Souvik Chattopadhyay Final Thesis For Submission-1 PDF

Formulation and Evaluation of Nasal Solution for
Migraine therapy
SUBMITTED TO
SIKKIM UNIVERSITY
FINAL DISSERTATION REPORT
In partial fulfillment of the degree of
MASTER OF PHARMACY IN PHARMACEUTICS
Submitted by
SOUVIK CHATTOPADHYAY
Roll.No.18HMPS10
Regd. No.-18SU29316
UNDER THE GUIDANCE OF
MR. SUJIT DAS
(Assistant Professor)
(DEPARTMENT OF PHARMACEUTICS)
HIMALAYAN PHARMACY INSTITUTE

MAJHITAR, EAST SIKKIM, 737136
2020
HIMALAYAN PHARMACY INSTITUTE
Affiliated to Sikkim University, Approved by Govt. of Sikkim, A.I.C.T.E and P.C.I.
Recognised by UGC u/s 2(f) of UGC Act, 1956
ISO 9001:2008 Certified Institution
ESTD 1990 Majhitar, East Sikkim-737136
Ph: 93325-21231
Email: hpinstitute@yahoo.co.in, Web: www.hpi.in
CERTIFICATE
This is to certify that the M.Pharm Research work “ Formulation and Evaluation of Nasal Solution
for Migraine therapy” being submitted by SOUVIK CHATTOPADHYAY, Regd. No. 18SU29316,
Roll No. 18HMPS10 in the partial fulfillment of the requirements for the award of Master of Pharmacy
(PHARMACEUTICS) at Himalayan Pharmacy Institute, Majhitar, East Sikkim affiliated to the Sikkim
University is a bonafide work carried out by him under the supervisions of MR. SUJIT DAS during
the academic year 2019-2020.
The final M. Pharm thesis report can be forwarded to the Controller of Examinations, Sikkim
University for assessment.
Dr. Prithviraj Chakraborty Mr. Sujit Das

Head of Department Assistant Professor,
Department of Pharmaceutics, Department of Pharmaceutics,
Himalayan Pharmacy Institute Himalayan Pharmacy Institute
Majhitar, E. Sikkim
Majhitar, E.Sikkim
Forwarded to COE, SU
Prof. (Dr.) N.R. Bhuyan

(Principal)
Himalayan Pharmacy Institute
Majhitar, E. Sikkim
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DECLARATION
I hereby declare that the work embodied in the final-semester

dissertation report “Formulation and Evaluation of Nasal Solution for
Migraine therapy” has been carried out by me in the department of
PHARMACEUTICS, under the supervision of MR. SUJIT DAS,
Department of Pharmaceutics, Himalayan Pharmacy Institute,
Majhitar, East Sikkim during the session of 2019 – 2020, has not been
submitted earlier for any degree or any award anywhere before.
Place: Sikkim
Date: Souvik Chattopadhyay
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ACKNOWLEDGEMENT
Let me take this kind opportunity to express my highest regard and gratitude to Dr. H.P.
Chhetri (Director, Himalayan Pharmacy Institute) for providing all the facilities required
for completing the project and at the same Time(Mins) allowing me to carry out my final
dissertation as a partial fulfillment for M. Pharm degree.
I would like to express my sincere regards to Dr. Abhinay Chhetri (Associate Director,
Himalayan Pharmacy Institute) for his valuable support.
This would be totally incomplete without the role of Mr. Sujit Das (Supervisor). His skills
of attitude and intelligence continuously imparted me in a spirit of adventure and
excitement in regard towards research work. Without his guidance and persistent help this
dissertation would not have been possible. So utmost thanks is not at all sufficient rather it
is the most humble submission of profound gratitude for a lifeTime(Mins) work.
I would like to thank Dr. Prithviraj Chakraborty (H.O.D.) for his valuable guidance, keen
interest and encouragement during various stages of my projects.
I would like to thank Dr. Nihar Ranjan Bhuyan (Principal) and Dr. K. Gauthaman (Dean,
Academic and Research) for their valuable guidance, interest and encouragement during
my project work.
Even I want to thank Mr. Dhiman Roy (Lab Assistant), Mr. Ashman Sharma (Lab
Assistant) and Mr. Jeewan Pradhan for all my practical works and can never be forgotten.
Last but not the least, my wholehearted thanks and gratitude to my Parents Sri Subinoy
Chattopadhyay and Smt.Amita Chatterjee, My constant inspiration CR7 and my close
friends especially Sayagni Sadhukhan, Suman Das, Koushik Narayan Sarma, Parichay
Ghorai, Dipjyoti Biswas and others.
Place:
Date: Souvik Chattopadhyay

For the loving memory of my Grandmother
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Dedicated to the game called life
&
The persons
Who
Never walk alone
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LIST OF ABBREVIATIONS
λmax Absorption maxima
conc. Concentration
oC Degree centigrade
gm Grams
hrs/ h Hours
∞ Infinity
g Microgram
mg Milligram
ml Milliliter
min Minutes
HPMC Hydroxypropyl methyl
cellulose
nm Nanometer
% Percent
PCM Prochlorperazine maleate
rpm Rotations per minute
UV Ultra violet
w/v Weight by volume
w/w Weight by weight
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Contents Page no.
1 INTRODUCTION
1.1. Anatomy & physiology of nose 11
1.2. Mechanism of Nasal Absorption 13
1.3. Obstacles to Nasal Absorption 14
1.4. Physicochemical properties of drug applicants & formulations 16
1.5. Improved nasal drug absorption progress to date 16
1.6. Nose to Brain Targeting 16
1.7. Inflowing factors of nasal drug absorption 17
1.8. Factors for formulation 18
1.9. Migraine: an overview 22
2 AIM & OBJECTIVE 24

3 REVIEW OF LITERATURE 26
4 MATERIALS & INSTRUMENTS 27

5 METHODOLOGY
5.1. PRE-FORMULATION STUDIES 43
5.2. POST-FORMULATION STUDIES 44
6 RESULTS & DISCUSSION 46
7 CONCLUSION 61
8 REFERENCE 62
9 ANNEXURE 66
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1.Introduction
With the current development of drug delivery routes(1), nasal route has taken special attention
from the very earlier Time(Mins)s of human civilization(2,3), our ancestors specifically tribal
people were involved in the practice of our very own Ayurvedic process called ‘Nasya Karma’(4).
Though various kinds of drugs can be administered by this route, our ancestors were involved in
basically with the drugs that are mainly psychotropic, or it can create hallucinations. They have
administered through powdered dosage forms known as ‘Snuffs’. Latin America was also known
for continuous practicing regarding the nasal route. Day by day, with the progress in this route,
nasal route assuring very good systemic bioavailability of several drugs than the same taken
through conventional oral route. But there are more hurdles, we must go. Such as, in case of drugs
having protein peptide properties displays very less absorption as well as low bioavailability. By
taking several approaches they are overcome, like absorption enhancer, inhibitory chemicals for
enzymes.
More novel approach is my formulating microsphere with bio-adhesive/bio-erodible polymers. As
per our general considerations, we always choose parenteral for absolute bioavailability. But for
pediatric patients or the patients with several neurodegenerative disorders are often found to be
very hard rock to break, as they are prone to be not the selective candidate for conventional
parenteral administration. In this kind of adverse situation, nasal route can be a breakthrough for
bypassing the parenteral administration.
As a route of administration, nasal route is having some unique positive features(5) such as: -
• Wavering the hepatic first pass metabolism.

• The bioavailability of plasma can be same as already with Intra venous route (I.V)
• The nasal route specifically, the cavity of nose is enriched with the network of blood
transporters like capillaries, veins & arteries which engifting best environment for systemic
absorption.
• The patient compliance and ease of administration at its class best.
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1.1.Anatomy & Physiology of Nose
1.1.1.Anatomy
If we consider the structure of the nose, we can say it is situated in the middle of the beneath of
two eyes that is symmetrical position. Nose acts as a gateway(opening) of the respiratory tract and
serves as an organ for the smell sensation. The gateway that allows the oxygen enriched air to get
inside which is suitable for respiration as well as the quality of air is maintained by filtration,
applying temperature, by humidification and expel out undesirable particulates from
inhaled/sucked air. The two hollow space that is divided by the partition made of cartilage, which
is known as septum. The outer holes are basically called nostrils. The canopy of mouth and the
ground of and the ground of the nose is constructed by palatine bone. Generally, the opening
constructed by palatine bone. Generally, the opening portion is known as solid palate. It acts a
valve that prevents refluxing of food outside the nose. It is very difficult to study the structure of
nasal cavity because of its intricacy. The progressive part of inside and outside part of each nostril
is known as vestibule. Backside of the vestibule and every external partition are basically three
preferment flowing generally from frontside to backside. Each preferment is basically known as
nasal concha or turbinate, draping over the cushion of air. In the side and the upper portion of the
concha is the olfactory area of the nasal cavity is responsible for responsible. The pathway surface
of respiration is humidified with mucous integument with prime capillaries called cilia, which act
as to contain lumber mucus helps in adhesion of dust mites, carbon and bacteria. The skull structure
made of bones contain sinus pockets on each side. The integument of mucus constructed the area
which is responsible for the sensation of smell known as olfactory region. It also consists of several
nerves which acts as the organ which regulates the organ for sense or natural reflex manager.
Spindles like dendrites coming outside from the nerve cells to the cavity is encapsulated by very
small wetness of water. The smell sensation is a chemical process occurred by solvation of small
entities with nasal moisture that enlite nervous cells.
1.1.2.Physiology of nasal cavity

The main action nasal cavity is to permit the air flow or wind to get into the place. The structural
matter. Olfactory organ is responsible for the sensation of smell. Nasal mucosa considering
Conchae extends the alley and inception of inhaled air occurs. The exposure between raw
infiltrated air and nasal mucosa causes the spinning movement of inhaled air. This bound particles
before getting into lungs. Olfactory systems work by effluvious response of body. Bowman’s
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glands help in emanation of the mucus. The special pigments which is expelling out creates pale
yellow colour of mucus. They by solvation of the inhaled objects, aromatic response of nose.
Paranasal sinuses are responsible for reverberate articulation and secretes the mucus into the nasal
aisle. Various functions of the sinus are still under discovery. Nasolacrimal Ducts are responsible
for tear production to the mucosal layer.
1.1.3.Physiology of nasal mucosa

