methodology....................................................................................... 27
5.1. Research method: Quantitative study................................................................................. 27
5.2. Research type: Lab-based survey....................................................................................... 27
5.3. Methodology ...................................................................................................................... 27
5.3.1. Sampling Unit:............................................................................................................ 27
5.3.2. Sample size: ................................................................................................................ 27
5.3.3. Sampling procedure: ................................................................................................... 27
5.4. Materials and Methods....................................................................................................... 27
5.4.1. Materials...................................................................................................................... 27
5.4.2. Instruments.................................................................................................................. 28
5.4.3. Labeling and packaging .......................................................................................... 28
5.4.4. Physical parameters................................................................................................. 28
5.4.5. Chemical parameters............................................................................................... 28
6. Results and Discussion ............................................................................................................. 30
6.1. Labeling Specification........................................................................................................ 30
6.1.1. Price fluctuation...................................................................................................... 31
6.1.2. Coating.................................................................................................................... 31
6.1.3. Precaution and warning........................................................................................... 31
6.1.4. Drug categorization................................................................................................. 31
6.1.5. Storage condition .................................................................................................... 31
6.2. Packaging Specification................................................................................................. 32
6.3. Appearance..................................................................................................................... 32
6.4. Physical parameters........................................................................................................ 33
6.4.1. Physical parameters comparison............................................................................. 35
6.4.2. Weight variation...................................................................................................... 36
6.5. Assay.............................................................................................................................. 37
6.6. Dissolution ..................................................................................................................... 38
6.7. Disintegration................................................................................................................. 39
7. Summary............................................................................................................................... 41
8. Conclusion ............................................................................................................................ 42
9. References:............................................................................................................................ 43

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List of tables
Table 1. 1 Excipients used in tablet manufacturing ..................................................................... 15
Table 6. 1 Labeling specification................................................................................................. 30
Table 6. 2 Labeling specification continue. ................................................................................. 30
Table 6. 3 Packaging specification............................................................................................... 32
Table 6. 4 Appearance.................................................................................................................. 32
Table 6. 5 Physical parameters of brand P1 ................................................................................. 33
Table 6. 10 Physical parameters comparison ............................................................................... 35
Table 6. 11 Weight variation of 5 different brands ...................................................................... 36
Table 6. 12 Results of Assay........................................................................................................ 37
Table 6. 13 Dissolution percentage .............................................................................................. 38
Table 6. 14 Disintegration time.................................................................................................... 39

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List of figures
Figure 1. 2 Structural formula of promethazine HCL.................................................................. 17
Figure 1. 1 Synthesis, storage and destruction of histamine ........................................................ 18
Figure 6. 1Physical parameters comparison ................................................................................ 35
Figure 6. 2 Graphical representation of result of Assay .............................................................. 38
Figure 6. 3 Graphical representation of result of Dissolution...................................................... 39
Figure 6. 4 Graphical representation of result of Disintegration ................................................. 40

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List of Abbreviations
DDA = Department of drug administration
CiST = Central institute of science and technology
IP = Indian pharmacopoeia
USP = United states pharmacopoeia
BP = British pharmacopoeia
Nrs =Nepalese rupees
UV = Ultra violet
GIT = Gastro intestinal tract
e.g., = Example
pH = Potential of hydrogen
APIs = Active pharmaceutical ingredients
WHO = World health organization
DNA = Deoxyribonucleic acid
ICH = International conference on harmonization
GMP =Good manufacturing practice
cGMP= Current Good manufacturing practice
HCl = Hydrochloric acid
Pvt. Ltd = Private Limited
Mg = Milligram
Ml = Milliliter
M = Molarity
N= Normality
Nm = Nanometer
ºC = Degree Celsius
RPM = Rotation per minute
DT = Disintegration time
Mfd. Date= Manufacturing date
Exp. Date = Expire date
i.e., = That is

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cm = Centimeter
kg/cm² = kilogram per square centimeter
gm = Gram
% = percentage
Avg. = Average
Q = +5%
Min = Minutes
Sec = Seconds
PO = Per oral
IM = Intramuscular
PR = Per rectal
PPI = Proton pump inhibitor
Ca²+ = Calcium ion
CYP2D6= Cytochromes 2D6
g/mol = Gram per mole
cAMP= Cyclic adenosine monophosphate
SD = Standard deviation

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1.INTRODUCTION
1.1 Background
Nepal National Drug Policy 1995 defines “drug as any substance which is intended to be used
inhuman beings or animals for diagnosis, treatment, cure, mitigation and prevention of diseases
or for promotion of health or for the destruction of microorganisms which have caused disease or
to affect the physical structure or function of a body” (1). Drugs play a crucial role in saving
lives, restoring health and preventing diseases and epidemics but when it is counterfeit
(deliberately and fraudulently mislabeled with respect to identity and/or source) or substandard
(not complying with the standard specification as per the related pharmacopoeia or not
complying with the specification of the manufacturer or the requirement of the drug regulatory
authority) , it results in life threatening issues, financial loss of consumers and loss in trust on
health system(2). So, the drug should be of standard quality in order to meet its therapeutic
efficacy.
The actual definition of photosensitivity is the response of drug or drug product to the exposure
of solar, UV and visible light in the solid, semisolid, or liquid state that leads to a physical or
chemical change(3). Exposure to light is a concern with numerous medications due to the
potential for photo degradation or other chemical reactions that affect drug stability(4). Light can
influence the active principle in a drug formulation, as well as the final product or package. In
this manner, the photo stability deals with the effect of the light (photons) on stability of
pharmaceutical substances. Photo degradation may be observed as bleaching or as discoloration
of products. The other effects include cloudy appearance of the product, a loss in viscosity of
formulation, precipitation of active principle, alteration in dissolution rate, although many drugs
are found to decompose when exposed to light(5).

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1.2. Substandard drugs
In 2009, the World Health Organization (WHO) defined ‘substandard’ drugs as ‘genuine
medicines produced by manufacturers authorized by the NMRA [national medicines regulatory
authority] which do not meet quality specifications set for them by national standards. A new
definition was proposed by the WHO in May 2010: ‘Each pharmaceutical product that a
manufacturer produces has to comply with quality standards and specifications at release and
throughout the product shelf-life required by the territory of use. Normally, these standards and
specifications are reviewed, assessed and approved by the applicable NMRA before the product
is authorized for marketing. Substandard medicines are pharmaceutical products that do not meet
their quality standards and specifications.’ (6)
The WHO defines ‘counterfeit’ drugs as ‘medicines that are deliberately and fraudulently
mislabeled with respect to identity and/or source’. It also states that both branded and generic
products may be counterfeited and that ‘counterfeit medicines may include products with the
correct ingredients or with the wrong ingredients, without active ingredients, with insufficient or
too much active ingredient, or with fake packaging’. However, because of the potential
misunderstanding of the term ‘counterfeit’ – which, in the context of intellectual property, refers
specifically to trademark infringement – the phrase ‘falsified medicines’ is used by some
authorities, particularly in Europe. The Commission of the European Communities defines these
as ‘medicinal products which are falsified in relation to their identity, history or source. These
products usually contain sub-standard or false ingredients, or no ingredients or ingredients in the
wrong dosage, including active ingredients’.(7)
Thus, falsified drugs are most likely of poor quality, possibly without APIs. However, only a
small percentage of substandard drugs are falsified; the rest reach the market due to inadequate
manufacturing practices, inadequate quality control processes, improper storage or packaging, or
a combination of these factors. It can affect both brand name drugs and generic drugs. In many
cases, the reason why a product is not indicated or it is not known whether a drug product is
inferior or not due to criminal intent or due to failures in manufacturing, storage, etc. it does not
matter to the patient because the impact on his health will be the same regardless of the cause.(8)

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1.2.1. Reason for substandard drugs
a. Uneven Manufacturing Quality
Any company will create mistakes, however adherence to sensible producing practices makes
mistakes less seemingly and easier to correct. A factory run in accordance with best practices
doesn't have to be the foremost technologically advanced or use progressive equipment, but there
are prices to bring a factory up to standard, train employees on applicable protocols, and observe
them consistently. There are several exemplary makers in developing countries that observe
international best practices. There are many who do not, but they operate anyway, either as a
result of the administrative unit is unaware of the problem, or because regulators are struggling
to ignore it within the name of promoting industry(9)
b. Tiered Production
Rich countries enforce high quality standards for medicines, and manufacturers recognize the
need to use good-quality ingredients and good manufacturing practices to sell in these markets.
United Nations (UN) agencies and the larger international aid organizations will also refuse to do
business with companies that cannot meet stringent regulatory authority quality standards.
Manufacturers are aware, however, that low- and middle-income countries are less likely to
enforce these standards. Some companies exploit this and produce drugs of lower quality for the
loosely regulated markets. When a manufacturer produces medicines of inferior quality for less
exacting markets, it is known as tiered or parallel production.(10)
Tiered production is a complicated problem, in part because some kinds of tiered production are
legal. International manufacturers may supply to multiple markets which use different legal
product quality standards. For example, the British Pharmacopoeia monograph for amoxicillin
gives no dissolution standard (British Pharmacopoeia, 2012); the U.S. Pharmacopeia does (USP-
NF, 2010). Assay limits may also be different, making a product illegal by one pharmacopeia but
legal by another.
c. Procurement and Substandard Medicines
No country is self-sufficient in its medicine supply. Pharmaceutical procurement almost always
means working with foreign suppliers. Good procurement also means that only organizations
that follow the model system should import medicines. Small-scale importation and procurement
by small sectors threaten the medicines supply chain. This risk is not only present in developing
countries. In many developed countries, pharmacies and private clinics import drugs directly
from suppliers, greatly increasing the risks of introducing a poor-quality product to the
market.(9)
Good procurement dictates that the cheapest tenders are not accepted if they are of inferior
quality, but it is difficult not to be swayed by price, especially for provincial health offices and
other small procurement agencies(11). Proper precaution in the medicine’s procurement process
can prevent poor-quality products from infiltrating the market. Good procurement also puts a
strong emphasis on controlling corruption and promoting transparency.

