A Project on

“FORMULATION AND EVALUATION OF PHENYTOIN ORAL TABLETS”

A Thesis Submitted

In partial fulfillment of the requirements

For the degree of

BACHELOR OF PHARMACY

By

JUNNAID AHMED

(Roll No. 1909080500041)

Under the Guidance of

MS. SWARUPANJALI PADHI

(Assistant Professor)

Noida Institute of Engineering and Technology

Pharmacy Institute

Greater Noida-201306, Uttar Pradesh, India

To the Faculty of Pharmacy

Dr. A.P.J Abdul Kalam Technical University, LUCKNOW

 ACKNOWLEDGEMENTS

It is a great pleasure for me to acknowledge all those who have contributed towards the
conception, origin and nurturing of this project.

With a deep sense of gratitude and respect, I thank my esteemed research guide
Ms. SWARUPANJALI PADHI, Department of Pharmacy, Noida Institute of Engineering and
Technology, Greater Noida for his inestimable guidance, valuable suggestions and constant
encouragement during the course of this study.

I am thankful to Dr. AVIJIT MAZUMDER and Dr. RUPA MAZUMDER for their constant
moral support, valuable suggestions directions and selfless support throughout the investigation.

At this moment, I thank my friends and classmates for their moral support, constant
encouragement and patience absolutely needed to complete my entire study. I am indebted
infinitely to care, support and trust being shown by my parents without whom it would not be
possible to complete this project.

JUNNAID AHMED

(ROLL NO: 1909080500041)

 STATEMENT OF THE CANDIDATE

As required by university regulations. I wish to state that this work embodied in the report title
“Formulation and Evaluation of Phenytoin Oral Tablets” form, my own contribution to the
work carried out under the guidance of Ms. SWARUPANJALI PADHI

This work has been submitted for any degree to this or any other university, where references
have been made to previous work of the others.

JUNNAID AHMED

(1909080500041)

BPHARM 7TH SEM, 4TH YEAR

 CERTIFICATE

The work described in this initiated “FORMULATIONS AND EVALUATION OF

PHENYTOIN ORAL TABLETS” by JUNNAID AHMED.

I certify that this is his bonafide work. This work described is original and has not
been submitted for any degree to this or any other university.

Date: -

Signature of Student

Signature of Internal Examiner Signature of External Examiner

 DECLARATION

I hereby declare that this submission is my own work and that to the best of my
knowledge and believe, it contains no materials previously published or written by
another person nor material which to a substantial accepted extend has been
accepted for the award of any other degree of the university or other institute of
higher learning except where due acknowledgement has been made in the text.
 CHAPTER NAME OF THE
S.NO. PAGE NO.
NO. CHAPTER

1 CHAPTER I INTRODUCTION 1-2

2 CHAPTER II LITERATURE REVIEW 3-4

3 CHAPTER III AIM AND OBJECTIVE 5

4 CHAPTER IV METHODS 6-7

RESULTS AND
5 CHAPTER V 8-11
DISCUSSION

6 CHAPTER VI CONCLUSION 12

7 CHAPTER VII REFERENCE 13-14

 CHAPTER I
INTRODUCTION

Anticonvulsant phenytoin is used to treat complicated partial psychomotor lobe seizures, partial
tonic-clonic seizures, and generalized seizures. The creation of phenytoin pills that dissolve
when taken orally is the focus of this study. The pills are said to dissolve within 30 seconds.
The project's goal was to create a more patient-friendly dose form for an already-available
medication. The experimental plan for the project can be roughly broken down into three steps:
first, preliminary studies were conducted to assess the suitability of the alternative method used
to measure disintegration time and to determine whether the excipients used with phenytoin
were compatible using FT-IR. It may be inferred that there are no significant interactions
between the medication and the excipient by contrasting the spectra of a binary combination of
excipients and phenytoin with those of pure phenytoin. Second, a DOE model was utilized to
assess how excipients affected tablet breaking force and disintegration time. It was shown that
crospovidone and sodium starch glycolate substantially impacted the response factors. The
tablets were made utilizing a manual hydraulic press and the direct compression technique. The
findings attained met the required requirements. For stability experiments, it was discovered
that the disintegration period of tablets stored outside of any container was longer than that of
tablets placed inside of aluminum pouches and HDPE bottles. Thermo gravimetric analysis and
moisture sorption analysis of mannitol were conducted in order to give an explanation for the
discrepant results of the disintegration time of tablets from petri plates.
ADVANTAGES OF PHENYTOIN
 Phenytoin is a medicine used to treat epilepsy.
 It can also be used to treat trigeminal neuralgia, a type of nerve pain that affect
your face.
 It comes as tablets that can be chewed or dissolved in water, capsules and a light
that you swallow.
 Efficacy
 Seizure freedom or reduced risk of seizures
 Uncertain: better health, lower morbidity and better survival
 Good tolerability and safety
 Absence of deleterious drug interaction
 No hypersensitivity reaction
 No organ damage

DISADVANTAGES OF PHENYTOIN
 Efficacy
 Seizure freedom or
 reduced risk of seizures
 Uncertain: better health, lower morbidity and better survival
 Good tolerability and safety
 Absence of deleterious drug interaction
 No hypersensitivity reaction
 No organ damage
 CHAPTER II
LITERATURE REVIEW

1. KATHARINE GOLLAPE et al. loading dose of phenytoin should be given to phenytoin

naïve patients for the emergency treatment of seizures; parenteral administration results
in therapeutic concentration sooner than oral administration but is associated with more
frequent and significant adverse effects. Phenytoin is used in the treatment of status
epilepticus although evidence here is limited; it may also be given to prevent early post-
traumatic seizures.
In conclusion, phenytoin is appropriate for treatment of some seizures seen in the ED; it
is associated with significant adverse effects; trials are ongoing regarding the use of other
anticonvulsants in the treatment of status epilepticus.