The nasal mucosa gives defense mechanism that boosts the power of immune system to protect
from foreign invaders. It protects/ bypass lungs from allergy forming substances and infectious
pathogens. The adhesive mechanism of nasal mucosal layer attaches dust particles. The inter
subject variability occurs due to the alteration of defense/immune system. Production of
IgE(immunoglobulin type E) is initiated by B cells which plays a major responsibility in Type-I
hypersensitivity reaction.
1.1.4.Epithelial cell
This wall act as a protective surface layer from foreign allergens and also mucus glands and cilia
for expelling out unwanted substances or particulate matter from nasal cavity. Current studies also
show their bigger roles/ responsibility if the physical barrier have not the capability to expel out
the pathogenic trespasser cell of nasal mucosa. The main content of the epithelium is antigen
binding proteins. The main job of these cells is to inaugurate pathogens to the T-lymphocyte cells
which causes massive destruction to them. The APCs (Antigen Presenting Cell) entraps the antigen
and show immune response. The factors given by epithelial cells give synergistic inflammatory
responses like cytokines. The allergy formers with the strong association with epithelial cells build
a great wall of defence. Epithelial cells also help in processing of IgE to show the activity against
various allergen.
1.1.5.Endothelial cell
They are responsible for allergic response by creating affinity of leukocyte from blood to site of
inflammation.
1.1.6.Mucus gland
Mucus glands secretes mucus for self-protection as well as to maintain the moisture inside the
nasal wall.
1.1.7.Cilia
Cilia is hairy structure belonging epithelium, which with their systematic movement secretes
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mucus from the nasal pathway to the throat cavity. Temperature has simple direct relation with
the activity of cilia and promotes either nasal congestion or runny nose.
1.1.8.Basal blood vessels
The basal vein with less encapsulation helps to increase the temperature of the inhaled air in the
respiratory module. These vessels are directly responsible for congestion in nasal pathway. The
nerves surrounded by nerves which acts as a regulator of congestion reflex.
1.1.9.Nerves
Trigeminal and Maxillary nerves regulate the stimulation of nasal mucosa. The touch, pressure
and temperature are regulated by trigeminal part whereas, the sympathetic and parasympathetic
reflexes controlled by maxillary nerve which includes the constriction and dilation of blood
transporter. The mast cells are responsible for allergic or sensitivity reactions.
1.2.Mechanism of Nasal Absorption
The major aim of the nasal drug delivery system is the captivation of the drug from the nasal
chamber is the leaks it through mucous layer. The size of the particle plays a vital role with the
permeability of the drug. It is very obvious that the particles which have very small size can pass
the membrane whereas the particles which have big size can’t easily cross the membrane. The
mucus layer which contains a specialized protein mucin attracts the solute and influences the
overall diffusion. Several exogenous factors either environmental or biological can also change
the overall edifice of the mucus coating. When a drug is passing through the mucus deposit, various
systematic procedures are involved which overall influences the captivation. The various methods
which are responsible for dispersion of active drugs are transcellular or simple diffusion which
occurs around the crust of mucosa. The vesicles perform the transcytosis which helps in
paracellular transport by maneuver drug between cells. Hypothetically, there are several
mechanisms but major are paracellular and transcellular pathways. Paracellular conveying is
deliberate and acquiescent. Intranasal captivation shows antithetical relation with molecular
weight of water-disintegrable complexes. Very low bioavailability has been observed with drugs
of molecular weight more than 1000 Daltons(7). Another way of haulage engages transport via
lipoidal track that is also called as the transcellular method which is accountable for the
conveyance of the lipophilic drugs which displays rate reliance on their lipophilicity. Drugs also
overlap cell sheath by the pathway of active transport through germinal of constricted
convergence(8). Therefore, we can derive mathematical manifestation of the effective
permeability coefficient Peff under steady state conditions across excised mucosa, as equation 1:
Peff = (dc/dt)ss V / (A CD)
Where (dc/dt)ss is the Time(Mins)-dependent change of concentration in the steady state, A is
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permeation area, V is the volume of the receiver compartment and CD is the initial concentration
in donor compartment(9,10).
1.3.Obstacles to Nasal Absorption
Nasal drug delivery ponders as the most economic and effective pathway for the formulators due
to simplest tactics and efficacy. Curative value and poisonous effects are controlled by several
following aspects(11).
1.3.1.Poor Bioavailability
From our normal concept, it is very obvious that lipophilic drugs have the largest tendency of
absorption in comparison with polar drugs. The bioavailability is highest i.e. 100% in case of intra
venous route which is approximately same as in case of lipophilic drugs. e.g. Though the
Tmax(Maximum Time(Mins) needed for absorption) is same for Fentanyl while the bioavailability
is 20% less in nasal route than the parenteral route. The low membrane permeability is the most
significant and blessed element restricting the nasal absorption of polar medicines and particularly
big molecular polar drugs, such as peptides and proteins. Medications may cross either the
transcellular route through which simulated concentration gradients are exploited, the transceiving
or transportation mechanisms of the receptors are mediated or vesicularly transported or by the
paracellular path through the tight junctions between cells. Polar drugs below 1000 Da usually go
through the membrane on the latter path. The shipping of mucus is strongly linked to the cilia on
respiratory epithelial cells. At the back, the cilia is twisted and moving in the pericellular fluid
only underneath the viscous mucus. This means that the mucus of the viscous membranes is bent.
The cilia carry the mucus at a velocity of ~1000 strokes per minute, and formulations administered
on the human breathing epithelium have been discovered to be removed from the nasal cavity with
a half-Time(Mins) clearance of approximately 15 minutes. The mucociliary clearance mechanism
can readily transfer the medicine away from the entry point in the nasal cavity into the esophagus
in polar drugs which are not easily transported across the nasal membrane that limits the
absorption. For instance, we take nasal spray of sumatriptan (Imigran®; GlaxoSmithKline,
http://www.gsk.com) which displays bioavailability of 15.8%. If we compare between nasal
administration with oral dosage form, we can easily observe that very small amount of drug is
absorbed through nasal route so the bioavailability of nasal dosage is relatively very low with
comparison with conventional oral dose. But there are some exceptions. The hydrous solution of
Sumatriptan which easily expelled out from nasal cavity shows better relief than tablet though very
small amount of drug is absorbed through this route. So, we can conclude that nasal route is very
potential route of drug delivery(12).
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1.3.2.Poor membrane conveyance
The overall fast removal of the administered oral cell structure owing to the mucociliary removal
system is another significant variable in minor membrane transportation. In particular, these drugs
are not readily taken throughout the nasal membrane. The half-life of the removal is in the range
of 15-20 minutes for both liquid and powder formulations not mucoadhesive(13).
1.3.3.Enzymatic drug mortification and prospective efflux
A few medicinal enzymes, including oxidase Phase I, conjugative phase II and proteolytic
enzymes, have been recognized in the Nasal Mucus. Recent surveys proved a comparable
population, communities and distributed of CYP enzymes by cattle nasal olfactory, respiratory
mucous membranes and brain tissue(14). The most significant function, however, for the shipment
of nasal drugs are proteolytic enzymes. These proteins include exopeptidases that are limited to
cell hydrolysis at / near the N- or C-terminal or endopeptidases, which are hydrolyzed within a
cell bond(15) Aminoproteinases, diaminopeptidases, postpropyl enzymes, angiotensine
converting enzymes, endophobiaptideses 24.11 (a metalloproteinase), and thioproteinase are
included in these exopeptidases and endopeptidases(16). During and after DNA intake, the
existence of membrane-like and cyto-cytoslic aminopeptidases shows that both proteins and
peptides may be degraded. The proteins that cause substance degradation are still not clear. It can
be assumed that, based on the exposure to protein or peptide medicines, intracellular proteases are
accountable. With regard to nasal enzyme activity and allocation, it shows in the olfactory region
that there are likely more enzymes and enzyme activity for the disablement of toxic odor vapors.
In laboratory animals (for example rodents) the high metabolic capacity of mucosa shows its roles
in toxic detoxification(17). But, in terms of drug metabolic status, their ability and their
prospective functions in people have not yet been proven. However, these enzymes can play a
major role in the metabolization of ciblated medicines. Brain supply due to absence of olfactory
classification, and delayed permeation to the brain of medication. P-gp has not been proved in
relation to nasally administered drug clinically important restrictions. It should be noted, however,
that P-gp is regional in the nose, with a greater level of olfactory mucovascular activity and
overexpression in certain chronic inflammation, which can affect drug delivery.
1.4.Physicochemical properties of drug applicants & formulations

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A careful study of physical chemical characteristics of a drug molecule for the nasal route involves
biopharmaceutical analysis of nasal absorption. Molecular Weight, partition coefficient, chemical
stability, solubility and surface charges are the prime parameters. Although crucial for the
absorption of oral medicines, these features take an significant part in the absorption of nasal
medications given that the dwelling period of the nasal drug is comparatively brief owing to the
concentration in mucocilia. The function of physical chemicals in nasal absorption was widely
discussed(18–20).
Not just to select suitable medication applicants, but also to ensure that the drug remains soluble
and stable during the absorption phase, the physicochemical characteristics of nasally administered
drug have a significant effect. If the oral mucosa is to absorb a medicine effectively, it should be
comparatively water soluble, secure, small molecular in weight (about 500 Daltons), unionized
and without a ground load.
1.5.Improved nasal drug absorption progress to date
Many methods to overcome nasal drug absorption problems have been employed or supported.
Includes common approaches:
• Hindrance of clearance inhibition using mucoadhesives;
• Improvement in intake by absorption enhancer;
• alteration of physicochemical characteristics by active component using medicines and
other policies;
• Inhibition of metabolism with inhibitors of enzymes;
• micro-/nano-particular formulation development;
• Design and feasibility of supply equipment;
• Using techniques for the testing and improvement of the intake of oral drugs ex vivo and
in vitro study;
It is essential to study processes of drug permeation throughout the nasal epithelium before
debating these approaches. Understanding the processes concerned is essential in the design and
optimisation of policies for absorption improvement.
1.6.Nose to Brain Targeting
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To present, most drugs for the treatment of CNS and associated brain disorders are used
systematically and are a condition for crossing the blood-brain barrier (BBB). BBB is the main
obstacle for the implementation of the medicine in the brain. BBB is the sensitive network of
endothelial ships that separate the brain from the circulatory system(21). It preserves the brain
against the introduction of toxins and bacteria. This barrier cannot be crossed by hydrophilic,
loaded molecules or by peptides, while lipophile medicines such as antidepressants, anxiolytics
and many enzymes are readily passable over endothelial cells(22).
Nasal delivery system can be considered as one of the main non-invasive routes of delivery. Apart
from DDS, another immediate transportation approach for the drug from nose to brain is to place
the medicine on the olfactory epithelium or nose area, which is internalized by trigeminal nerves
in order to carry more medicines into their brain through olfactory / trigeminal pathways. In order
to achieve this, scientists have researched and developed numerous efficient and effective new
nasal drugs distribution systems. This include pressurized olfactory devices, nebulizers, atomizers,
pressurized meter dose inhalers and bidirectional breath powdered equipment, which has been
accessed in clinical conditions which are depicted in Figure 1.(23) There has been also evidence
of an immediate nose for the transport of drugs into the brain by humans, mainly as regards
pharmacodynamic impacts on CNS, such as impacts on event-related potential during a subject's
oddball task in nasal and intravenous delivery paths contrasting drug
administration(24,25).
1.7.Inflowing factors of nasal drug absorption

Various variables influence the intrinsic bioavailability of drugs administered by the oral pathway.
The physiochemical properties, the nasal cavity's anatomic and physiologic properties and the sort
and features of chosen nasal drugs are affected by these variables. There are multiple
circumstances which can affect the nasal absorption. They are,
1.7.1.Physiochemical properties of drug