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d. Corruption and Organized Crime
Making substandard or fake medicine is not difficult. Production costs on such drugs are low
and, because the supply chains mix in unregulated markets, the odds of getting away with the
crime are good. The global burden of falsified and substandard medicines is borne
disproportionately by low- and middle-income countries. There is wide evidence that criminals
frequently target inexpensive anti-infective medicines, mostly because they are bought often and
by the largest segment of the population. The UNODC therefore describes making falsified
medicines as an “opportunistic crime, emerging where regulatory capacity is low, not where
profits would be highest” (12)
Corruption allows the crime to continue. Government officials are often bribed with revenue
from the underground pharmaceutical business; criminal executives may be embedded in the
government hierarchy. Threats and bribery are the cause of members of organized crime, who
are often responsible for trafficking falsified medicines, perhaps attracted by the mild
punishments.(13)
e. Expense and Scarcity
The demand for medicines is relatively consistent, though the supply is not. The private
medicines market can be expensive and drug scarcity drives up prices. Reducing the costs and
increasing the availability of medicines would remove some of the financial incentive to produce
falsified and substandard drugs.
A robust generics market can keep drug prices down, but there are cost barriers to market entry
for many good-quality generics companies. A more straightforward registration and application
process would reduce burdens on industry and regulators. Falsified and substandard medicines
circulate because of weaknesses in the regulatory system. Regulators in low- and middle-income
countries need training, equipment, and technology, as well as guidelines for strategic decisions
about what to invest in first. (9)
1.2.2. Problems in substandard drugs
a. Drug content
Any formulation of a medication may be regarded as substandard if it has either too much or too
little of the API compared with the formulation specifications. Official national pharmacopoeias,
such as the British Pharmacopoeia (BP) and United States Pharmacopeia (USP), publish the
quality standards for medicinal substances and preparations manufactured or sold in the country.
The information given specifies the acceptable limits for the amount of the API that should be
present in a given formulation.
Inappropriate packaging can also affect formulation content in certain storage conditions. In
some cases, a product may contain no API or the drug content may be completely different to
that stated on the label. This may occur through deliberate falsification or due to accidental
mislabeling(6).

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b. Impurities
An impurity may be defined as any substance in the product that is neither the chemical entity
defined as the drug nor an excipient. Impurity profiling is required as part of the registration
process by many regulatory authorities, including the FDA and the European Union’s Committee
for Medicinal Products for Human Use (CHMP). Impurities fall into one of three categories –
organic substances, inorganic substances and residual solvents and may include starting
materials, intermediate compounds, reagents and catalysts, heavy metals, degradation products,
polymorphic forms (alternative crystal forms with potentially different dissolution profiles) and
enantiomeric impurities, as well as extraneous contaminants. Impurities can arise in formulations
due to poor manufacturing procedures and storage conditions. Impurities can alter medication
properties or be toxic(14) . In many cases, contamination has clearly occurred due to poor
manufacturing and/or quality control processes, or unsuitable packaging.
c. Pharmacological variability and economic burden
Clinical results treated with poor drugs may lead to loss of confidence in the drug by both the
prescribing physician and the patient. Effective drug classes may be perceived as ineffective due
to inadvertently suboptimal dosing, which could lead to unnecessary testing for suspected
resistance and unnecessary changes or increases in drugs. Paying for replacement or additional
medications, or for repeated courses of inadequate medication, can be a heavy financial burden
on a family. (15)
1.2.3. Ways to improve drug quality
a. Better understanding of the problem
There is an urgent need for greater understanding of the problem, in particular through better
systematic collection and accurate, transparent documentation of information on substandard
drug manufacture and dissemination. This would help inform national authorities about the scale
of the problem and provide a database against which batches of drugs could be checked.
Carefully conducted surveys with precise targets and incorporating standardized testing could be
used to help define the extent of the problem (6)
b. Improved regulatory control and monitoring
Implementation of strong regulatory control is the key to the improvement and maintenance of
drug quality. One of the main factors for maintaining quality drug production is regulation of
Good Manufacturing Practice standards for every pharmaceutical industry with regular follow
ups. The WHO estimates that only approximately 20% of its 191 member states have well-
developed drug regulation; approximately 30% are thought to have no or minimal drug
regulation in place (16).
The Good Governance for Medicine Program was set up by the WHO in 2004 to help combat
corruption in the pharmaceutical sector and is currently operating in 26 countries. The WHO
reports a number of successes for the program but emphasizes that high-level government
commitment is required(17).

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d. Human and material resources
Lack of human and material resources to test drug quality is the main issue for substandard
drugs. A number of relatively simple and inexpensive tests have been developed for drug testing.
It is not necessary to be as sensitive or specific as Pharmacopeial methods but they can be used
to screen samples quickly. Such techniques include thin-layer chromatography, simple
colorimetric assays, Dissolution and disintegration tests, which has been used as a screening
method for a range of suspected substandard drugs(18).
There are many levels in the drug production and marketing processes that may be influenced by
corruption and lead to substandard drugs entering the market. This may occur during the
construction or equipping of manufacturing facilities, drug registration or certification, quality-
control checks, including drug testing and site inspections, and during drug procurement(19).
1.3. Light sensitive drugs
Exposure to light is a concern with numerous medications due to the potential for photo
degradation or other chemical reactions during manufacturing, storage, and administration. This
may result in potency loss, altered efficacy and adverse biological effects. The sensitivity of a
drug to a distinct spectral region of light may vary with its chemical structure, photo reactivity,
and nature of the dosage form. The photochemical behavior of a drug provides guidance for
handling, packaging, and labeling of drug products. The use of the appropriate containers and
packaging material can protect the products from the deleterious effects of light.
Light induces the interaction between the molecules of the compound that leads to the formation
of a new compound, generally referred as an impurity. Light has energy that can activate the
molecule of the drug. Photodegradation usually occurs due to absorption of short wavelength
light between 300 to 500 nm. Visible blue, violet and ultraviolet light generally cause this
degradation. For example, ofloxacin remains 80% when exposed to direct light for a period of
240 hours. Some drugs are affected by light of special wavelength that should be studied before
developing the formulation and product should be protected from that light. Excipients added in
the formulation can also reduce the effect of light on a light sensitive drug. The formulation
should be tested for photostability to determine the effect of light on formulated product and to
develop the protected measures.
During the manufacturing process, these products should be protected from light degradation.
Lights having a long wavelength (more than 500 nm) are used in granulation, compression and
packing areas. Brown colored light having a wavelength between 500 and 800 nm is the best
option for this purpose. Tablets containing light sensitive products should be coated with a
colored film coating which protects the sensitive drug from degradation due to light. These
tablets should be packed in alu-alu or in amber colored blisters. Injections containing light
sensitive drugs should be filled in amber colored vials or containers.
Analysis of light sensitive products should be done carefully because light may cause an error in
the analytical results. Sample preparation should be done in amber colored glassware and also
wrapped with aluminum foil when stored. The analysis should be done in dark or brown colored
light(20) .