2. JAMIR PITTON et al. Future studies need to further describe the clinical picture and the
outcomes of each MD to improve the management of patients affected by these
conditions. The mechanisms underlying the adverse events caused by
PHT probably depend on the presence of predisposing factors such as epilepsy type and
structural brain changes, although MDs have been reported in patients without any
preexisting brain disorders.

3. SALCMAN et al. described a series of five men with intractable epilepsy who underwent
surgery to implant cerebral electrodes. All five patients had been treated with phenytoin,
although only one had evidence of ataxia at the time of biopsy. Biopsies showed severe
loss of Purkinje cells in four patients, and moderately severe loss in the remaining case.
Salcman et al drew attention to the findings of Spielmeyer, who had described loss of
Purkinje cells in patients with epilepsy in postmortem specimens obtain.
 4. KOKENGE et al. studied 36 rats given phenytoin 100–200 mg/kg/day and 12 cats given
up to 30 mg/kg/day. There was loss of Purkinje cells and edema of Bergmann’s glial
layer in all animals examined at 18 days. The cats proved much more susceptible to
phenytoin than the rats.

5. KIEFER et al. compared 30 mice treated with phenytoin and 30 control mice, sacrificed
in groups of six treated and six control animals at 3, 6, 10, 14, and 48 days after the start
of (high-dose) phenytoin treatment. These workers demonstrated progressive changes in
morphology and reduction of number of Purkinje cells in the cerebellum from day 6,
although clinical effects of ataxia, drowsiness, and weight loss were seen only from day
35

6. KOLLER et al. In 1980, Koller and colleagues published a letter with preliminary data on
eight patients 'on long-term phenytoin therapy' whose CT scans showed cerebellar
atrophy, but who had no clinical signs of a cerebellar disorder

7. LUEF at al. examined MRI scans in 11 patients with epilepsy, all of whom had been
treated with phenytoin and had at least one episode during which the serum phenytoin
concentration (21.4–95.6 mg/L) exceeded the reference range. At the time of the
increased serum phenytoin concentration, clinical signs of cerebellar disorder were absent
in three patients; and eight had nystagmus, which was associated with ataxia in two
patients. Six of the 11 patients had MRI evidence of cerebellar atrophy, involving the
vermis (one patient), the cerebellar hemispheres (one patient) or both (four patients).

.
 CHAPTER III

AIM AND OBJECTIVE

Optimized orally disintegrating pills of phenytoin dissolve within 30 seconds according to the
project's theory.

The project's overarching goal is to develop phenytoin ODTs and further assess the optimized
batches of tablets for expedited stability testing and Q.C testing. Listed below is an overview of
the project's goals:

To carry out in vitro disintegration and tablet breaking force tests on commercial formulations
in order to assess the suitability of a different technique for calculating in vitro disintegration
times.

 The overall objective of the project is to formulate phenytoin ODT's and further evaluate the
optimized batches of tablets for Q.C testing and accelerated stability testing.

 To perform drug – excipient compatibility studies using FT-IR.

 To perform the experiments as mentioned in DOE model and evaluate the effect of
excipients on disintegration time and tablet breaking force.

 To perform quality control testing on optimized batches.

 CHAPTER IV
METHODS

Since the In vitro disintegration testing will not be performed on USP mentioned apparatus
there is a need to evaluate the appropriateness and reliability of the modified method used.

For this purpose, a marketed orally disintegrating tablet closely resembling the excipients was
evaluated for In vitro disintegration time and tablet breaking force.

The marketed formulation that was selected is 'Allegra Children's Allergy 12 Hour Orally
Disintegrating Tablets' [Lot no - 6PHSE].

The assumption is that any marketed ODT formulation should disintegrate within 30s
irrespective of its ingredients.

Hence if the tablet does not disintegrate within the 30s then it reflects errors in the method of
testing.

Artificial saliva was prepared and used for all In-vitro disintegration time measurements.

Protocol 1: Drug – excipient compatibility studies the drug – excipient compatibility studies
were performed using FT-IR [Spectrum one FT-IR, Mfg. PerkinElmer, Serial no: 000710].

The objective of the protocol was to evaluate the compatibility of the API with the excipients.

Further spectra's of each excipient with API in 50:50 ratio was obtained.

All the spectra's were obtained within the frequency range of 400 – 4000 cm-1.