1.7.1.1.Molecular Size(26,27)
The molecular dimension of the drug impact the nasal absorption of the medicine. Lipophilic
drugs are directly related to the permeation of the MW, whereas water-soluble substances represent
a reverse relation. The permeation level for MW compounds of more than or equal to 300 Daltons
is extremely molecular-sensitive.The nasal membrane permeability for drugs seems to rely on the
magnitude of the drug molecules. In a thorough assessment of various drugs with molecular weight
ranging from 160 to 34000 Da, the impact of molecular sizes was explored(28). The findings
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indicate that the molecular weight of nasal absorption reduces exponentially. For rats and people,
the same pattern was observed. The molecular weight of the nasal rate limiting was 1000 Da as
against 300 Da for the oral route. In other research, rat have exposed with oral intake of various
water-soluble compounds, including p-aminohippuric acid, potassium cromolyn, inulin and
dextran with distinct molecular weights(29). The findings showed a strong linear correlation
between the logarithm of percent absorbed and the log of molecular weight , indicating aquatic
channels' involvement in water-soluble molecules ' respiratory intake(30). It is been also found
that there is an overall impact of nasal absorption with the molecular weight of polydisperse
polyethylene glycols(PEGs, 600,1000 & 2000) in rats(31). Higher the molecular weight, lesser is
the absorption.
1.7.1.2.Chemical Form
In determining absorption, the chemical type of a drug is essential. Converting the drug to salt or
ester can also change its absorption, for instance. Huang et al., observed the impact on absorption
of the drug structural alteration(32) In-situ nasal absorption of L-tyrosine carboxylic acid esters
has been found to be much higher than L-tyrosine.
1.7.1.3.Polymorphism
Polymorphism happened when one drug can exist in more than one crystalline form. It is very
common that polymorphism can alter the dissolution rate and solubility of drugs. This can also
change the absorption via physiological sheath(33).
1.7.1.4.Particle Size
The oral cavity has been revealed to contain particulate dimensions above 10μm. Particles 2 to 10
μm in the atmosphere may be maintained and ions below 1 μm exhale.
1.7.1.5.Solubility & dissolution Rate
Drug solubility and rate of dissolution are key considerations in the determination of powder and
suspension nasal absorption. The nasal cavity stored ions must be disbanded before they are
absorbed. No absorption happens when a drug stays as droplets or has been removed.
1.8.Factors for formulation
1.8.1.Formulation pH
In order to optimize systemic absorption, both the pH of the nasal cavity and the pKa of a certain
drug must be taken under contemplation. When delivering products with a pH range of 4.5 to 6.5
nasal irritation is minimized. It is also essential to remember quantity and intensity. The amount
of shipment is restricted to the nucleus of the nose. A maximum restriction of 25 mg / dose has
been proposed and a quantity of 25-200 μL / nostril.Maintenance of pH is much important in case
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of nasal formulation preparation. The reasons are following:
• To prevent nasal mucosal inflammation
• In nasal passage, to avoid the development of disease bacteria
• To keep excipients such as preservatives functional
• Maintain excipient features such as preservatives
• Support ordinary ciliary physiological motion
The nasal secretions that cause some bacteria to be removed in acidic pH are lysozyme. Lysozyme
is blocked under alkaline conditions and the tissue of the nose is prone to microbial infection.
Therefore, it is advisable to take into account the physicohemical characteristics of the drug at a
pH of 4.5 to 6.5 when taking drug products unionized.
1.8.2.Buffer Capacity
In general, tiny amounts of nasal formulations varying from 25 to 200μL are administered. Nasal
secretions can therefore change the pH of the given sample. The level of the unionized drug
accessible to absorb may be affected (34). A sufficient buffer capacity may therefore be necessary
to keep the pH present.
1.8.3.Osmolarity
Tonicity of formulation preparation may affect drug absorption. The decline in the existence of
hypertonic alternatives has been noted for epithelial cells. Hypertonicsaline solution are
responsible for constraining bustle of cilia. Low pH has an impact comparable to hypertonics.
Suzuki et al.,1999 have shown that a drug holder like hydroxypropyl cellulose can improve the
absorption of low-molecular weight drugs but does not have the same effects for high-molecular
peptides(35).
1.8.4.Solubilizers
Aqueous drug solubility is a nasal drug delivery constraint in equilibrium. Conventional solvents
or co-solvents, such as glycols, tiny amounts of drugs, transcutol, medium chain glycerides and
labrasol, may be used to improve drug solubility(36). Other options include the application, in
conjunction with lipophilic absorption boosters, of surfactants or cyclodextrins such as HP‐β-
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cyclodextrin as a biocompatible solubilizer and stabilizer.
1.8.5.Preservatives
The majority of nasal formulations are consisting with water which are very prone to microbial
growth should be added with preservative. Generally, Parabens,benzalkonium chloride, phenyl
ethyl alcohol, EDTA and benzoyl alcohol are used. Van de Donks et al., 1980, demonstrated the
rapid and irreversible impact on ciliary motion of mercury comprising preservatives and should
not be used for nasal devices(37).
1.8.6.Antioxidants
Antioxidants usually do not trigger nasal discomfort or drug uptake. As portion of the formulated
design programmed, chemical / physical interactions of antioxidants and preservatives should be
regarded with medication, excipients, manufacturing machinery and packaging elements. Sodium
metabisulfite, sodium bisulfite, butylated hydroxyl toluene, and tocopherol are commonly used
antioxidants. Significant clinical improvement has been found with the use of antioxidant with
fluticasone furoate rather than single use of fluticasone furoate(38).
1.8.7.Humectants
Many allergic and chronic conditions are often linked to crusts and mucus washing. In order to
prevent dehydration, adequate intranasal moisture is crucial. Thus, particularly in gel-based nasal
products, humectants can be introduced. Nasal infection is prevented by humectants and is unlikely
to impact drug absorption. Glycerine, sorbitol and mannitol are common instances. The use of
sorbitol or glycerine have shown improvement in the permeation of apomorphine(39).
1.8.8.Drug Concentration, Dose & the volume of dose
Drug levels, drug and quantity are three interrelated parameters that affect the efficiency of the
nasal service. In nasal perfusion studies, nasal absorption of LTyrosine increased with drug
level(40–42).
1.8.9.Role of Absorption boosters

Added absorption improvers may be needed if the drug shows bad membrane permeability, big
molecular size, insufficient lipophilicity, and amino-peptidased enzyme degradation. The
improvement impact can increase osmolarity and pH. For example, surfactants, glycosides,
cyclodextrin and glycols are enhancement substances. Improve absorption through a number of
distinct processes, including increased fluidity of the membrane, increased blood flow of the nose,
reduced mucus viscosity, and inhibition of enzymes(43–48).
1.9.1.Physiological factors
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1.9.1.1.Effect of Deposition on Absorption
The deposition of the formulation in the anterior part of the nose offers a larger period of nasal
dwelling. The previous part of the nose is poor permeability and the rear part of the nose with a
greater drug permeability offers longer stay.
1.9.1.2.Circulation of blood through nasal route

A vasculature-rich nasal mucosal membrane performs an important part in thermal
regulation and moisturization of the breathed air. Vasoconstriction and vasodilatation of blood
vessels will determine the circulation in the blood and thus the drug absorption.
1.9.1.3.Mucociliary Clearance effect

Drug absorption is affected by the moment between the drug and the epithelial tissue.
Mucociliary removal is inversely related to the moment of stay and, consequently, inversely linked
to drug absorption. The mucociliary clearance relates inversely to the period of residency and,
consequently, to drug absorption. The use of bioadhesive polymers or an increase of the viscosity
of the product can also achieve a longer stay in the nasal cavity.
1.9.1.4.Action of Enzyme
Various enzymes current in the nasal mucous membrane could influence drug stabilization.
Proteins and peptides, for instance, have been degraded in the mucosal membrane by proteases
and amino peptidase. The amount of aminopeptidase in the gastrointestinal system is considerably
smaller. Peptides can also create immunoglobulin clusters (Igs) that boost molecular weight and
decrease permeability of the nasal cavity.
1.9.1.5.Effect of Pathological Status

The nasal mucociliary method and/or the ability for nasal absorption could be affected by
intranasal diseases such as allergic rhinitis, diseases, or pervious nasal surgery. In the freezing, the
intranasal drug's efficacy is frequently affected. Insulin-dependent diabetes decreases nasal
clearance. Nasal disorder may also change the pH of the mucosa and consequently influence
absorption.
1.9.2.Systems of Nasal Drug Delivery

1.9.2.1.Nasal drops and sprays
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Nasal drops are among all formulations one of the most simple and comfortable shipping
processes. The primary limit is the absence of accuracy in the dosage given and the danger of
contamination during use(49) . A pipette or a squeezed tube can be supplied to the nasal drops.
These are generally suggested for local circumstances, but difficulties include microbial
development, mucociliar dysfunction and unspecified nose or neck reduction (50,51). A piston
and a tube working actuator are the nasal spray devices. Relatively more precise nasal sprays than
drops produce accurate amounts (25-200 μl) per spray(34). Several trials show that a coherent dose
of reproducible plum geometry is generated through nasal sprays. Properties of formulation, such
as thixotropy, surface tension and viscosity may affect droplet volume and dosage precision. The
most used form of dosage for nasal administration of drugs is liquid preparation. They are focused
primarily on aqueous formulations of the state. Their moisturizing impact is practical and practical,
given that many allergic and chronic diseases are often linked to crusts and mucosal membrane
processing. The significant drawbacks connected with the water-dose formations are
microbiological strength, discomfort and allergic rhinitis, because the necessary preservatives
affect the mucosal structure(52).
1.9.2.2.Instillation and rhinyle catheter

Drops are readily supplied to a certain area of the nasal cavity with catheters. The formula was
placed on the nose on the one side of the pipe and the remedy was supplied through the other by
the mouth into the nasal cavity(53).
1.9.2.3.Compressed air nebulizers
Nebulizer is a medicine that is breathed into the lungs in the shape of a brist. The condensed water
fills into the machine and is therefore referred to as forced water nebulizers. For all nebulizers the
common technical principle is either to use oxygen, compressed air or ultrasound energy as a
means of breaking up medical solutions/suspensions in small droplets, for direct inhalation from
a device's mouthpiece.
1.9.2.4.Squeezed bottle
The most commonly used for the supply of decongestants is squeezed nasal containers. A soft
metal container with a straightforward gas inlet is included. The wind in the container is pushed
out from the tiny punch while the plastic bottle is pushed and a certain quantity atomised. Air is
taken into the jar by pulling the stress again. This operation usually ends in micro-organism and
nasal secretion contaminating the liquid(54).
1.9.2.5.Metered-dose pump sprays