7
Many drug substances and drug products are found to decompose in vitro under exposure to
light. All are sensitive to light, but the same precautions are not required in handling these
compounds. Knowledge about the photostability of drug substances and drug products is
important in order to evaluate:
i. Handling, packaging, and labeling
The ability of a drug substance to degrade or undergo a gradual change in color upon light
exposure is not an uncommon property. Light protection of the drug substance during storage
and production must therefore be recommended in many cases. Change in the selection of
packing materials combined with a change in storage conditions or conditions during
administration of the drug products seems to generate new stability problems in vitro. Most
people are familiar with the traditional brown medicinal flask or the white pill box. These
containers offer adequate protection of most drug products during storage and distribution(21).
The precautions taken in managing those drugs, along with adequate labeling and selection of
packaging, will in every case rely on the photochemical half-life of the drug substance in the
formulation. Because primary information about the photostability of the compounds is needed,
assessment of in vitro stability is important to ensure good quality over the entire life span of the
drug.
ii. Adverse effects
Although a drug product is shown to be photochemically inert in the sense that it does not
decompose during exposure to light, it can still act as a source of free radicals or form phototoxic
metabolites in vivo. The drug will then be photoreactive after administration if the patient is
exposed to light, causing light-induced adverse effects. The increase in number of reported
adverse effects that can be ascribed to the combination of drugs and light is due to an increase in
exposure to artificial light sources such as daylight lamps and solaria; a change in human leisure
habits (more time spent outdoors); and a widespread use of drugs(22).
1.4. Packaging
Packaging is defined as a technique which allows containment of pharmaceutical product from
the time of production in a unit till its use. Role of pharmaceutical packaging is to provide
lifesaving drugs, surgical devices, blood and blood products, nutraceuticals, powders, poultices,
liquid and dosage forms, solid and semisolid dosage forms. Packaging of pharmaceuticals
essentially provides containment, drug safety, identity, convenience of handling and delivery.
Pharmaceutical packaging has to balance lots of complex considerations. Leaving behind
relatively simple issues such as developing good designs and communicating with customers,
pharmaceutical packagers are concerned to more pressing concerns which include fighting with
counterfeiting, encouraging patient compliance, ensuring drug integrity and balancing child-
resistance and accessibility for the elderly. Issue of environment safety is also key concern for
both developed and developing countries packaging industry.

8
1.4.1. Types of packaging
1. Primary Packaging:
This is the first packaging envelope which is in touch with the dosage form or equipment. The
packaging needs to be such that there is no interaction with the drug and will provide proper
containment of pharmaceuticals. E.g., Blister packages, Strip packages, Alu- Alu packaging etc.
a. Blister packaging
Blister packs are pre-formed plastic/paper/foil packaging used for formed solid drugs. The
primary component of a blister pack is a cavity or pocket made from a thermoformed plastic.
This usually has a backing of paperboard or a lidding seal of aluminum foil or plastic film.
Blister packs are useful for protecting drugs against external factors, such as humidity and
contamination for extended periods of time.
b. Strip packaging
A strip packaging is formed by feeding two webs of a heat seal-able flexible film through a
heated crimping roller. This type of packaging gives proper protection from light and
moisture.
c. Alu- Alu packaging
Alu-Alu packaging means aluminum foil at both the upper and lower side of pack. This is
similar to blister packaging; the only difference is that the forming film is formed of
aluminum foil instead of plastic material. It is highly suitable for medicines which are UV
light sensitive and moisture sensitive.
2. Secondary Packaging:
This is consecutive covering or package which stores pharmaceuticals packages in it for their
grouping. E.g., Cartons, boxes, etc.
3. Tertiary packaging:
This is to provide bulk handling and shipping of pharmaceuticals from one place to another. E.g.,
Containers, barrels, etc.(23)
1.4.2. Packaging requirements for light sensitive drugs
Light-sensitive substances are often filled into brown glass vials to protect them against UV
irradiation and light. The disadvantage is that the original color of the solution is no longer
discernible, and the medicine cannot be visually inspected for particles or color changes before
dispensing.
Tablets containing light sensitive products should be coated with a colored film coating which
protects the sensitive drug from degradation due to light. These tablets should be packed in alu-
alu or in amber colored blisters. Injections containing light sensitive drugs should be filled in
amber colored vials or containers.(20)

9
1.5. UV Spectroscopy
UV spectroscopy is type of absorption spectroscopy in which light of ultra-violet region (200-
400 nm.) is absorbed by the molecule. Absorption of the ultra-violet radiations results in the
excitation of the electrons from the ground state to higher energy state.
In all the compounds (other than alkanes), the electrons undergo various transitions. Some of the
important transitions with increasing energies are: nonbonding to pie*
, nonbonding to sigma*
, pie
to pie*
, sigma to pie*
and sigma to sigma*
.
1.5.1. Principle of UV Spectroscopy
UV spectroscopy obeys the Beer-Lambert law, which states that: when a beam of
monochromatic light is passed through a solution of an absorbing substance, the rate of decrease
of intensity of radiation with thickness of the absorbing solution is proportional to the incident
radiation as well as the concentration of the solution.
The expression of Beer-Lambert law is-
A = log (I0/I) = Ecl
Where, A = absorbance
I0 = intensity of light incident upon sample cell
I = intensity of light leaving sample cell
C = molar concentration of solute
L = length of sample cell (cm.)
E = molar absorptivity
From the Beer-Lambert law it is clear that greater the number of molecules capable of absorbing
light of a given wavelength, the greater the extent of light absorption. This is the basic principle
of UV spectroscopy.

10
1.5.2. Instrumentation and working of UV Spectroscopy
Instrumentation and working of the UV spectrometers can be studied simultaneously. Most of
the modern UV spectrometers consist of the following parts;
1. Light Source: Tungsten filament lamps and Hydrogen-Deuterium lamps are most widely used
and suitable light source as they cover the whole UV region. Tungsten filament lamps are rich in
red radiations; more specifically they emit the radiations of 375 nm, while the intensity of
hydrogen - deuterium lamps fall below 375 nm.
2. Monochromator: Monochromators generally composed of prisms and slits. The most of the
spectrophotometers are double beam spectrophotometers. The radiation emitted from the
primary source is dispersed with the help of rotating prisms. The various wavelengths of the light
source which are separated by the prism are then selected by the slits such the rotation of the
prism results in a series of continuously increasing wavelength to pass through the slits for
recording purpose. The beam selected by the slit is monochromatic and further divided into two
beams with the help of another prism.
3. Sample and reference cells: One of the two divided beams is passed through the sample
solution and second beam is passé through the reference solution. Both sample and reference
solution are contained in the cells. These cells are made of either silica or quartz. Glass can't be
used for the cells as it also absorbs light in the UV region.
4. Detector: Generally, two photocells serve the purpose of detector in UV spectroscopy. One
of the photocells receives the beam from sample cell and second detector receives the beam from
the reference. The intensity of the radiation from the reference cell is stronger than the beam of
sample cell. This results in the generation of pulsating or alternating currents in the photocells.
5. Amplifier: The alternating current generated in the photocells is transferred to the amplifier.
The amplifier is coupled to a small servo meter. Generally current generated in the photocells is
of very low intensity, the main purpose of amplifier is to amplify the signals many times so we
can get clear and recordable signals.
6. Recording devices: Most of the time amplifier is coupled to a pen recorder which is
connected to the computer. Computer stores all the data generated and produces the spectrum of
the desired compound.(24)

11
1.6. Tablets
Tablet is defined as a compressed solid dosage form containing medicaments with or without
excipients. They vary in shape and differ greatly in size and weight, depending on amount of
medicinal substances and the intended mode of administration.(25)
1.6.1 Types of Tablets
The various types of tablets are described below:
a. Multiple compressed tablets
Multiple compressed tablets are prepared by subjecting the fill material to more than a single
compression. This process is best suited when separation of active ingredients is needed for
stability purposes or if the mixing process is inadequate to guarantee uniform distribution of two
or more active ingredients. There are three categories under this class, Compression coated
tablets, Layered tablets and Inlay tablets.(26)
b. Sublingual tablets
They are to be placed under the tongue and produce immediate systemic effect by enabling the
drug absorbed directly through mucosal lining of the mouth beneath the tongue. The tablets are
usually small and flat, compressed lightly to keep them soft. The tablet must dissolve quickly
allowing the drugs to be absorbed quickly. It is designed to dissolve in small quantity of saliva.
Sublingual, meaning literally 'under the tongue' refers to a method of administering substances
via the mouth in such a way that the substances are rapidly absorbed via the blood vessels under
the tongue rather than via the digestive tract.(27)
c. Chewable tablets
Chewable tablets which are required to be broken and chewed in between the teeth before
ingestion. These tablets are given to the children who have difficulty in swallowing and to the
adults who dislike swallowing. These tablets are intended to disintegrate smoothly in mouth at a
moderate rate either with or without actual chewing. Chewable tablet is often employed when the
active ingredient is intended to act in a localized manner rather than systemically the
composition of chewable tablet consists of gum core, which may or may not be coated. The core
is composed of an insoluble gum base like fillers, waxes, antioxidants, sweeteners, flavoring
agents. The percentage of gum base varies from 30-60%. Mannitol is widely used as an excipient
in chewable tablet for its non-hygroscopic nature for moisture sensitive drugs.(28, 29)
d. Effervescent tablets
Effervescent tablets are designed to break in contact with liquid such as water or juice, often
causing the tablet to dissolve into a solution the benefit of effervescent tablets is that they
dissolve completely and evenly meaning that localized concentrations of the ingredients cannot
occur. This means not only a better taste but also less chance of irritation and a more efficient
means of ingesting the ingredients. Effervescence consists of a soluble organic acid and an alkali
metal carbonate salt, one of which is often the API. Carbon dioxide is formed if this mixture
comes into contact with water. They have good stomach and intestinal tolerance.(30)

12
e. Tablet Triturates
Tablet triturates are small, usually cylindrical molded or compressed tablets containing small
amounts of usually potent drugs. Today only a few tablet triturate products are available
commercially. Since tablet triturates must be readily and completely soluble in water, only a
minimal amount of pressure is applied during their manufacture.(31)
f. Hypodermic tablets
These are one type of sterile preparations. In these, tablets are dissolved in the WFI or sterile
water to inject before the actual injection in the hypodermic cavity. They are intended to be
added in WFI of sterile water to form a clear solution which is to be injected parentally. They are
widely used by rural physician due to its portability. It can be used for medicaments whose
stability in water is very poor. Their use in this manner should be discouraged, since the resulting
solutions are not sterile.(31, 32)
g. Vaginal tablets
Designed for vaginal administration in treatment of local vaginal infections, for systemic
absorptions and absorption into the vaginal tissue can be inserted with the aid of an applicator.
These are uncoated bullet shaped or ovoid tablets. Designed to undergo slow dissolution and
drug release in the vaginal cavity.(31, 33)
h. Implants
These tablets are implanted into the body cavities for a prolonged effect from several days to
months up to a year. These tablets are smaller in size and cylinder-like in shape. They are
designed for subcutaneous implantation by surgical procedure where they are slowly absorbed
over a period of months or years. Special injector with a hollow needle and plunger is used to
administer the rod-shaped tablet. For other shapes surgery is used. They are sterile formulations
without excipients. Mainly these tablets are prepared to deliver growth hormones to food
producing animals. Ear is preferred site for administration of drug.(31, 32)
i. Buccal tablets
These drugs are intended to be dissolved in buccal pouch. Tablets are designed not to
disintegrate. It is placed near the opening of parotid duct to provide the medium to dissolve the
tablet. Buccal tablets are most often used when replacement hormonal therapy is the goal. Long–
Acting Buccal Tablets include use of viscous natural or synthetic gums or mixtures of gums can
be compressed to form a hydrated surface layer from which the medicament slowly diffuses and
is available for absorption through buccal mucosa. Mucoadhesive polymers like PANA and
Carbopol 934 are used.(31, 33)
j. Colon targeting tablets
It provides a desired drug concentration in the body by delivering a therapeutic amount of drug to
a target site i.e., colon. It is suitable and required for the drugs having instability, low solubility,
and short half-life, a large volume of distribution, poor absorption, low specificity, and
therapeutic index. The pH in this region (colon) varies from 6.4-7 and presence of microbial
flora plays an important role in drug release. Various mechanisms adopted for drug release in
this area are: Coating with pH sensitive polymer e.g., Eudragit S100 and L100; Biodegradable
polymer which are sensitive to colonic bacteria; Bio- adhesive polymer e.g., poly carbophils.

13
Redox sensitive polymers. It provides delivery of drugs accurately into the lower GI tract (by
avoiding the drug release in upper GIT), which occurs primarily in the large intestine (i.e.,
colon)(34)
k. Dispersible tablets
Dispersible tablets as defined in European Pharmacopoeia are uncoated or film coated tablets
intended to be dispersed in water before administration giving a homogeneous dispersion.
Typically, a dispersible tablet is dispersed in about 5 to 15 ml of water (e.g., in a tablespoonful or
a glass of water) and the resulting dispersion is administered to the patient. Dispersible tablets
are required to disintegrate within 3 min in water at 15 to 25. Also, the dispersion produced from
a dispersible tablet should pass through a sieve screen with a nominal mesh aperture of 710
µm.(35)
1.6.2. Common Tablet Defects
a) Capping
Capping is the term used, when the upper or lower segment of the tablet separates horizontally,
either partially or completely from the main body of a tablet and comes off as a cap, during
ejection from the tablet press, or during subsequent handling. Capping is usually due to the air–
entrapment in a compact during compression, and subsequent expansion of tablet on ejection of a
tablet from a die.(36, 37)
b) Lamination
It is major problem among of all defects. Occur upon storage period, or soon after compression.
Air entrapment between layers of tablet. Low levels of binding agent. It minimized by improving
lubricant concentration. Change the method of granulation. By direct compression technique it is
prevented to some extent.(38)
c) Sticking
Sticking always occurs in low melting point substances, and moisture supports this defect, lower
the speed up of upper and lower punch leads to weight variation of tablets. It produces rough and
chipping surface tablets. It develops material on both punches. Lack of drying is basis of this
one.(38)
d) Picking
Picking is the term used when a small amount of material from a tablet is sticking to and being
removed off from the tablet surface by a punch face. The problem is more prevalent on the upper
punch faces than on the lower ones. The problem worsens, if tablets are repeatedly manufactured
in this station of tooling because of the more and more material getting added to the already
stuck material on the punch face. Picking is of particular concern when punch tips have
engraving or embossing letters, as well as the granular material is improperly dried.(39)
e) Mottling
Mottling is the term used to describe an unequal distribution of color on a tablet, with light or
dark spots standing out in an otherwise uniform surface. One cause of mottling may be a colored
drug, whose color differs from the color of excipients used for granulation of a tablet.(40)

14
f) Chipping
Chipping is defined as the breaking of tablet edges, while the tablet leaves the press or during
subsequent handling and coating operations. Incorrect machine settings, especially mis-set
ejection take-off.(36)
g) Double impression
It is due to free rotation of the punches, which have some engraving on the punch faces. Further,
in this section, each problem is described along-with its causes and remedies which may be
related to either of formulation (granulation) or of machine (dies, punches and entire tablet
press).(41)
h) Cracking
Small, fine cracks observed on the upper and lower central surface of tablets, or very rarely on
the sidewall are referred to as Cracks. It is observed as a result of rapid expansion of tablets,
especially when deep concave punches are used.(42)
i) Bridging
This occurs when the coating fills in the lettering or logo on the tablet and is typically caused by
improper application of the solution, poor design of the tablet embossing, high coating viscosity,
high percentage of solids in the solution, or improper atomization pressure. During drying, the
film may shrink and pull away from the sharp corners of an in tagliation or bisect, resulting in a
bridging of the surface. This defect can be so severe that the monogram or bisect is completely
obscured.(43)

15
1.7. Excipients used in tablet manufacturing
Table 1. 1 Excipients used in tablet manufacturing
Excipient Function Examples
Diluents Provide bulk and enable accurate dosing of
potent ingredients
Sugar compounds e.g., lactose,
dextrin, glucose, sucrose, sorbitol
Inorganic compounds e.g.,
silicates, calcium and magnesium
salts, sodium or potassium
chloride
Binders,
compression aids,
granulating agents
Bind the tablet ingredients together giving form
and mechanical strength
Mainly natural or synthetic
polymers e.g., starches, sugars,
sugar alcohols and cellulose
derivatives
Disintegrants Aid dispersion of the tablet in the
gastrointestinal tract, releasing the active
ingredient and increasing the surface area for
dissolution
Compounds which swell or
dissolve in water e.g., starch,
cellulose derivatives and alginates.
Glidants Improve the flow of powders during tablet
manufacturing by reducing friction and
adhesion between particles. Also used as anti-
caking agents.
Colloidal anhydrous silicon and
other silica compounds
Lubricants Similar action to glidants, however, they may
slow disintegration and dissolution. The
properties of glidants and lubricants differ,
although some compounds, such as starch and
talc, have both actions.
Stearic acid and its salts (e.g.,
magnesium stearate)
Tablet coatings
and films
Protect tablets from the environment (air, light
and moisture), increase the mechanical
strength, mask taste and smell, aid swallowing,
assist in product identification. Can be used to
modify release of the active ingredient. May
contain flavors and colorings.
Sugar (sucrose) has now been
replaced by film coating using
natural or synthetic polymers.
Polymers that are insoluble in
acid.
Coloring agents Improve acceptability to patients, aid
identification and prevent counterfeiting.
Increase stability of light-sensitive drugs.
Mainly synthetic dyes and natural
colors. Compounds that are
themselves natural pigments of
food may also be used.(44)

16
1.8. TabletCoating
Tablet coating is one of the oldest pharmaceutical processes still is existence. Coating is a
process by which an essentially dry, outer layer of coating material is applied to the surface of a
dosage form in order to confer specific benefits over uncoated variety. It involves application of
a sugar or polymeric coat on the tablet.(45)
Coated tablets are tablets which are covered with one or more layers of mixture of various
substances such as resins, gums sugar, plasticizer etc. Substances used for coating are usually
applied as solution or suspension under conditions where vehicle evaporates.(46)
1.8.1. Types of coating
1. Sugar coating
Sugar coating was done to mask bitter taste of tablets. Bitter tablets are coated with sugar coat in
order to mask the taste of tablet. It also provides good appearance to tablets.
2. Film coating
As the sugar-coating process is very time consuming so this technique has been replaced by film
coating technology. The process involves spraying of a solution of polymer, pigments and
plasticizer onto a rotating tablet bed to form a thin, uniform film on the tablet surface. The choice
of polymer mainly depends on the desired site of drug release (stomach/ intestine), or on the
desired release rate.
3. Dip coating
Coating is applied by dipping tablet into coating liquid then wet tablets are dried in conventional
coating pans. Alternate dipping and drying steps can be repeated several times until the desired
coating is achieved.
4. Press coating
Compression is used to form coat around a pre-formed core. Used mainly to separate chemically
incompatible materials
5. Enteric coating
An enteric coating is a barrier that controls the location of oral medication in the digestive
system where it is absorbed. The word “enteric” indicate small intestine; therefore, enteric
coatings prevent release of medication before it reaches the small intestine. The enteric coated
polymers remain unionize at low pH, and therefore remain insoluble. But as the pH increases in
the GIT, the acidic functional groups are capable of ionization, and the polymer swells or
becomes soluble in the intestinal fluid.(47)