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A metered-dose pump spray is provided with many of the pharmaceutical nasal preparations that
contain alternatives, emulsions or suspensions on the market. Nasal sprays or nasal mists are used
for the shipment of a drug or drugs locally to relieve the general signs of pain or allergies such as
nasal congestion. Although the techniques of shipping variable, most nasal sprays work through
the instillation of a good nebula in the nose by hand pumping. The three principal kinds of local
effects accessible are: antihistamines, corticosteroids, and topical decongestion. The container, the
valve's pump, and the actuator include measured volume pump sprays.
1.9.3.Migraine: An Overview
Migraine can be considered as an incapacitating and ubiquitous neurovascular ailment, commonly
categorized with a headache with ≥2 features of pulsation, one-sided position, moderate to
unembellished strength and deteriorating by the scheduled physical bustle, associated with ≥1
indication of nausea and/vomiting, photophobia and phonophobia. But all the symptoms are
subjective as well as different. Moreover, one out of three subjects of migraine are sufferers of a
special type of focal neurologic visual syndrome called aura. Throughout the spell, the blood
vessels in the brain expand and then assemble by triggering nerve culminations near the
exaggerated blood vessels. There lies the main reason for pain or discomfort. The duration of the
pain varies from 2 hours and even up to 3 days and it may move from one half to another. Several
hereditary and environmental influences are considered as two main reasons behind migraine. As
a preliminary statistics hereditary cases lead to two-third of migraine cases. Variability in gender
also causes an alteration in the disease population. Females are more susceptible to the migraine
than the males especially the difference rises after adolescence. The research revealed 3 out of 4
patients with migraine are females.
Migraines became well recognized in ancient human culture. In the Old World (7000 BCE )
Trepanation (drilling a hole in a hole in the skull) has been recommended for migraine care. The
people believed this practice back then let certain evil spirits escape the mind. In the position
William Harvey suggested trepanation as an effective migraine treatment even in the 17th century.
That was 1868 when the "ergot" fungus was first used in migraine medication. Ergotamine was
eventually successfully isolated from ergot in 1918 and used for migraine treatment. Then
methysergide was synthesized in 1959 and sumatriptan(the first triptan) was developed in 1988.
Migraine is typically separated into two types : ( 1) aura migraine and (2) non-aura migraine.
Migraine disorder pathophysiology not well established; some experts theorize that the CNS bears
sole responsibility for the pain. Others assume the peripheral one sensory neuron and including
blood supplying vessels play a significant function in the initiation of disease. Standard analgesics
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such as paracetamol, headache ibuprofen, and popular nausea prescription items are used for
primary treatment. If these are unsuccessful, the prescription is for triptans and ergotamines.
Caffeine can also someTime(Mins)s be used to treat serious pain. Analysis Present Calcitonin-
based gene peptides (CGRP) such as telcagepant and olcegepant claiming to be
pathophysiologically working on migraine medication focused on the use of pain associated genes.
Unfortunately, in 2011 Merck failed to perform a Phase III clinical trial on telcagepant. CGRP
monoclonal antibodies are now also being tested for competent migraine therapy.
Several drugs are being used in treatment of migraine. Prochlorperazine can be a potential
candidate for treatment of migraine and its associated symptoms like dizziness, nausea, vomiting
and anxiety. The nasal route can be beneficial for the better patient compliance, rapid relief, ease
of administration etc. With the help of permeation enhancer, the bioavailability can be improved
whereas, the use of co-solvent can improve the solubility of the drug as well as can improve
absorption and provide better stability of the formulation.
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2.AIM & OBJECTIVE
The present aim of this study is to formulate & evaluate Prochlorperazine nasal solution.
In the current scenario, migraine therapy with Prochlorperazine is facing a lack of compliance
with conventional oral tablets and injections. The nasal route can increase patient compliance.
The objective of this study will be to see the efficacy of the drug through the nasal route. The
formulation will be evaluated with certain criteria such as characterization of materials, viscosity,
pH testing,clarity study & drug release study.
Our soul objective will be to formulate the nasal solution which can be a breakthrough for the
patients who needs quicker relief with ease of administration.
PLAN OF WORK
a. The characteristics of the drug to be evaluated.
b. The pre-formulation study will be carried out.
c. The formulation will be prepared by the dilution method.
d. Post formulation parameters will be checked.
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3.REVIEW OF LITERATURE
Chokshi et al., 2019 observed that Rizatriptan produces antimigraine activity by acting as
selective agonist of 5-HT1B and 5-HT1D receptors present on intracranial and extracerebral blood
vessels. Absorption from oral tablet is slow with Tmax of approximately 1-1.5 h. A few attempts
have been made to promote rapid absorption such as oral or sublingual films with limited success.
The aim of their study was to develop intranasal spray formulation of rizatriptan with quick onset
of action. Solubility was enhanced by a co-solvent system where we studied solubility of
rizatriptan benzoate in pure solvents, binary and ternary mixtures. Binary and ternary co-solvents
using ethanol, water, propylene glycol and polyethylene glycol resulted rizatriptan equivalent base
solubility more than 60 mg/mL. Same co-solvents were used at different level to make nasal spray
formulations and evaluated pharmacokinetics using beagle dog animal model. Nasal spray
formulation containing 20% w/w ethanol exhibited highest exposure, where Cmax (312 ng/mL)
reached in 5 min and maintained higher concentration than oral dose for more than 30 min(55).
Khejri et al., 2019 described Migraine has recently become a major interest to the
neuroscientists.Zolmitriptan is an effective medicine used in the treatment of migraine. The nasal
spray was prepared from Zolmitriptan loaded chitosan nanoparticles and evaluated for
pharmacokinetic properties(56).
Lipton et al., 2019 confirmed the commercial formulation of sumatriptan nasal spray is an
effective option for migraine patients requiring or preferring a non-oral route of drug
administration, but its utility is limited by poor absorption and tolerability issues. DFN-02, a new
formulation of sumatriptan 10 mg nasal spray, is co-formulated with a permeation enhancer that
gives it pharmacokinetics comparable to subcutaneous sumatriptan. As reported previously, DFN-
02 was significantly better than placebo on multiple efficacy endpoints at 2 h postdose, including
pain freedom, absence of the most bothersome symptom, and pain relief, and its safety and
tolerability profiles were excellent(57).
Pitta et al., 2018 elaborated optimized zolmitriptan (ZT)-loaded transfersome formulation using
Box-Behnken design for improving the bioavailability by nasal route for quick relief of migraine
and further to compare with a marketed nasal spray. Here, three factors were evaluated at three
levels. Independent variables include: amount of soya lecithin (X1), amount of drug (X2) and
amount of tween 80 (X3). The dependent responses were vesicle size (Y1), flexibility index (Y2)
and regression coefficient of drug release kinetics (Y3). Prepared formulations were evaluated for
physical characters and an optimal system was identified. Further, in vivo pharmacokinetic study
was performed in male wistar rats to compare the amount of drug in systemic circulation after
intranasal administration. Optimized ZT-transfersome formulation containing 82.74 mg of lecithin
(X1), 98.37 mg of zolmitriptan (X2) and 32.2 mg of Tween 80 (X3) and had vesicle size of
93.3 nm, flexibility index of 20.25 and drug release regression coefficient of 0.992. SEM picture
analysis revealed that the vesicles were spherical in morphology and had a size more than 1 µm.
The formulations were found to be physically stable upon storage at room temperature up to
2 months period, as there were no significant changes noticed in size and ZP. The nasal
bioavailability of optimized transfersome formulation was found to be increased by 1.72
Time(Mins)s than that of marketed nasal spray (Zolmist®). The design and development of
26 | P a g e
zolmitriptan as transfersome provided improved nasal delivery over a conventional nasal spray for
a better therapeutic effect(58).
Yellepeddi, 2018 explained that the preservative-free prochlorperazine nasal spray was prepared
by adding 250 mg of prochlorperazine edisylate to 50 mL of citrate buffer in a low-density
polyethylene nasal spray bottle. A stability-indicating high-performance liquid chromatography
(HPLC) method was developed and validated using the major degradant prochlorperazine
sulfoxide and by performing forced-degradation studies. For chemical stability studies, 3 100-mL
samples of the preservative-free prochlorperazine from 5 nasal spray bottles stored at room
temperature were collected at days 0, 20, 30, 45, and 60 and were assayed in triplicate using the
stability-indicating HPLC method. Microbiological testing involved antimicrobial effectiveness
testing based on United States Pharmacopeia (USP) chapter 51 and quantitative microbiological
enumeration of aerobic bacteria, yeasts, and mold
based on USP chapter 61. Samples for microbiological testing were collected at days 0, 30, and
60(59).
Munjal et al., 2016 described that Intranasal sumatriptan (Imitrex® ) may be an alternative for
patients who refuse injections and cannot tolerate oral agents, but due to low bioavailability and
slow absorption, the clinical utility of the currently marketed formulation is limited, highlighting
an unmet need for an effective non-oral migraine medication with a rapid onset of action. To
overcome the slow absorption profile associated with intranasal administration, we evaluated the
impact of 1-O-n-Dodecyl-β-D-Maltopyranoside (DDM, Intravail A-3™), a permeation enhancer,
on sumatriptan's pharmacokinetic profile by comparing the pharmacokinetic characteristics of two
commercial sumatriptan products, 4 mg subcutaneous and 6 mg subcutaneous in healthy adults,
with DFN-02 - a novel intranasal agent comprised of sumatriptan 10 mg plus 0.20% DDM. We
also determined the pharmacokinetic characteristics of DDM and evaluated its safety and
tolerability(60).
Tepper and Johnstone, 2018 confirmed that the acute treatment of migraine requires matching
patient need to drug and formulation. In particular, nausea and vomiting, quick Time(Mins) to
peak intensity, and the common gastroparesis of migraineurs, all call for a variety of non-oral
formulations for treatment of attacks. A novel breath-powered powder sumatriptan intranasal
treatment offers an improvement, at least in pharmacokinetics, over conventional liquid nasal
sumatriptan spray. The device for delivery in this breath-powered nasal sumatriptan uses natural
nose anatomy to close the soft palate and propel the sumatriptan high up in the nasal cavity on one
side with bidirectional airflow coming out the other side. This approach has the potential to reduce
adverse events and improve efficacy. Phase 3 data on this system are in press at the Time(Mins)
of this writing and results appear promising. The clinical role for a fast acting non-oral nasal
formulation will be in those for whom tablets are bound to fail, that is, in the setting of nausea and
vomiting or when the Time(Mins) to central sensitization, allodynia, and disabling migraine is too
short for the patient to respond to a tablet. This review provides a clinical perspective on the breath-
powered powder sumatriptan intranasal treatment(61).
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4.MATERIALS
DRUG
Prochlorperazine Maleate-(Yarrow Chem. Products Wadala (E), Mumbai.)
POLYMER
HPMC K4M
CO-SOLVENT
PEG 400- (S.D. Fine-Chem. Limited, Mumbai.)
PERMEATION ENHANCER
Bile Salt- Sodium Cholate (Sigma Aldrich)
HUMECTANT
Glycerine
PRESERVATIVE
Benzalkonium Chloride
OTHERS
• Sodium Chloride
• Chloroform
• Ethanol
• Methanol
• DMSO
• Potassium dihydrogen phosphate
• Disodium phosphate
• Water
INSTRUMENTS
• Electronic balance (PB 303 – S, Mettler Toledo Switzerland.)
• Universal Hot Air Oven (IC 108K, Instruments and Chemical Pvt.Ltd. Ambala.)
• Four blade mechanical stirrer (RQ – 122, Remi Motors, Mumbai.)
• Magnetic stirrer with hot plate (Instruments and Chemical Pvt.Ltd., Ambala.)
• UV Spectrophotometer (UV – 1700 pharmaspec, Shimadzu, Japan.)
• FTIR Spectrophotometer (84000s Shimadzu Corp., Japan.)
• Bath Sonicator
• Ostwald’s Viscometer
• Litmus Paper
• Franz diffusion cell
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DRUG AND EXCIPIENTS PROFILE
DRUG
Prochlorperazine Maleate
CLASS- Phenothiazine
STRUCTURE
TRADE NAMES- STEMETIL, COMPAZINE

PHARMACOLOGY
Prochlorperazine is thought to exert its antipsychotic effects by blocking dopamine receptors.
Prochlorperazine is analogous to chlorpromazine; both of these agents antagonize dopaminergic
D2 receptors in various pathways of the central nervous system. This D2 blockade results in
antipsychotic, antiemetic and other effects. Hyperprolactinemia is a side effect of dopamine
antagonists as blockade of D2 receptors within the tuberoinfundibular pathway results in increased
plasma levels of prolactin due to increased secretion by lactotrophs in the anterior pituitary.
Following intramuscular injection, the antiemetic action is evident within 5 to 10 minutes and lasts
for 3 to 4 hours. Rapid action is also noted after buccal treatment. With oral dosing, the start of
action is delayed but the duration somewhat longer (approximately 6 hours)
PHARMACOKINETICS
Protein binding-91–99%
Metabolism-Mainly Liver (CYP2D6 and/or CYP3A4)
Elimination half-life- 4–8 hours, differs with the method of administration
Excretion-Biliary, (colored) inactive metabolites in urine
Absorption-Cmax is approximately 3.9 ± 1.0 ng/mL (Dose Dependent) and oral bioavailability is
low approx. 12.5 ± 4.3%. tmax is approximately 3-4hrs.
INDICATIONS AND USAGE