17
1.8.2. Objectives of coating
 To mask the disagreeable odor, color, taste of the tablet and increase patient compliance.
 To offer physical and chemical protection to the drug.
 To prolong the shelf life of drugs.
 To enhance ease of swallowing large dosage forms.
 To retard loss of volatile ingredients.
 To incorporate incompatible drugs together in a single dosage form
 Increasing the mechanical strength of the dosage form. (47)
1.9. Drug review
Promethazine is a first-generation antihistamine that is widely used to prevent nausea and to a
lesser extent to treat allergy symptoms. Because of its sedating effects, promethazine is also used
for anxiety, tension and as a mild sleeping aid.(48)
Figure 1. 1 Structural formula of promethazine HCL(49)
Molecular formula: C17H21ClN2S
Molecular weight: 320.88 g/mol (50)

18
1.9.1. Histamine and anti-histamine
Histamine is one of the most extensively studied biological amines in medicine. It
stimulates smooth muscle contraction and gastric acid secretion, increases vascular permeability,
functions as a neurotransmitter and plays various roles in immunomodulation, allergy,
inflammation, hematopoiesis and cell proliferation.(51)
1.9.1.1. Synthesis, storage and destruction of histamine
Histamine is beta imidazolyl ethylamine. It is synthesized from amino acid histidine and
degraded rapidly by oxidation and methylation. Liver degrades all histamine that is absorbed by
intestines.(52)
Figure 1. 2 Synthesis, storage and destruction of histamine(52)

19
1.9.1.2. Histaminic receptor
Histamine exerts its effects through four receptors, designated;
1. H1
2. H2
3. H3
4. H4
H1 and H2 receptors are widely distributed, H3 receptors are mainly presynaptic, and H4
receptors are mainly hematopoietic. H1 antihistamines are classified as first- and second-
generation compounds. First-generation compounds lack specificity and cross the blood–brain
barrier causing sedation. Second-generation compounds are less sedating and highly specific. H1
antihistamines have well-documented anti-allergic and anti-inflammatory effects and are well
established in the treatment of a variety of allergic disorders. First-generation antihistamines are
also used in the treatment of vestibular disorders and can be used as sedatives, sleeping aids
and anti-emetics. H2 antihistamines are widely used in the treatment of gastric acid-related
disorders; however, proton pump inhibitors are becoming the drugs of first choice in some of
these disorders. H3 antihistamines are expected to be of potential value in the treatment of
some cognitive disorder. H4 antihistamines could be of potential therapeutic benefit in the
management of various immune and inflammatory disorders.(51)
1.9.1.3. Histamine antagonist
It is broadly classified into two group as:
1. H1 antagonist and
2. H2 antagonist
1. H1 antagonists
These drugs competitively antagonize action of histamine at H1 receptors.
2. H2 antagonists
It blocks the H2 receptor and primarily used in peptic ulcer, gastroesophageal reflux and other
gastric hypersecretory states.(52)
1.9.2. Pharmacokinetics
1.9.2.1. Absorption
Promethazine is well absorbed from the gastrointestinal tract. Peak plasma concentrations occur
after 2 to 3 hours when promethazine is administered orally (25 to 50mg) or intramuscularly
(25mg). Following rectal administration of promethazine in a suppository formulation, peak
plasma concentrations were observed after about 8 hours. Oral bioavailability is approximately
25%. Rectal bioavailability has been reported at 23%.(50)

20
1.9.2.2. Distribution
Promethazine is widely distributed in body tissues and has a large apparent volume of
distribution following oral and intramuscular administration. Promethazine has been reported to
be 93% protein-bound when determined by gas chromatography and as 76 to 80% protein-bound
when determined by HPLC. Promethazine rapidly crosses the placenta, appearing in the cord
blood within 1.5 minutes when given intravenously at term. Promethazine crosses the blood
brain barrier.(50)
1.9.2.3. Metabolism
Promethazine is metabolized principally to promethazine sulphoxide and to a lesser degree
desmethylpromethazine. The major site of metabolism is the liver and that the drug is subjected
to extensive first-pass hepatic biotransformation, explaining the oral bioavailability of 25%.
Metabolism also occurs in the gut wall but to a lesser degree than earlier postulated. The
sulphoxide metabolite has not been detected after intramuscular dosing as circulating levels are
probably below analytical detection limits due to a combination of slow absorption, lower dose
(50% of oral), and bypass of first-pass metabolism in the liver.(50)
1.9.2.4. Elimination
The elimination half-life of promethazine following oral administration has been estimated to be
within the range of 12 to 15 hours. After intravenous administration of 12.5mg, blood
concentrations of promethazine declined bio-exponentially with a terminal elimination half-life
of 12 hours.(50)
1.9.3. Pharmacodynamics
1.9.3.1. Mechanism of action
Promethazine is a phenothiazine antihistamine, antagonizing the central and peripheral effects of
histamine mediated by histamine H1 receptors. The drug does not antagonize histamine at H2
receptors. Antihistamines competitively antagonize most of the smooth muscle stimulating
actions of histamine on the H1 receptors of the gastrointestinal tract, uterus, large blood vessels,
and bronchial muscle. Increased capillary permeability and oedema formation, flare, and
pruritus, resulting from actions of histamine onH1 receptors, are also effectively antagonized.
Promethazine appears to act by blocking H1 receptor sites, preventing the action of histamine on
the cell. Promethazine rapidly crosses the blood brain barrier and it is thought that the sedative
effects are due to blockade of H1 receptors in the brain. Promethazine is not used clinically for
its antipsychotic properties but in common with other phenothiazines exhibits antidopaminergic
properties. The antiemetic effect of promethazine may be due to blockade of dopaminergic
receptors in the chemoreceptor trigger zone (CTZ) of the medulla. Promethazine has strong
anticholinergic properties, blocking the responses to acetylcholine that are mediated by
muscarinic receptors. These atropine-like actions are responsible for most of the side effects
observed in clinical use of the drug. Promethazine also has anti-motion sickness properties that
may be due to central antimuscarinic action. In concentrations several times higher than those
required to antagonize histamine, promethazine exhibits local anesthetic effects. Promethazine
has also been shown to inhibit calmodulin. Authors have suggested that calmodulin inhibition by
promethazine could be a mechanism involved in the blockade of histamine secretion at cellular
level.(53)

21
1.9.3.2. Side effects
Side effects usually reported are severe breathing problems or death in child younger than 2
years old. In adults, overdosage is usually characterized by CNS depression resulting in sedation
and coma sometimes followed by excitement. In young children, CNS stimulation is dominant;
symptoms include excitation, hallucinations, dystonia’s, and occasionally seizures.
Anticholinergic manifestations such as dry mouth, mydriasis, and blurred vision are usually
present. Overdosage may also present with various cardiorespiratory symptoms such as
respiratory depression, tachycardia, hypertension or hypotension, and extrasystoles. Sedation,
ranging from mild drowsiness to deep sleep, is probably the most common adverse effect.
Dizziness, lassitude, disturbed coordination, and muscular weakness have all been reported.
Gastrointestinal effects including epigastric distress, nausea, diarrhea, or constipation can occur.
Promethazine can also cause immune allergic reactions. Leucopenia and agranulocytosis have
occurred rarely and usually in patients receiving promethazine in combination with other drugs
known to cause these effects. Jaundice and thrombocytopenic purpura have been reported rarely.
Extrapyramidal effects can occur, especially at high doses. Venous thrombosis has been reported
at the site of intravenous injections. Arteriospasm and gangrene may follow inadvertent intra-
arterial injection. Respiratory depression, sleep apnea, and sudden infant death syndrome (SIDS)
have occurred in a number of infants or young children who were receiving usual doses of
promethazine.(54-58)
1.9.3.3. Adverse reaction
Most reference texts suggest that the toxicity of promethazine is mainly due to its
anticholinergic actions at muscarinic receptors. Many of the signs and symptoms of poisoning
are similar to those observed with atropine. In the presence of anticholinergic effects, serious
manifestations such as seizures, hallucinations, hypertension, and arrhythmias have been
reversed by the administration of physostigmine. Besides anticholinergic 5 effects, promethazine
can also exhibit toxic effects typical of antipsychotic phenothiazines. Hypotension and
extrapyramidal signs may be attributable to antidopaminergic actions of promethazine.(59)
1.9.4. Medicinal uses
Promethazine hydrochloride is used as antihistamine; antiemetic; central nervous system
depressant; sedative; anticholinergic; anti serotoninergic; local anesthetic; in the treatment of
motion sickness, cough linctus’s, nausea, and allergic conditions; used to control Parkinsonian
symptoms and as central nervous system depressant; in pills, syrup, injections and
suppositories.(50)
1.10. Drug categorization
For the purpose of categorization of drugs pursuant to Section 17 of the Act, drugs are classified
in categories "a", "b" and "c" and every category may have sub categories. The drugs classified
in categories "a", "b" and "c" and sub categories under such categories shall be as mentioned in
Schedule –4.
1. Category "a" (Ka) consists of narcotic and poisonous drugs. Under the categories "a"
a. Sub category 1 shall consist of the narcotic drugs mentioned in that subcategory and
the drugs which contains any substance related to it.