Vomiting
Prochlorperazine is used to prevent vomiting caused by chemotherapy, radiation therapy and
in the pre- and postoperative setting. A 2015 Cochrane review found no differences in efficacy
among drugs commonly used for this purpose in emergency rooms.
Migraine
Prochlorperazine, generally by intravenous, is used to treat migraine. Such use is
recommended by The American Headache Society. Compared with metoclopramide, PCP had
an almost 3 Time(Mins)s higher odds of headache relief within the 60 minutes of PCP
administration.
Labyrinthitis
In the UK prochlorperazine maleate has been used for labyrinthitis, which include not only
nausea and vertigo, but spatial and temporal 'jerking' and distortion.
CONTRAINDICATIONS
Should not be used in patients with known hypersensitivity to phenothiazines Do not use in
comatose states or in the presence of large amounts of central nervous system depressants
(alcohol, barbiturates, narcotics, etc.), in pediatric surgery, or in pediatric patients under 2 years
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of age or under 20 lbs. Should not be used in children for conditions for which dosage has not
been established.
DOSING
<2 years: Not recommended.
Severe Nausea and Vomiting:
≥2 years:
9-13 kg: 2.5 mg PO daily or 12 hourly; Maximum dose: 7.5 mg/day.
14-18 kg: 2.5 mg PO every 8-12 hours; Maximum dose: 10 mg/day.
19-37 kg: 2.5 mg PO 8 hourly or 5 mg PO every 12 hours; Maximum dose: 15 mg/day.
Psychotic disorder:
>2 years: Initially 2.5 mg PO/PR every 8-12 hours.
Maximum dose: 20 mg/day in 2-6 years and 25 mg/day in 6-12 years; do not exceed 10 mg on
day 1.
Prochlorperazine Maleate, the main drug will be diluted with saline solution and it will be
randomly mixed with solvents and co-solvents. Calcium Chloride for preparation of artificial
nasal electrolyte solution. PEG 400 will be used as solvent 1, Propylene Glycol will be used as
solvent 2. Sorbitol and Polysorbate 80 will be used as co-solvent. Sodium Phosphate dibasic
heptahydrate and Sodium Phosphate monobasic monohydrate as buffer solution. 0.22-mm Nylon
Syringe Filters as filtering purpose. Franz Diffusion Cell as In-vitro release study. Dialysis
Membrane-70 as membrane for filter.
ADVERSE EFFECT
Sedation, excitation, weakness, cerebral oedema, poikilothermia, ECG changes, tachycardia,
agitation, dry mouth and insomnia. Extrapyramidal symptoms may occur. Rarely neuroleptic
malignant syndrome may occur. In susceptible patients, respiratory depression may occur.
Postural hypotension has also been reported.
INTERACTION
Metoclopramide and Lithium: Increased extrapyramidal side-effects with metoclopramide and
lithium.
Antiepileptics: Decreased effect of antiepileptics.
Antacids: Decreased levels with antacids.
Anxiolytics and Hypnotics: Enhanced sedative effects with anxiolytics and hypnotics.
Deferoxamine: Avoid with deferoxamine.
EXCIPIENTS
Sodium chloride
BP: Sodium chloride
JP: Sodium chloride
PhEur: Natrii chloridum
USP: Sodium chloride
Synonyms
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Alberger; chlorure de sodium; common salt; hopper salt; natural halite; rock salt; saline; salt;
sea salt; table salt.
Chemical Name and CAS Registry Number

Sodium chloride [7647-14-5]
Empirical Formula and Molecular Weight
NaCl 58.44
4.3.2.5 Structural Formula
NaCl
4.3.2.6 Functional Category
Tablet and capsule diluent; tonicity agent
Applications in Pharmaceutical Formulation or Technology
Sodium chloride is widely used in a variety of parenteral and nonparenteral pharmaceutical

formulations, where the primary use is to produce isotonic solutions. Sodium chloride has been
used as a lubricant and diluent in capsules and direct-compression tablet formulations in the past,
although this practice is no longer common. Sodium chloride has also been used as a channeling
agent and as an osmotic agent in the cores of controlled-release tablets. It has been used as a
porosity modifier in tablet coatings, and to control drug release from microcapsules.
Description
Sodium chloride occurs as a white crystalline powder or colorless crystals; it has a saline taste.
The crystal lattice is a face-centred cubic structure. Solid sodium chloride contains no water of
crystallization although, below 08C, salt may crystallize as a dihydrate.
Typical Properties
Boiling point: 141.3 C
Density: 2.17 g/cm3;
1.20 g/cm3 for saturated aqueous solution.
Density (bulk): 0.93 g/cm3
Density (tapped): 1.09 g/cm3
Stability and Storage Conditions

Aqueous sodium chloride solutions are stable but may cause the separation of glass particles
from certain types of glass containers. Aqueous solutions may be sterilized by autoclaving or
filtration. The solid material is stable and should be stored in a well-closed container, in a cool,
dry place. It has been shown that the compaction characteristics and the mechanical properties of
tablets are influenced by the relative humidity of the storage conditions under which sodium
chloride was stored.
Incompatibilities
Aqueous sodium chloride solutions are corrosive to iron. They also react to form precipitates
with silver, lead, and mercury salts. Strong oxidizing agents liberate chlorine from acidified
solutions of sodium chloride. The solubility of the antimicrobial preservative methylparaben is
decreased in aqueous sodium chloride solutions and the viscosity of carbomer gels and solutions
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of hydroxyethyl cellulose or hydroxypropyl cellulose is reduced by the addition of sodium
chloride.
HPMC K4M
Melting point 225-230 °C
Density 1.39
Solubility H2O: 50 mg/mL, clear to very faintly turbid, faintly yellow
Form powder
Colour White to cream
Odour Odourless
Water Solubility SOLUBLE
Merck 14,4842
Stability: Stable. Solid is combustible, incompatible with strong oxidizing agents
Description:
Cellulose is a natural substance normally present in most diets because it is the major structural
carbohydrate of green plants. Cellulose is essentially a linear polymer of glucopyranose units
connected by (3-1,4-glucoside links. In nature, cellulose is present in plant cell walls as fibers.
The molecular weight of isolated cellulose is approximately 50,000. The principal sources of
cellulose for food related purposes are cotton linters and wood pulp. Chemical processing
converts cellulose into forms or derivatives suitable for incorporation into food products, or for
use in food packaging materials. Hydroxypropylmethyl cellulose is synthesized from methyl
cellulose by the action of alkali and propylene oxide. The resultant product is a water soluble
ether derivative of cellulose containing both methoxy and hydroxypropyl groups. The degree of
substitution is 1.08 to 1.83 with the hydroxypropyl groups as the minor constituent. It is used as
a thickening agent, stabilizer, and emulsifier.
Pharmaceutical Application
Hypromellose is widely used in oral, ophthalmic, nasal, and topical pharmaceutical formulations.
In oral products, hypromellose is primarily used as a tablet binder, in film-coating,and as a
matrix for use in extendedrelease tablet formulations. Concentrations between 2% and 5% w/w
may be used as a binder in either wet- or dry-granulation processes. High-viscosity grades may
be used to retard the release of drugs from a matrix at levels of 10–80% w/w in tablets and
capsules. Hypromellose is also used in liquid oral dosage forms as a suspending and/or
thickening agent at concentrations ranging from 0.25–5.0%.
Depending upon the viscosity grade, concentrations of 2–20% w/w are used for film-forming
solutions to film-coat tablets. Lowerviscosity grades are used in aqueous film-coating solutions,
while higher-viscosity grades are used with organic solvents. Examples of film-coating materials
that are commercially available include AnyCoat C, Spectracel, Pharmacoat, and the Methocel E
Premium LV series. Hypromellose is also used as a suspending and thickening agent in topical
formulations. Compared with methylcellulose, hypromellose produces aqueous solutions of
greater clarity, with fewer undissolved fibers present, and is therefore preferred in formulations
for ophthalmic use. Hypromellose at concentrations between 0.45–1.0% w/w may be added as a
thickening agent to vehicles for eye drops and artificial tear solutions. It is also used
commercially in liquid nasal formulations at a concentration of 0.1%. Hypromellose is used as
an emulsifier, suspending agent, and stabilizing agent in topical gels and ointments. As a
protective colloid, it can prevent droplets and particles from coalescing or agglomerating, thus
32 | P a g e
inhibiting the formation of sediments. In addition, hypromellose is used in the manufacture of
capsules, as an adhesive in plastic bandages, and as a wetting agent for hard contact lenses. It is
also widely used in cosmetics and food products.
Pharmaceutical uses:
Hypromellose powder is a stable material, although it is hygroscopic after drying.
Solutions are stable at pH 3–11. Hypromellose undergoes a reversible sol–gel transformation
upon heating and cooling, respectively. The gelation temperature is 50–90°C, depending upon
the grade and concentration of material. For temperatures below the gelation temperature,
viscosity of the solution decreases as temperature is increased. Beyond the gelation temperature,
viscosity increases as temperature is increased.
Aqueous solutions are comparatively enzyme-resistant, providing good viscosity stability during
long-term storage. However, aqueous solutions are liable to microbial spoilage and should be
preserved with an antimicrobial preservative: when hypromellose is used as a viscosity-
increasing agent in ophthalmic solutions, benzalkonium chloride is commonly used as the
preservative. Aqueous solutions may also be sterilized by autoclaving; the coagulated polymer
must be redispersed on cooling by shaking.
Hypromellose powder should be stored in a well-closed container, in a cool, dry place.
Incompatibilities:
Hypromellose is incompatible with some oxidizing agents. Since it is nonionic, hypromellose
will not complex with metallic salts or ionic organics to form insoluble precipitates.
PEG 400
CAS: 25322-68-3
Melting point: 64-66 °C
Boiling point: >250°C
density: 1.27 g/mL at 25 °C
vapor density: >1 (vs air)
vapor pressure: <0.01 mm Hg (20 °C)
Freezing point -270 °C
storage temp. 2-8°C
solubility H2O: 50 mg/mL, clear, colorless
form: waxy solid
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Colour: White to very pale yellow
Specific Gravity: 1.128
PH 5.5-7.0 (25℃, 50mg/mL in H2O)
Water Solubility Soluble in water.
λmax λ: 260 nm Amax: 0.6
λ: 280 nm Amax: 0.3
Sensitive Hygroscopic
Merck 14,7568
Stability: Stable. Incompatible with strong oxidizing agents
Chemical properties: Polyethylene glycol is a polymer which is hydrolysed by ethylene oxide.