22
b. Sub category 2 shall consist of the poisonous drugs consisting the active ingredients
mentioned in the sub category or any substance related to it.
2. Category "b"(Kha) consists Antibiotics, Hormones etc. drugs.
Category "b" shall consist of the drugs containing the active ingredients mentioned in that
category or any substance related to it.
The drugs under categories Ka and Kha shall be sold only on the prescription of a Doctor and
these drugs shall be sold by a pharmacist or professional own self or only in the presence of any
one out of either a pharmacist or a professional.
3. Category “c”
The drugs under category "c"(Ga) may be sold by any seller on the basis of experience
and even without the prescription of doctor and the presence of a pharmacist or a
professional shall not be compulsory while selling the drug. Under the category "c",
a. Sub category 1, shall consist the drugs that contain prescribed percentage of prescribed
drugs in that sub category.
b. Sub category 2, consist of the drugs containing the active ingredients mentioned in that
sub category or any substance related to it. (60)

23
2. Problem statement
Updated list of light sensitive drugs published in SAGE journal clearly indicates promethazine as
a light sensitive drug in its oral formulation(61). The study on quality on “Quality of drug and
drug use pattern at different level of health care settings in Nepal” carried out in 2016 by Nepal
Health Research Council has clearly indicated the existence of substandard drugs in Nepalese
market including few essential drugs supplied at free of cost by Government of Nepal and also
information regarding drug use pattern. Similarly, Department of Drug administration through its
regular post market surveillance has also found some substandard products in the pharmaceutical
market of Nepal. There is no adequate database in Nepal that ensures safety, efficacy and quality
of essential medicines that are available at different health facilities. Amongst them,
promethazine is of top priority. Being light sensitive, in the various pharmaceutical processes
like manufacturing, packaging and transportation, the percentage degradation of the
promethazine tablets is very high by the time they reach in the hands of the consumers.
Therefore, we have selected this particular drug for the quality evaluation among other products.

24
3. Literaturereviewand research gaps
The issues on substandard and counterfeit drugs are increasing globally. Many reports on drug
quality assessment have indicated wide regulation of substandard and/or counterfeit drugs in
pharmaceutical market in both developed and developing countries. In a study carried out in
South East Asian countries including Myanmar (Burma), Cambodia, Vietnam, Laos, and
Thailand, among 104 samples were 39(38%) counterfeit and 30 (29%) contained no artesunate
(62). A recent report of WHO provides information about the origin of counterfeit drugs in South
East Asian countries. Our two neighbor countries, China and India are the leaders in counterfeit
drug production and most of the bulk active ingredients produced by China and India are used in
the manufacture of counterfeit pharmaceuticals worldwide including Nepal (63).
Time and again various news on substandard have been reported in Nepal. The study on “Quality
of drug and drug use pattern at different level of health care settings in Nepal” carried out in
2016 by Nepal Health Research Council has clearly indicated the existence of substandard drugs
in Nepalese market including few essential drugs supplied at free of cost by Government of
Nepal and also information regarding drug use pattern. Similarly, Department of Drug
administration through its regular post market surveillance has also found some substandard
products in the pharmaceutical market of Nepal. There is no adequate database in Nepal that
ensures safety, efficacy and quality of essential medicines that are available at different health
facilities.
In a recent study, authored by Singh J , Dwivedi A et al, concluded that Ambient UV – B
exposure reduces the binding of ofloxacin with bacterial DNA gyrase and induces DNA damage
mediated apoptosis (64).
Another study, which was done by Chopra C , Tripathi A et al , reported that under ambient
UVA exposure, pefloxacin exhibits both immunomodulatory and genotoxic effects via multiple
mechanisms (65).
Ahmad I, Ahmed S, Anwar Z, et al. conducted a study on Photostability and photostabilization
of drugs and drug products.They highlights the role of the photochemistry in the photostability
studies, describes the functional groups important for the photo reactivity of drugs, explains
photophysical processes, and deals with the kinetics of photochemical reactions. The various
modes of photodegradation of drugs with examples of selected compounds are presented. The
biological consequences of the effect of light on the drug degradation are described. The
photostability testing of drugs and drug products and the requirements under ICH guideline are
discussed. Some information on the packaging requirements for the formulated products is
provided. The various methods used for the photostabilization of solid and liquid dosage forms
are also discussed.(66)

25
Sheraz MA, Kazi SH, Ahmed S, et al, concluded that riboflavin and analogues are chemically
degraded by cleavage of the isoalloxazine ring to produce a variety of compounds An optimum
pH with most appropriate buffers would provide a better stabilization of the vitamin in aqueous
solutions. Similarly, the addition of stabilizers, complexing agents, quenchers or incorporation
into liposomes is also suggested for better protection of RF from photodegradation.The thermal
degradation of RF takes place at high temperatures and pH and does not occur under normal
storage conditions, protected from light..(67)
Astanov S, Sharipov MZ, Fayzullaev AR, et al, reported that the proportion of molecules, which
have undergone degradation, are in the range of 4–28%, and depends on the concentration and
quantity of temperature effects. It was established that in a wide temperature range 290–423 K
there is a decline of absorbance and fluorescence ability, which is explained by thermo
destruction of riboflavin. It is shown Introduction of hydrochloric and sulfuric acids, as well as
different metal ions leads to an increase in the photostability of riboflavin solutions by 2–2.5
times. The observed phenomena are explained by the formation protonation form of riboflavin
and a complex between the metal ions and oxygen atoms of the carbonyl group of riboflavin,
respectively. (68)
Astanov S, Sharipov M, Faizullaev A, et al, reported that riboflavin powders were rather resistant
to heat treatments. The fraction of destroyed riboflavin molecules in aqueous solutions was in the
range 4–28% and depended on the drug concentration and the magnitude of the heat treatment. It
was found that the absorption spectrum of the riboflavin thermal destruction products agreed
satisfactorily with the absorption band of uric acid. Therefore, aqueous solutions of riboflavin for
medical and biological practice should be sterilized at temperatures below 373–393 K.(69)
Yadav N DA, Mujtaba SF, Verma A, Chaturvedi R, Ray RS, et al, suggested that mefloquine
may damage DNA and produce DNA lesions which may induce differential biological responses
in the skin on brief exposure to UVB and sunlight. Photosensitized MQ reduced the viability of
keratinocytes to 25 %. (70)
Farzana Hasin, Md. Mofazzal Hossain, Milon Kumar Ghosh, Samir Paul, et al, found that all the
collected cefuroxime axetil tablet (500 mg) brands were found Pharmaceutically Equivalent and
also Physio-chemically Equivalent. The results of all the tests performed showed that GMP and
cGMP guidelines have been followed accordingly during manufacturing. After performing
dissolution profile test of all collected brands was in the standard limit range. All brands were
shows equivalency in therapeutically. However, out of these three marketed brands C has been
showed better dissolution profile and comparatively of low cost against innovator product. (71)
Tasnim T, and Monirul Hasan
concluded that marketed pharmaceutical tablets of Olmesartanmedoxomil of these brands
are safe, effective and efficacious as well as satisfy quality control limits of pharmacopoeia.
Therefore, patients can safely shift from one brand to another. (72)

26
4. Objective of study
4.1. General objective
• To evaluate quality parameters of Promethazine HCl tablets marketed in Nepal.
4.2. Specific objectives
• To describe packaging and labeling specification.
• To test for the physical parameters.
• To evaluate various quality specifications (assay, in-vitro dissolution test and
disintegration test) of selected brands of promethazine tablets

27
5. Researchdesign and Methodology
5.1. Research method: Quantitative study
5.2. Research type:Lab-based survey
5.3. Methodology
5.3.1. Sampling Unit:
Since all the samples are not uniform and manufactured from different manufacturer, so 1.5√n
rule was used for sampling.(73)
5.3.2. Sample size:
As per the information obtained from the authorized source in DDA, there are 8 brands of
promethazine tablets (excluding combination products.) According to the sampling rule of 1.5√n,
we took 5 different brands for the evaluation.
5.3.3. Sampling procedure:
Five different brands of promethazine tablets registered in DDA were selected by lottery
methods. All the products were collected from DDA registered pharmacy retail shops of
Kathmandu valley. The samples were properly checked for batch numbers, manufacturing and
expiry dates, group, storage condition as well as price. The collected products/samples were
analyzed in CIST College using all the required instruments.
Different brands of promethazine were coded as;
1. P1
2. P2
3. P3
4. P4
5. P5
5.4. Materialsand Methods
5.4.1. Materials
Standard of promethazine HCl was a gift from Accord pharmaceutical pvt. Ltd, Mahalaxmi-8,
Bishnudol, Lalitpur, Nepal.

28
5.4.2. Instruments
All the analytical work were performed in the Cist College using necessary equipment.
S.N. Instruments Source
1 Electronic balance phoneix instrument, India
2 Dissolution apparatus optics technology, Delhi
3 UV spectrophotometer ShimadzuUV spectrometer,Model no.UV 1800 240V, Japan
4 Hardness tester optics technology, Delhi
5 Sonicator Daihan scientific, Korea
6 Vernier caliper Rolux, India
7 Disintegration apparatus optics technology, Delhi
5.4.3. Labeling and packaging
Packaging and labeling specification were reviewed by desk review.
5.4.4. Physical parameters
1. Diameter and thickness:
From each brand, 5 tablets were taken and Diameter and thickness was measured by using
vernier caliper.
2. Hardness:
From each brand, 5 tablets were taken and hardness was measured by using hardness tester.
3. Weight variation
20 tablets were taken from each brand and the average weight as well as standard deviation was
calculated.
5.4.5. Chemical parameters
1. Assay
Drug content of tablet of each brand were performed using Indian pharmacopoeia (IP) as
reference.
From each brand, 20 tablets were taken and finely powdered. A quantity of the powder
containing about 50 mg of Promethazine Hydrochloride were Weighed accurately, suitably
dissolved in 10 ml of 2 M hydrochloric acid and 200 ml of water was added in it. The mixture
was then sonicated for 15 minutes and sufficient amount of water was added to produce 500ml.
The mixture was then filtered. To 5 ml of the filtrate, 10 ml of 0.1 M hydrochloric acid was
added and sufficient amount of water was added to produce 100 ml. The absorbance of the
resulting solution was measured spectrophotometrically using UV spectrophotometer at 249 nm.

29
2. Dissolution
Dissolution of tablet of each brand were performed using USP as reference as dissolution of
promethazine tablets were not mentioned in IP.
The in-vitro release of promethazine tablets of each brand was carried out in 0.01 N HCl
medium for 45 minutes. The studies were performed in USP dissolution apparatus I, at 37 ± 0.5
ºC and 100 RPM speed.
From each brand, 6 tablets were taken and introduced into the 900 ml of 0.01 N HCl medium
and the dissolution apparatus was operated. Samples were taken after 45 minutes from the
dissolution apparatus and was filtered. To 5 ml of the filtrate, 25ml of 0.01 N HCl was added
and was analyzed at 249 nm by using UV spectrophotometer.
3. Disintegration
Six tablets taken from each brand were engaged for the disintegration test by distilled water at
maintaining the temperature of 37 °C at a Tablet Disintegration Tester. The disintegration time
(DT) of tablet was taken as the time when no tablet particle remained in the basket of the system.

30
6. Results and Discussion
6.1. Labeling Specification
Table 6. 1 Labeling specification
product code batch no. Mfd. Date Exp. Date price pharmacopoeia claim
P1 AVA9006 Sep 2019 Aug 2022 Nrs 67.2 per 10 tablets IP
P2 DV-0221 Feb 2021 Jan 2024 Nrs 50 per 10 tablets IP
P3 SNTF-20107 Oct 2020 Sep 2023 Nrs 30 per 10 tablets IP
P4 VMT-56003 Dec 2018 Nov 2021 Nrs 50 per 10 tablets BP
P5 335015 Feb 2021 Jan 2023 Nrs 26per 10 tablets USP
Table 6. 2 Labeling specification continue.
Product
code
Coating content dose Precaution and
warning
group Storage condition
P1 Uncoated Promethazine
HCl
25mg Keep out of reach
of children
Kha Store protected from light
and moisture and
temperature not exceeding
30º C
P2 Uncoated Promethazine
HCl
25mg Keep out of reach
of children
Ga Store protected from light
and moisture and
temperature not exceeding
30º C
P3 Film
coated
Promethazine
HCl
25mg Avoid alcoholic
drinks
May cause
drowsiness, if
affected do not
drive or operate
machinery
Ga Protect from direct sunlight
Store in dry and cold place
P4 Film
coated
Promethazine
HCl
25mg Do not use
without
prescription
Kha Protect from direct sunlight
Store in dry and cold place
P5 Film
coated
Promethazine
HCl
25mg Do not use
without
prescription
Keep out of reach
of children
Kha Protect from direct sunlight

31
6.1.1. Price fluctuation
Price fluctuation was observed in different brands of promethazine tablets which ranges from
Nrs 26 per 10 tablets to Nrs 67.2 per 10 tablets. Highest price was for brand P1 (Nrs 67.2 per 10
tablets) and minimum for brand P5 (Nrs 26 per 10 tablets).
6.1.2. Coating
Tablet containing light sensitive products should be coated with a colored film coating to protect
the product from light and prevent degradation.(20) But only Product P3, P4 and P5 are film
coated and Product P1 and P2 are uncoated.
6.1.3. Precaution and warning
As promethazine is classified under category Kha by the drug act 2035 it should mention “Do
not use without prescription” in its label. But only brands P4 and P5 mentioned it. Keep out of
reach of children were mentioned in P1, P2 and P5. Brand P3 mention specific type of warning
that says “Avoid alcoholic drinks and May cause drowsiness, if affected do not drive or operate
machinery”.
6.1.4. Drug categorization
Promethazine is a drug that should not be sold without prescription as it is classified under
category Kha by the drug act 2035 of Nepal thus it should be in category-kha but the brands P2
and P3 mis-categorized the drug in category-Ga. However, Product P1, P4 and P5 categorized
the drugs under category Kha as directed by the Drug Act 2035 of Nepal.
6.1.5. Storage condition
Protect from light were mentioned in all 5 products but temperature was mentioned only in
product P1 and P2. (i.e., temperature not exceeding 30º c). Store in dry and cold place was
mentioned in product P3 and P4.

32
6.2. Packaging Specification
Table 6. 3 Packaging specification
Product code Packaging type Packaging
appearance
Light resistance
packaging
P1 Blister Amber color Yes
P2 Blister Yellow color Yes
P3 Blister Transparent No
P4 Blister Transparent No
P5 Blister Amber color Yes
Primary packaging was not uniform in every brands. Out of 5 brands, only 3 brands (P1, P2 and
P5) use colored packaging to protect from light. P1 and P5 use amber color packaging whereas
P2 use yellow color packaging. Usually light sensitive drugs use alu-alu packaging or amber
colored blister packaging to protect the light sensitive drug.(20) But only 2 brands (P1 and P5)
were blister packaging. Though brands P1, P2 and P5 use colored packaging to protect from
light, brands P3 and P4 are neither alu-alu packed nor colored packed.
6.3. Appearance
Table 6. 4 Appearance
Product code Appearance Color of drug
P1 Round shape White
P3 Round shape Light blue

33
6.4. Physicalparameters
Diameter, thickness and hardness of 5 tablets of each brand were measured and following are our
results in this study:
a) P1
SN Diameter(cm) Thickness(cm) hardness(kg/cm²)
1 0.87 0.35 1.5
2 0.87 0.35 1.5
3 0.86 0.35 1.5
4 0.87 0.34 1.5
5 0.86 0.34 1.5
Table 6. 5 Physical parameters of brand P1
The diameter, thickness and hardness of the tablets of brand P1 were ranged from 0.86 cm to
0.87 cm, 0.34 cm to 0.35 cm and 1.5 kg/cm2 respectively.
b) P2
1 0.70 0.28 2.3
2 0.70 0.28 3.3
3 0.71 0.27 2.5
4 0.71 0.28 3.3
5 0.71 0.27 2.5
0.71 cm, 0.27 cm to 0.28 cm and 2.5 kg/cm2 to 3.3 kg/cm2 respectively.