It has no toxicity and irritation. It is widely used in various pharmaceutical preparations. The
toxicity of low molecular weight polyethylene glycol is relatively large. In general, the toxicity
of diols is very low. Topical application of polyethylene glycol, especially mucosal drug, can
cause irritant pain. In topical lotion, this product can increase the flexibility of the skin, and has a
similar moisturizing effect with glycerine. Diarrhoea can occur in large doses of oral
administration. In injection, the maximum polyethylene glycol 300 concentration is about 30%
(V/V). Haemolysis could occur when the concentration is more than 40% (V/V).
Pharmaceutical Application: Polyethylene glycols (PEGs) are widely used in a variety of
pharmaceutical formulations, including parenteral, topical, ophthalmic, oral, and rectal
preparations. Polyethylene glycol has been used experimentally in biodegradable polymeric
matrices used in controlled-release systems.
Polyethylene glycols are stable, hydrophilic substances that are essentially nonirritant to the
skin;They do not readily penetrate the skin, although the polyethylene glycols are water-soluble
and are easily removed from the skin by washing, making them useful as ointment bases.Solid
grades are generally employed in topical ointments, with the consistency of the base being
adjusted by the addition of liquid grades of polyethylene glycol.
Mixtures of polyethylene glycols can be used as suppository bases,for which they have many advantages
over fats. For example, the melting point of the suppository can be made higher to withstand exposure to
warmer climates; release of the drug is not dependent upon melting point; the physical stability on storage
is better; and suppositories are readily miscible with rectal fluids. Polyethylene glycols have the following
disadvantages: they are chemically more reactive than fats; greater care is needed in processing to avoid
inelegant contraction holes in the suppositories; the rate of release of water-soluble medications decreases
with the increasing molecular weight of the polyethylene glycol; and polyethylene glycols tend to be
more irritating to mucous membranes than fats.
Aqueous polyethylene glycol solutions can be used either as suspending agents or to adjust the
viscosity and consistency of other suspending vehicles. When used in conjunction with other
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emulsifiers, polyethylene glycols can act as emulsion stabilizers. Liquid polyethylene glycols are
used as water-miscible solvents for the contents of soft gelatin capsules. However, they may
cause hardening of the capsule shell by preferential absorption of moisture from gelatin in the
shell.
In concentrations up to approximately 30% v/v, PEG 300 and PEG 400 have been used as the
vehicle for parenteral dosage forms. In solid-dosage formulations, higher-molecular-weight
polyethylene glycols can enhance the effectiveness of tablet binders and impart plasticity to
granules. However, they have only limited binding action when used alone, and can prolong
disintegration if present in concentrations greater than 5% w/w. When used for thermoplastic
granulations, a mixture of the powdered constituents with 10–15% w/w PEG 6000 is heated to
70–75°C. The mass becomes paste like and forms granules if stirred while cooling. This
technique is useful for the preparation of dosage forms such as lozenges when prolonged
disintegration is required. Polyethylene glycols can also be used to enhance the aqueous
solubility or dissolution characteristics of poorly soluble compounds by making solid dispersions
with an appropriate polyethylene glycol. Animal studies have also been performed using
polyethylene glycols as solvents for steroids in osmotic pumps. In film coatings, solid grades of
polyethylene glycol can be used alone for the film-coating of tablets or can be useful as
hydrophilic polishing materials. Solid grades are also widely used as plasticizers in conjunction
with film-forming polymers. The presence of polyethylene glycols in film coats, especially of
liquid grades, tends to increase their water permeability and may reduce protection against low
pH in enteric-coating films. Polyethylene glycols are useful as plasticizers in microencapsulated
products to avoid rupture of the coating film when the microcapsules are compressed into
tablets.
Polyethylene glycol grades with molecular weights of 6000 and above can be used as lubricants,
particularly for soluble tablets. The lubricant action is not as good as that of magnesium stearate,
and stickiness may develop if the material becomes too warm during compression. An ant
adherent effect is also exerted, again subject to the avoidance of overheating.
Polyethylene glycols have been used in the preparation of urethane hydrogels, which are used as
controlled-release agents. Polyethylene glycol has also been used in insulin-loaded
microparticles for the oral delivery of insulin; it has been used in inhalation preparations to
improve aerosolization; polyethylene glycol nanoparticles have been used to improve the oral
bioavailability of cyclosporine; it has been used in self-assembled polymeric nanoparticles as a
drug carrier; and copolymer networks of polyethylene glycol grafted with poly(methacrylic acid)
have been used as bio adhesive controlled drug delivery formulations.
35 | P a g e
Storage: Polyethylene glycols are chemically stable in air and in solution, although grades with
a molecular weight less than 2000 are hygroscopic. Polyethylene glycols do not support
microbial growth, and they do not become rancid.
Polyethylene glycols and aqueous polyethylene glycol solutions can be sterilized by autoclaving,
filtration, or gamma irradiation.
Sterilization of solid grades by dry heat at 150℃ for 1 hour may induce oxidation, darkening,
and the formation of acidic degradation products. Ideally, sterilization should be carried out in an
inert atmosphere. Oxidation of polyethylene glycols may also be inhibited by the inclusion of a
suitable antioxidant.
If heated tanks are used to maintain normally solid polyethylene glycols in a molten state, care
must be taken to avoid contamination with iron, which can lead to discoloration. The
temperature must be kept to the minimum necessary to ensure fluidity; oxidation may occur if
polyethylene glycols are exposed for long periods to temperatures exceeding 50℃. However,
storage under nitrogen reduces the possibility of oxidation.
Polyethylene glycols should be stored in well-closed containers in a cool, dry place. Stainless
steel, aluminium, glass, or lined steel containers are preferred for the storage of liquid grades.
Incompatibilities: The chemical reactivity of polyethylene glycols is mainly confined to the two
terminal hydroxyl groups, which can be either esterified or etherified. However, all grades can
exhibit some oxidizing activity owing to the presence of peroxide impurities and secondary
products formed by autoxidation.
Liquid and solid polyethylene glycol grades may be incompatible with some colouring agents.
The antibacterial activity of certain antibiotics is reduced in polyethylene glycol bases,
particularly that of penicillin and bacitracin. The preservative efficacy of the parabens may also
be impaired owing to binding with polyethylene glycols.
Physical effects caused by polyethylene glycol bases include softening and liquefaction in
mixtures with phenol, tannic acid, and salicylic acid. Discoloration of sulphonamides and
dithranol can also occur, and sorbitol may be precipitated from mixtures. Plastics, such as
polyethylene, phenol formaldehyde, polyvinyl chloride, and cellulose-ester membranes (in
filters) may be softened or dissolved by polyethylene glycols. Migration of polyethylene glycol
can occur from tablet film coatings, leading to interaction with core components.
Sodium Cholate
Principle and Interpretation
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Cholic acid, sodium salt is used as a selective inhibitory agent for bacteriological culture media.
Also acts as permeation enhancer in formulation.
Appearance
White, free flowing powder.
Solubility
Freely soluble in distilled water and methanol.
Reaction
Reaction of 5% w/v aqueous solution at 25ºC
pH
8.00- 9.50
Glycerine
Chemical Properties Glycerine is the polyhydric alcohol 1,2,3 propanetriol [HOCH2-

CH(OH)CH2OH] also known as glycerol. A clear, colourless, syrupy liquid having a sweet taste.
It has not more than a slight characteristic odour, which is neither harsh nor disagreeable. It is
hygroscopic and its solutions are neutral. Glycerine is miscible with water and with alcohol. It is
insoluble in chloroform, in ether, and in fixed and volatile oils.
In the animal body, glycerine may be formed from ingested carbohydrates, from glycogen by
glycolysis, and from fats and other lipids by hydrolysis. Commercially, glycerin can be produced
by a number of methods including microbial fermentation of sugars, as a by-product in the
manufacture of soap, or by synthesis from propylene.
Animal and vegetable fats contain about 10 percent by weight of glycerine. It is present in
animal tissues to the extent of about 1 percent of the body weight. Glycerine is not an essential
nutrient, but it furnishes energy by contributing to the general pool of oxidizable organic
compounds.
Pharmaceutical Applications Glycerine is used in a wide variety of pharmaceutical

formulations including oral, nasal, ophthalmic, topical, and parenteral preparations.
37 | P a g e
In topical pharmaceutical formulations and cosmetics, glycerine is used primarily for its
humectant and emollient properties. Glycerine is used as a solvent or cosolvent in creams and
emulsions. Glycerine is additionally used in aqueous and nonaqueous gels and also as an
additive in patch applications. In parenteral formulations, glycerine is used mainly as a solvent
and cosolvent.
In oral solutions, glycerine is used as a solvent, sweetening agent, antimicrobial preservative,
and viscosity-increasing agent. It is also used as a plasticizer and in film coatings.
Glycerine is used as a plasticizer of gelatine in the production of soft-gelatine capsules and
gelatine suppositories.
Glycerine is employed as a therapeutic agent in a variety of clinical applications, and is also used
as a food additive.
Safety Profile Poison by subcutaneous route. Mildly toxic by ingestion. Human systemic effects
by ingestion: headache and nausea or vomiting. Experimental reproductive effects. Human
mutation data reported. A skin and eye irritant. In the form of mist it is a nuisance particulate and
inhalation irritant. Combustible liquid when exposed to heat, flame, or powerful oxidizers.
Mixtures with hydrogen peroxide are highly explosive. Ignites on contact with potassium
permanganate, calcium hypochlorite. Mixture with nitric acid + sulfuric acid forms the explosive
glyceryl nitrate. Mixture with perchloric acid + lead oxide forms explosive perchlorate esters.
Confined mixture with chlorine explodes if heated to 70-80'. Can react violently with acetic
anhydride, aniline + nitrobenzene, Ca(OCl)2, Cr03,Cr203, F2 + PbO, phosphorus triiodide,
ethylene oxide + heat, KMnO4, K2O2, AgClO4, Na2O2, NaH. Energetic reaction with sodium
hydride. Mixture with nitric acid + hydrofluoric acid is a storage hazard due to gas evolution. To
fight fire, use alcohol foam, CO2, dry chemical. When heated to decomposition it emits acrid
smoke and fumes.
Storage: Glycerine is hygroscopic. Pure glycerine is not prone to oxidation by the atmosphere
under ordinary storage conditions, but it decomposes on heating with the evolution of toxic
acrolein. Mixtures of glycerine with water, ethanol (95%), and propylene glycol are chemically
stable.
Incompatibilities: Glycerine may explode if mixed with strong oxidizing agents such as
chromium trioxide, potassium chlorate, or potassium permanganate. In dilute solution, the
reaction proceeds at a slower rate with several oxidation products being formed. Black
discoloration of glycerine occurs in the presence of light, or on contact with zinc oxide or basic
bismuth nitrate.
38 | P a g e
An iron contaminant in glycerine is responsible for the darkening in color of mixtures containing
phenols, salicylates, and tannin.
glycerine forms a boric acid complex, glyceroboric acid, that is a stronger acid than boric acid.
Benzalkonium chloride
Benzalkonium chloride (BAC) is a compound of the class of quaternary ammonium compounds
(QAC) used as a cationic surfactant in personal hygiene, cosmetic and skin disinfection products.
BAC is a mixture of alkylbenzyldimethylammonium chlorides [C6H5CH2N(CH3)2RCl], in
which R = C12, C14, C16, C18 are the main compounds, and the antibacterial effects being
given by the alkyl chain length and the quaternary ammonium groups.
Melting point -73°C
Storage Temp. Store below +30°C.
Solubility: Benzalkonium chloride is soluble in water (100 mg/ml), yielding a clear, colourless
to faint yellow solution. It is also very soluble in alcohol and acetone, slightly soluble in
benzene, and almost insoluble in ether. Solutions may be autoclaved or aseptically filtered.
pH 5-8 (10g/l, H2O, 20°C)
Pharmaceutical Applications
Benzalkonium chloride appears to be the main preservative in ophthalmic preparations on the
EU market, approximately 74% of ophthalmic preparations contain benzalkonium chloride as a
preservative. Benzalkonium chloride is further used as a preservative in more than 200 medicinal
products for the nasal route of administration and about 10 preparations for inhalation use are
authorised on EU markets based on the additional survey performed amongst a limited number
of member states. Only a few medicinal products containing benzalkonium chloride are intended
for other routes of administrations i.e. cutaneous, oral, oromucosal, rectal, vaginal and parenteral
use.
Safety
39 | P a g e
Repeated dose oral toxicity studies have shown that within 2 days of dosing benzalkonium
chloride is lethal in mice and rats at concentrations of approximately 500 mg/kg/day (dietary
administration) and above due to local effects in the gastrointestinal (GI) tract. However, no
organ-specific toxicity was observed in these two species at concentrations below those causing
direct effects on the GI tract. Results of 90-day and chronic toxicity studies have only shown
changes in body weight and other general responses.
Substantial literature data indicate that benzalkonium chloride may induce ocular damage. In
vivo studies have been mainly performed in rabbits and, therefore, careful extrapolation to
humans is required due to the differences between these two species. A recent study of the
toxicity of ophthalmological solutions containing 0.005% and 0.01% of benzalkonium chloride
applied twice daily in rabbits and monkeys for up to 52 weeks did not show ophthalmological
changes of irritation or corneal damage.
In vitro studies have suggested that benzalkonium chloride (0.001–0.05%) may cause ciliary beat
stasis as well as nasal lesions in rats when applied eight Time(Mins)s daily.
Available experimental data indicate that benzalkonium chloride is neither genotoxic nor
carcinogenic nor a reproductive toxicant.
Chloroform
CAS: 67-66-3
MF: CHCl3
Solubility: Miscible with diethyl ether, oils, ligroin, alcohol, carbon tetrachloride and carbon
disulphide.
Chemical Properties At ambient temperature and pressure, chloroform exists as a clear,
colourless liquid with a non-irritant ethereal odour and a sweet taste. It is very volatile, and may
dissolve some plastics and rubber. It is highly water soluble and is miscible in volatile organic
compounds (VOCs) and alcohols.
Storage: In the presence of light, chloroform undergoes autoxidation to generate phosgene; this
can be minimized by storing this substance in the dark under nitrogen. Commercial samples of
chloroform frequently contain 0.5 to 1% ethanol as a stabilizer.
40 | P a g e
Incompatibilities: Though non-flammable, chloroform decomposes to form hydrogen chloride,
phosgene, and chlorine upon contact with a flame. Chloroform decomposes slowly in air and
light. Reacts violently with strong caustics (bases), strong oxidants, chemically active metals
(especially powders), such as aluminium, lithium, magnesium, potassium, and sodium, causing
fire and explosion hazard. Attacks plastic, rubber, and coatings. Corrodes iron and other metals
in the presence of moisture.
Potassium dihydrogen phosphate
Melting point 252.6 °C