34
c) P3
1 0.73 0.30 3.0
2 0.74 0.29 2.5
3 0.74 0.29 2.8
4 0.73 0.30 3.0
5 0.74 0.29 2.9
d) P4
1 0.72 0.30 3.0
2 0.73 0.31 3.0
3 0.73 0.29 3.5
4 0.71 0.30 3.5
5 0.73 0.31 3.5
e) P5
1 0.70 0.24 2.9
2 0.71 0.21 3.1
3 0.70 0.25 3.0
4 0.73 0.27 3.1
5 0.72 0.21 3.2

35
6.4.1. Physical parameters comparison
Table 6. 10 Physical parameters comparison
Code P1 P2 P3 P4 P5
Average Diameter(cm)* 0.87 ± 0.005 0.71 ± 0.005 0.74 ± 0.005 0.74 ± 0.009 0.71 ± 0.013
Average Thickness(cm)* 0.35 ± 0.005 0.28 ± 0.005 0.29 ± 0.008 0.30 ± 0.008 0.24 ± 0.026
Average Hardness(kg/cm²) * 1.50 ± 0 2.78 ± 0.482 2.84 ± 0.207 3.3 ± 0.274 3.06 ± 0.114
*Values are expressed as mean ± SD
Figure 6. 1Physical parameters comparison
Diameter, thickness and hardness of each brand were measured and was found to be satisfactory.
As we can observe from the table, the average diameter for the products Pl, P2, P3, P4 and P5
were found to be 0.87 cm, 0.71 cm, 0.74 cm, 0.74 cm and 0.71 cm respectively.
The average thickness of the products Pl, P2, P3, P4 and P5 were found to be 0.35 cm, 0.28 cm,
0.29 cm, 0.30 cm and 0.24 cm respectively.
The average hardness of the products Pl, P2, P3, P4 and P5 were found to be 1.50 kg/cm², 2.78
kg/cm², 2.84 kg/cm², 3.30 kg/cm² and 3.06 kg/cm² respectively.
0.87
0.71 0.74 0.74 0.71
0.35 0.28 0.29 0.30 0.24
1.50
2.78 2.84
3.30
3.06
0
0.5
1
1.5
2
2.5
3
3.5
P1 P2 P3 P4 P5
Physical
Parameters
Products
Physical parameters comparision
Diameter(cm) Thickness(cm) Hardness(kg/cm²)

36
6.4.2. Weight variation
Table 6. 11 Weight variation of 5 different brands
Sn. P1 P2 P3 P4 P5
1 251 mg 140 mg 160 mg 132 mg 82 mg
2 260 142 158 128 84
3 254 141 156 131 84
4 251 142 159 137 80
5 253 142 160 130 87
6 253 142 154 129 83
7 251 143 159 130 86
8 247 286 158 135 82
9 252 140 160 130 83
10 255 142 155 133 87
11 251 144 155 138 83
12 250 146 158 138 80
13 249 287 153 133 85
14 255 144 154 129 81
15 251 142 155 130 86
16 249 140 152 132 83
17 249 142 156 124 82
18 253 142 157 135 83
19 255 143 152 127 85
20 256 143 156 133 84
Average wt. 252.0526 157.3684 156.3684 131.6316 83.4737
Std. Deviation 3.0240 44.4312 2.6011 3.6721 2.0647
Upper limit 264.6553 169.1711 168.0961 141.5039 91.8211
Lower limit 239.4500 145.5658 144.6408 121.7592 75.1263
Max 260 287 160 138 87
Min 247 140 152 124 80
The standard limit of weight variation for p1 is between 239.4500 to 264.6553 mg. Weight
variation for p1 passed as the lower limit was found to be at 247 mg and the upper limit was
found to be at 260 mg.
The standard limit of weight variation for p2 is between 145.5658 mg to 169.1711 mg. Weight
variation for p2 failed as the lower limit was found to be at 140 mg and upper limit was found to
be at 287 mg. P2 failed the weight variation test as weight on the 8th reading was found to be 286
mg and weight on the 13th reading was found to be 287 mg.

37
variation for p5 passed as the lower limit was found to be at 80 mg and the upper limit was found
to be at 87 mg.
6.5. Assay
Drug content(assay) of tablet of each brand were performed using Indian pharmacopoeia (IP) as
reference. Following are the results calculated after examining the absorbance of all the samples
using UV spectrophotometer at 249 nm.
Table 6. 12 Results of Assay
Code
Spl1 (% Assay) Spl2(% Assay) Avg. assay (%)
p1 97.61 97.95 97.78
p2 96.80 98.30 97.55
p3 101.09 103.47 102.28
p4 104.80 102.10 103.45
p5 102.86 104.47 103.67
The drug content of all brands showed values within the monograph specifications (92.5 % -
107.5 %). As we can see in the table above, the assay result for the 5 different product is within
the limit determined by the IP. Thus, all of the 5 products, passed the assay.
%Assay of product P1 and P2 is comparatively less than other 3 products. This may be due to
those products being uncoated. so, from our study, what we can say that coating of the light
sensitive drug may affect its drug content.

38
Figure 6. 2 Graphical representation of result of Assay
6.6. Dissolution
Dissolution test using 6 tablets of each brands were conducted in 0.01N HCl medium at 100
RPM for 45 minutes. Following are the results calculated after examining the absorbance of all
the samples.
Table 6. 13 Dissolution percentage
Code Tablet1 Tablet2 Tablet3 Tablet4 Tablet5 Tablet6 Range in dissolution % Average dissolution%
p1 69.16 64 68.79 63.81 71.19 68.61 64-71.19 67.59
p2 77.83 72.11 70.64 67.32 67.87 74.32 67.32-77.83 71.68
p3 99.97 81.38 99.56 97.70 100.80 92.54 81.38-100.80 95.33
p4 104.72 85.72 82.42 83.04 91.30 91.09 82.42-104.72 89.72
p5 97.30 93.60 86.63 92.84 89.68 93.38 86.63-97.30 92.24
The result of invitro dissolution of pl, p2, p3, p4 and p5 were found to be 64 -71.19 %, 67.32-
77.83 %, 81.38-100.80 %, 82.42-104.72 % and 86.63-97.30 % respectively.
The dissolution profiles showed 3 brands (P3, P4 and P5) attained 75%(Q) dissolution and
complied with USP monograph whereas 2 brands (P1 and P2) don’t comply with limit. Hence,
P1 and P2 failed the dissolution test. This may be due to either those products being uncoated or
our technical error.
On the other hand, P3, P4 and P5 passed the dissolution test as per the USP as the range of
dissolution for them is more than 75%(Q). Since, these three products are film coated, it is likely
that this may be the reason that they easily passed the dissolution test.
97.78 97.55
102.28
103.45 103.67
94
95
96
97
98
99
100
101
102
103
104
105
P1 P2 P3 P4 P5
Assay
%
Products
Avg. Assay (%)

39
Figure 6. 3 Graphical representation of result of Dissolution
6.7. Disintegration
Disintegration test of each brands were conducted in distilled water at maintaining the
temperature of 37 °C at a Tablet Disintegration Tester. Following are the result obtained;
Table 6. 14 Disintegration time
Product code Disintegration time
P1 4 min 6 sec (4.10 min)
P2 4 min 24 sec (4.40 min)
P3 6 min 57 sec (6.95 min)
67.59 71.68
95.33
89.72 92.24
0
20
40
60
80
100
120
p1 p2 p3 p4 p5
Dissolution
%
Products
Average Dissolution (%)

40
Figure 6. 4 Graphical representation of result of Disintegration
All samples of each brand disintegrated within 4.1 minutes to 7.05 minutes. (i.e., brand P1 has
the lowest disintegration time and brand P4 has the highest disintegration time). This difference
is due to some brands are uncoated and some brands are film coated. As brands P1 and P2 are
uncoated, they disintegrate at around 4 minutes. Whereas brands P3, P4 and P5 disintegrate at
around 7 minutes as they are film coated.
4.10
4.40
6.95 7.05 7.02
0
1
2
3
4
5
6
7
8
P1 P2 P3 P4 P5
Time
(minutes)
Products
Disintegration time (minutes)

41
7. Summary
Table 7. 1 Summary Table
Product
code
Coated/
Uncoated Price
Avg. Assay
%
Avg.
Dissolution %
Disintegration time
(minutes)
P1 Uncoated
Nrs 67.2 per 10
tablets 97.78 67.59 4.1
P2 Uncoated
Nrs 50 per 10
tablets 97.55 71.68 4.4
P3
Film
Coated
Nrs 30 per 10
tablets 102.28 95.33 6.95
P4
Film
Coated
Nrs 50 per 10
tablets 103.45 89.72 7.05
P5
Film
Coated
Nrs 26per 10
tablets 103.67 92.24 7.02
After completing this study, it is suggested that coating may affect the quality of light sensitive
drugs as the uncoated product P1 and P2 do not comply with limit as per the USP and failed the
dissolution test whereas product P3, P4 and P5 passed the dissolution test which are film coated.
Moreover, the result of all quality parameters of brands (P3, P4 and P5) were in the
pharmacopoeia limits. So, it could be concluded that marketed pharmaceutical tablets of
promethazine of brands (P3, P4 and P5) satisfy quality control limits of pharmacopoeia.
However, out of these three brands, P5 has been showed better drug content, dissolution profile
and comparatively of low cost against other brands.

42
8. Conclusion
In packaging specifications, primary packaging was not uniform in every brands. Out of 5
brands, only 3 brands (P1, P2 and P5) use amber and yellow colored packaging to protect from
light. In labeling specifications, price, drug categorization, coating and important precautions
were not uniform in every brands. Diameter, thickness, hardness and weight variation of each
brand were measured and was found to be satisfactory (except for brand P2 as it fails its weight
variation test). The drug content of all brands showed values within the pharmacopeial
specifications (92.5 % - 107.5 %). The dissolution profiles showed 3 brands (P3, P4 and P5)
attained 75%(Q) dissolution and complied with USP monograph whereas 2 brands (P1 and P2)
don’t comply with limit. All samples disintegrated within 4.1 minutes to 7.05 minutes.

43
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