Solubility H2O: 1.5 M at 20 °C, clear, colourless
Form powder
Colour White transparent
Odour Odourless
PH 4.2-4.6 (20g/l, H2O, 20℃)
Uses Potassium Dihydrogen is a buffer, neutralizing agent, and sequestrant. It is mildly acid,
with a pH of 4.5, and fairly soluble in water, with a solubility of 25 g in 100 ml at 25°c. It is used
in whole eggs for colour preservation and is also used in low-sodium products, milk products,
and meat products. Typical usage ranges from 0.1 to 0.5%. It is also termed monopotassium
phosphate orthophosphate, potassium phosphate monobasic, and monopotassium
monophosphate.
Disodium phosphate
41 | P a g e
Boiling point 482.4±51.0 °C(Predicted)
Density 1.064 g/mL at 20 °C
Vapor density 4.9 (vs air)
Solubility H2O: 0.5 M at 20 °C, clear, colourless
pKa 4.60±0.30(Predicted)
Form powder
Description N-(Isoxazol-5-yl) sulphanilamide is one of the inorganic compounds that is
commonly used in food industry thanks to its ability of acting as a chemical buffer. It helps
stabilize the PH value, prevent coagulation, and enhance food characteristics like nutritional
value and cooking performance. It also finds application in medical use. It can stimulate general
liver activities, allowing it to operate in the first place. Besides, disodium phosphate can be used
in non-food industries. It can be applied in water treatment for retarding the formation of calcium
scale. It is also found in some flame retardants, detergents and cleaning agents.
Uses N-(Isoxazol-5-yl) sulphanilamide is the disodium salt of phosphoric acid which functions
as a protein stabilizer, buffer, dispersant, and coagulation accelerator. It is mildly alkaline with a
1% solution having a ph of 9.2. It is moderately soluble in water with a solubility of 12 g in 100
ml at 25°c. It is used in farina and macaroni to shorten the cooking Time(Mins) by making the
particles swell faster and cook more thoroughly. In evaporated milk it acts as a buffer and
prevents gelation, also acting as a buffer in coffee whiteners. It is an accelerator of the setting
Time(Mins) in instant puddings. In cream sauce and whipped products, it functions as a
dispersant by producing a swelling of protein.
42 | P a g e
5.METHODOLOGY
5.1.Preformulation Studies
Preparation of Phosphate Buffer pH 5.5
In a volumetric flask of 1000 litre 13.61gm of KH2PO4 is dissolved. From that 964 ml is taken
out and mixed with 36ml of Na2HPO4 solution prepared by dissolving 3058 gm in 100 ml. The
pH was adjusted to 5.5
Calibration curve of Prochlorperazine at pH 5.5
100 mg pure drug is dissolved in 20ml of PEG 400 and adjusted to volume to 100 ml with buffer
solution of pH 5.5. This was uses as a standard stock solution.
▪ Working standard solution:
10 ml of the stock solution was further diluted to 100 ml with pH 5.5 buffer from that working
standard, 5ml, 10ml,15 ml,20 ml, 25ml & 30 ml was pipetted into different volumetric flask and
volume made up with buffer up to 100ml.
FTIR Spectroscopy
Fourier-transform infrared spectroscopy (FTIR) is a technique used to obtain an infrared
spectrum of absorption or emission of a solid, liquid or gas. An FTIR spectrometer
simultaneously collects high-spectral-resolution data over a wide spectral range. This confers a
significant advantage over a dispersive spectrometer, which measures intensity over a narrow
range of wavelengths at a Time(Mins).
The goal of absorption spectroscopy techniques (FTIR, ultraviolet-visible ("UV-Vis")
spectroscopy, etc.) is to measure how much light a sample absorbs at each wavelength.
The drug sample has been taken a little amount for FTIR study and output graph is recorded. The
drug prochlorperazine maleate was scanned in the range of 400 to 4000 cm–1 with 1 cm–1
resolution. FTIR spectrum of pure drug was interpreted. The drug excipient compatibility has
been assured by the support of previous research.
Solubility
A small amount of Prochlorperazine maleate is put into multiple test tube of same quantity. Each
test tube contains equal amount of Water, Ethanol, Chloroform, PEG 400 and Glycerine. It has
been taken into the observation that all test tube must contains same amount of drug as well as
solvent. The test tubes are shaken so that the drug can be mixed with the solvent. They are kept
in test tube holders and remain untouched for 4-5 hrs and they were observed if there is any
precipitation.
43 | P a g e
5.2. Post formulation study
Preparation of Nasal Solution
The preparation of nasal solution involves 3 steps which are following:
• Mixing of cosolvent: In a mechanical stirrer, required amount of cosolvent or PEG 400
is mixed with little amount of humectant or Glycerine. This process is continued up to 5-
7 minutes.
• Incorporation of drug and polymer: In that particular mixture required amount of drug
(Prochlorperazine maleate) is added slowly with continuous magnetic stirring and to that
particular mixture polymer (HPMC K4M) is slowly incorporated.
• Sonication and Storage: The solution is then placed into small beaker and put into bath
sonicator and crystal-clear liquid obtained. Finally, few drops of preservative
(Benzalkonium chloride) is added and stored in refrigerator.
Clarity Test: Clarity testing is carried out to check the particulate matter in the sample. In this
test transparent particles or white particles observed against the black background and the black
or dark particles observed against the white background.
Determination of pH
In chemistry, pH or potential for hydrogen is a scale used to specify how acidic or basic a water-
based solution is. Acidic solutions have a lower pH, while basic solutions have a higher pH. At
room temperature (25°C or 77°F), pure water is neither acidic nor basic and has a pH of 7.
The pH scale is logarithmic and inversely indicates the concentration of hydrogen ions in the
solution (a lower pH indicates a higher concentration of hydrogen ions).
Each formulation were taken into separate containers and pH has been studied using litmus paper
and the reading has been taken.
Viscosity
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The viscosity of a fluid is a measure of its resistance to deformation at a given rate. The study
was carried out by using Ostwald’s Viscometer.
The instrument must first be calibrated with materials of known viscosity such as pure
(deionized) water. Knowing the value of viscosity of one liquid, one can calculate the viscosity
of other liquid.
where η1 and η2 are viscosity coefficients of the liquid and water, and ρ1 and ρ2 are the
densities of liquid and water, respectively. ( Generalic, Eni. "Ostwald’s viscometer." Croatian-
English Chemistry Dictionary & Glossary. 20 Oct. 2018. KTF-Split. 4 July 2020.
<https://glossary.periodni.com>.)
RELEASE STUDY
For evaluating the drug release from any liquid formulation, the diffusion technique is most
widely used.
Diffusion is, by definition, the random movement of molecules through a domain driven by a
concentration gradient, from high concentration to low concentration. In vitro diffusion is
generally passive diffusion of a permeant from a vehicle in the donor chamber, through an
artificial or biological membrane into a receptor fluid in a receptor chamber, disregarding
delivery systems such as iontophoresis and microneedles. The permeant is the molecular species
moving through or into the tissue/membrane.
Each formulation were put into donor compartment of Franz diffusion cell. The cell was filled
with buffer of pH5.5 and Dialysis membrane 70 was taken as a semi-permeable membrane.
The same amount of sample was taken out at a Time(Mins) interval of 5 minutes and fresh same
amount of fresh buffer has been incorporated in the cell. The release study has been calculated.
Clarity Test
45 | P a g e
Clarity testing is carried out to check the particulate matter in the sample. In this test transparent
particles or white particles observed against the black background and the black or dark particles
observed against the white background. Clarity is very important for the overall look and feel of
any liquid formulation.
6.RESULTS & DISCUSSIONS

6.1.PRE-FORMULATION STUDY
Calibration curve of Prochlorperazine at pH 5.5
A calibration curve for Prochlorperazine was successfully obtained by measuring the
Absorbance of a series of concentrations of Prochlorperazine at the λmax of 254 nm. The
corresponding standard curve generated by linear regression analysis is shown in fig.1 with a
linear regression coefficient of 0.999.
Abs.
0.9
0.8
0.7
0.6
Absorbance
y = 0.0346x + 0.095
0.5 R² = 0.9999
0.4
Series1
0.3
Linear (Series1)
0.2
0.1
0
0 5 10 15 20 25
Concentration(µg/ml)
Fig.1 Standard calibration curve of Prochlorperazine in phosphate buffer pH 5.5
FTIR STUDY
46 | P a g e
Fig.2 FTIR spectra of Prochlorperazine Maleate Pure Drug
Discussion:
The Fourier transform infrared spectroscopy (FTIR) spectrum for the pure prochlorperazine
maleate as shown in fig. (2) displayed band at 3156 cm-1 assigned to the (C-H) aromatic rings
in the backbone of the prochlorperazine. The (C-H) of aliphatic groups (CHR3R and CHR2R)
appeared in the expected area for the stretching vibration at 2286 cm-1. The bands appeared at
1686 cm-1 and 1617 cm-1 attributed to the (C=O) stretching of two carboxylic
groups of maleate structure. The band appeared at 1568 cm-1Pattributed to (C=C) of the aromatic
ring. The band appeared at 1089 cm-1 attributed to (C-Cl) stretching in the benzene ring. While
the fingerprint area showed the bending bands of the drug (62)
.
47 | P a g e
SOLUBILITY STUDY
A small amount of Prochlorperazine maleate is put into multiple test tube of same quantity. Each
test tube contains equal amount of Water, Ethanol, Chloroform, PEG 400 and Glycerine.
Water: Very slightly soluble
Ethanol: Very slightly soluble
Chloroform: Slightly soluble
PEG 400: Soluble
Glycerine: Partially soluble
Discussion:
The drug shows very good solubility in the PEG 400 and shows slightly solubility in
Chloroform. Partially soluble in glycerine and very slightly soluble in water and ethanol.
POST-FORMULATION STUDIES:
Preparation of Nasal Solution
The nasal solution was prepared by using the above-mentioned method. The formulation chart is
given as following:
No. PCM(mg) HPMC Bile PEG Glycerine(ml) Benzalkonium

K4M(mg) Salt(mg) 400(mg) Chloride
F1 20 20 10 2 0.50 0.006
F2 20 20 15 2 0.50 0.006
F3 20 20 20 2 0.50 0.006
F4 20 20 10 3 0.50 0.006
F5 20 20 15 3 0.50 0.006
F6 20 20 20 3 0.50 0.006
F7 20 20 10 4 0.50 0.006
F8 20 20 15 4 0.50 0.006
F9 20 20 20 4 0.50 0.006
Fig 3: Formulation Chart
48 | P a g e
Determination of pH
The formulations were evaluated and the results are following:
F1: 5.4
F2: 5.5
F3: 5.7
F4: 5.5
F5: 5.8
F6: 5.5
F7: 6.0
F8: 5.3
F9: 5.6
Discussion:
All the formulations are found within range. That means they are suitable for nasal formulation.
Determination of Viscosity
Viscosity of nasal spray is very important in prevention of dripping and increasing residence
Time(Mins) and thereby prolonging therapeutic action.
The results obtained are within range of the recommended criteria i.e. 1.35cP to3.95cP(63).
Discussion:
The viscosity of nasal preparation was found within the range. This viscosity provide better
residence Time(Mins) as well as better stability.
Clarity Study
Every formulation was studied in front of the Black and White background. The formulations
were found to be crystal clear.
Drug Release Study

49 | P a g e
Diffusion study was carried out using Franz diffusion cell. The results are following:
F1
Time(Mins) Absorbance %cdr
5 0.806 16.48372
10 1.362 30.84826
15 3.608 85.11715
20 3.843 92.38532
% cumulative drug release

100
80
60
%cdr
40
20
0
0 5 10 15 20 25
Time(Mins)
Fig 4: In-vitro release profile of F1
F2
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5 0.596 11.6
10 1.372 30.93547
15 2.725 63.94782
20 3.829 91.40785
%Cumulative Drug Release

100
80
60
%CDR
40
20
0
0 5 10 15 20 25
Time(mins)
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F3

5 0.629 12.36744
10 1.393 31.46308
15 3.709 87.56192
20 4.002 96.27195

120
100
80
%CDR
60
40
20
0
0 5 10 15 20 25
Time(Mins)
F4
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5 0.576 11.13488
10 1.361 30.65712
15 2.849 66.91366
20 3.761 89.86715
100
90
80
70
60
%CDR
50
40
30
20
10
0
0 5 10 15 20 25
Time(Mins)
F5
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5 0.472 8.716279
10 1.025 22.5234
15 1.982 45.8766
20 3.268 77.41366

90
80
70
60
%CDR
50
40
30
20
10
0
0 5 10 15 20 25
Time(Mins)
F6
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5 0.815 16.69302
10 1.324 29.94346
15 2.681 62.8577
20 3.875 92.47907

100
90
80
70
60
%CDR
50
40
30
20
10
0
0 5 10 15 20 25
Time(Mins)
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F7
5 0.857 17.66977
10 1.058 23.59462
15 3.251 76.33445
20 3.862 92.58154

100
90
80
70
60
%CDR
50
40
30
20
10
0
0 5 10 15 20 25
Time(Mins)
F8
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5 0.629 12.36744
10 1.275 28.63314
15 2.362 55.17166
20 3.583 85.24433

90
80
70
60
%CDR
50
40
30
20
10
0
0 5 10 15 20 25
Time(Mins)
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F9
5 0.631 12.41395
10 0.841 18.22616
15 2.736 63.82573
20 3.438 82.03866

90
80
70
60
50
%CDR
40
30
20
10
0
0 5 10 15 20 25
Time(Mins)
58 | P a g e
Comparative drug release study
%CDR %CDR %CDR %CDR %CDR %CDR %CDR %CDR %CDR
Time(Mins) F1 F2 F3 F4 F5 F6 F7 F8 F9
0 0 0 0 0 0 0 0 0 0
5 16.48 11.6 12.36 11.13 8.71 16.69 17.66 12.36 12.41
10 30.84 30.93 31.46 30.65 22.52 29.94 23.59 28.63 18.22
15 85.11 63.94 87.56 66.91 45.87 62.85 76.33 55.17 63.82
20 92.38 91.4 96.27 89.86 77.41 92.47 92.58 85.24 82.03
Comparitive % CDR
120
100
80
%CDR
60
40
20
0
0 10 20 30 40 50 60 70 80 90 100
Time(Mins)
%CDR F2 %CDR F3 %CDR F4 %CDR F5

%CDR F6 %CDR F7 %CDR F8 %CDR F9
Fig 12.1: Comparative release study
Discussion:
Comparing all the formulations, it has been found that F3 shows better drug release among
others.
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7.CONCLUSION
The Prochlorperazine maleate nasal formulation was prepared by using several components. The
preformulation studies has been carried out which proves the purity of the drug. The solubility
and other parameters also checked. By altering the amount of co-solvent and permeation
enhancer, 9 formulations have been prepared. Post formulation evaluation has been carried out.
It is observed that HPMC K4M doesn’t interfere in absorption or overall release. Sodium
Cholate (Bile Salt) can be used as excellent permeation enhancer. The PEG-400 shows great
results in solubility. It increases the stability as well.
Considering all parameters, the F3 formulation shows better result. So, we can conclude that, by
using this method and ratio of ingredients the nasal formulation of Prochlorperazine can be
prepared which can show better efficacy and quicker relief. Further study must be needed to see
any other newer aspects of this research which can be a breakthrough in Migraine therapy.
60 | P a g e
8.REFERENCES
1. Marttin E, Verhoef JC, Merklus FWHM. Efficacy, safety and mechanism of cyclodextrins
as absorption enhancers in nasal delivery of peptide and protein drugs. Vol. 6, Journal of
Drug Targeting. Harwood Academic Publishers GmbH; 1998. p. 17–36.
2. Karami Z, Saghatchi Zanjani MR, Hamidi M. Nanoemulsions in CNS drug delivery: recent
developments, impacts and challenges. Drug Discovery Today. 2019.
3. Review: Clinical opportunities provided by the nasal administration of peptides. J Drug
Target. 1993;1(2):101–16.
4. Neelam A, Anita S, Gothecha V, Kumar K. AYURVEDIC MANAGEMENT OF ECZEMA
(VICHARCHIKA)-A REVIEW. Int J Ayurveda Pharma Res. 2016;4(4).
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64 | P a g e
ANNEXURE
1 Presented a poster on 14th September 2018 on NATIONAL SEMINAR on Pharmacy &

Healthcare: Traditional Knowledge to Modern Techniques organized by, Department of
Pharmaceutical Technology, Jadavpur University, Kolkata-700032
2 Participated on NATIONAL LEVEL WORKSHOP on SCIENTIFIC WRITING &
PUBLICATION on 6th October, 2018 by Himalayan Pharmacy Institute, Majhitar, East
Sikkim-737136
3 Presented a poster on BCRCPiCON-2019, A TWO DAYS INTERNATIONA CONFERENCE
on “Key Concerns and Considerations in Pharmaceutical Sciences & Technology, South-East
Asian Perspective” on 4-5 February, 2019 organised by, Dr. B.C. Roy College of Pharmacy &
Allied Health Sciences, Durgapur-713206
4 Completed Online Course on “Artificial Intelligence & Drug Discovery” on 19th April, 2020
organized by SVERI, Pandharpur, Maharashtra, India
5 Completed the webinar-based module on “COVID-19 AWARENESS & PREVENTION
BRACE” organized by SPCOP, Pune, Maharashtra-412409 on 27th April,2020
6 Participated on Webinar on “INTELLECTUAL PROPERTY RIGHTS(IPR) FOR THE
DEVELOPMENT OF ACADEMIC PHARMACEUTICAL RESEARCH9IPR-2020)
organized by SPCOP, Pune, Maharashtra on 9th June, 2020.
7 Participated on Webinar on “IMMUNITY BOOSTERS IN INFECTIOUS DISEASES” on 11th
June, 2020 organized by SPCOP, Pune, Maharashtra.
8 Participated on Webinar on BCRCP Webinar Series – 2020 on (Post Covid-19 Opportunities
in Pharmaceutical Industry & Research) Episode#2 Management Protocol of COVID-19:
Govt. of West Bengal. On 13th June 2020.
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Formulation and Evaluation of Nasal Solution for

HIMALAYAN PHARMACY INSTITUTE

the academic year 2019-2020.

University for assessment.

Dr. Prithviraj Chakraborty Mr. Sujit Das

Prof. (Dr.) N.R. Bhuyan

I hereby declare that the work embodied in the final-semester

Date: Souvik Chattopadhyay

2 AIM & OBJECTIVE 24

4 MATERIALS & INSTRUMENTS 27

6 RESULTS & DISCUSSION 46

• Wavering the hepatic first pass metabolism.

1.1.2.Physiology of nasal cavity

1.1.3.Physiology of nasal mucosa

1.4.Physicochemical properties of drug applicants & formulations

1.6.Nose to Brain Targeting

1.7.Inflowing factors of nasal drug absorption

1.7.1.Physiochemical properties of drug

1.8.9.Role of Absorption boosters

1.9.1.2.Circulation of blood through nasal route

1.9.1.3.Mucociliary Clearance effect

1.9.1.5.Effect of Pathological Status

1.9.2.Systems of Nasal Drug Delivery

1.9.2.2.Instillation and rhinyle catheter

1.9.2.5.Metered-dose pump sprays

TRADE NAMES- STEMETIL, COMPAZINE

INDICATIONS AND USAGE

Chemical Name and CAS Registry Number

Empirical Formula and Molecular Weight

Applications in Pharmaceutical Formulation or Technology

Sodium chloride is widely used in a variety of parenteral and nonparenteral pharmaceutical

Stability and Storage Conditions

Chemical properties: Polyethylene glycol is a polymer which is hydrolysed by ethylene oxide.

Chemical Properties Glycerine is the polyhydric alcohol 1,2,3 propanetriol [HOCH2-

Pharmaceutical Applications Glycerine is used in a wide variety of pharmaceutical

Melting point 252.6 °C

6.RESULTS & DISCUSSIONS

Fig.1 Standard calibration curve of Prochlorperazine in phosphate buffer pH 5.5

No. PCM(mg) HPMC Bile PEG Glycerine(ml) Benzalkonium

Drug Release Study

Time(Mins) Absorbance %cdr

% cumulative drug release

Fig 4: In-vitro release profile of F1

%Cumulative Drug Release

Fig 5: In-vitro release profile of F2

Time(Mins) Absorbance %cdr

%Cumulative Drug Release

Fig 6: In-vitro release profile of F3

Fig 7: In-vitro release profile of F4

%Cumulative Drug Release

Fig 8: In-vitro release profile of F5

%Cumulative Drug Release

Fig 9: In-vitro release profile of F6

Time(Mins) Absorbance %cdr

%Cumulative Drug Release

Fig 10: In-vitro release profile of F7

%Cumulative Drug Release

Fig 11: In-vitro release profile of F8

Time(Mins) Absorbance %cdr

%Cumulative Drug Release

Fig 12: In-vitro release profile of F9

%CDR F2 %CDR F3 %CDR F4 %CDR F5

Fig 12.1: Comparative release study