For each DOE run, 8 tablets were prepared and for each optimized batch 30 tablets were
prepared.
Each excipient equivalent to the weight of 8 tablets/30 tablets was weighed individually on
analytical balance [Metter AE 240, Serial no: 000508].

Further, all the excipients were mixed according to geometric dilution's principle.

For punching each tablet, approximately 200 mg of this mixture was weighed and filled in the
die cavity.

After which the die and punch assembly were put inside the Carver press.

Obtained tablets were used for further analysis

The procedure mentions using the disintegration apparatus for the testing.

Disintegration time for 3 tablets was measured in a beaker containing a mesh.

Each tablet was placed on the mesh and time required for complete disintegration of the tablet
was measured.

Out of 3 tablets, the tablet which showed highest disintegration time was considered as the
reading for the test.

For each DOE run 3 tablets and 6 tablets for each optimized batch were used for analysis.
Average value of these readings was considered as the response value for the particular DOE
run or batch.

Weight and thickness variation: The general chapter <905> Uniformity of dosage units provide
guidelines for this test. Observations were recorded, and further average weight/thickness
&%RSD were calculated.

Out of 6 tablets, the tablet which showed the highest disintegration time was considered as the
reading for the test. Tablet breaking force determination: This test was performed as mentioned
in protocol 4.

Content determination: For this test 6 tablets from each batch were triturated in mortar and
pestle. From the obtained absorbance readings content of phenytoin was determined and
recorded in terms of % label strength.
 CHAPTER V
RESULTS AND DISCUSSION

As a preliminary study 6 marketed ODT’s were tested for In-vitro disintegration and tablet
breaking force.

Following are the results:

Tablet breaking force

Tablet no. Weight (g) Tablet breaking force (kP)
1 0.45 3.8
2 0.44 3.4
3 0.44 3.9
4 0.46 4.1
5 0.44 4.1
6 0.45 3.8

For the first tablet, the disintegration time was measured without moving the beaker.

The tablet was found to disintegrate completely but a lump of powder got accumulated in the
corner of the beaker.

For further tablets, the beaker was rotated slowly in small circular motion.

In the measurement of tablet disintegration time in the further sections of the project, this
motion of beaker will be performed.

Since the tablets disintegrated within the 30s it confirms the appropriateness of the method
used for measuring the disintegration time.

Fourier – Transform Infrared spectroscopy was used to evaluate the compatibility of

excipients used with phenytoin.

Hence, any changes in spectra are reflective of changes in molecular structure and possible
interaction between two components (Barbara, 2004).
Hence, the binary mixture of drug-excipient spectra should show distinct peaks
corresponding to drug and excipient both.

Phenytoin is an aromatic amide.

For aromatic amides presence of absorption peak between 3400 – 3200 cm-1 is
characteristic and is due to aromatic nitrogen-hydrogen stretch vibration (Sigma- Aldrich,
1997, p. 2963).

Crospovidone is a polymer of N-vinyl pyrrolidone.

Hence in spectra of Crospovidone functional vibrations associated with N-vinyl pyrrolidone

can be seen.

The peak at around 3500 cm-1 in Crospovidone spectra is associated with C-N stretch.

While peak around 1700 cm-1 is associated with C=O group.

Importantly it can be seen that N-H stretch associated with phenytoin remains intact in a
binary mixture of Crospovidone and phenytoin.

EVALUATION
o SIZE AND SHAPE-The thickness of a tablet is only variables. Tablet thickness can be
measured by micrometer or by other device.
o HARDNESS AND FRIABILITY-Tablet requires a certain amount of strength or
hardness and resistance to friability to withstand mechanical shakes of handling in
manufacture, packaging and shipping.
o WEIGHT VARIATION-Calculate average weight and compare the individual tablet
weight to the average. The tablet pass the U.S.P. test if no more than 2 tablets are
outside the percentage limit
o DISINTEGTRATION TEST-The U.S.P. device to test disintegration uses 6 glass
tubes that are 3” long; open at the top and 10 mesh screen at the bottom end.
According to the test the tablet must disintegrate and all particles must pass through
the 10 mesh screen in the time specified.
o DISSOLUTION TEST-A single tablet is placed in a small wire mesh basket attached
to the bottom of the shaft connected to a variable speed motor. The motor is adjusted
to turn at the specified speed and sample of the fluid are withdrawn at intervals to
determine the amount of drug in solutions.
CLINICAL FEATURES
Age was documented in 87 cases, with a median of 28 [range 2.7–78] years.

At least one feature of a cerebellar disorder was mentioned explicitly in 81 of the 92 cases; one
case showed no signs.

Of the 81 clinical case reports, 78 (96%) described ataxia, 51 (63%) recorded dysarthria or
speech difficulties, and 57 (70%) noted nystagmus.

Fifteen patients were recorded to have ataxia alone, and two to have nystagmus alone.

Twenty-three cases (28%) exhibited two of the three features, and 41 cases (51%) exhibited all
three.

PHENYTOIN CONCENTRATION MANAGEMENT

The maximum phenytoin concentration at or soon after presentation was provided in 47 case
reports.

The median value was 50 (range 3–128; interquartile range 31–67) mg/L, and only four values
were below 20 mg/L.

RADIOLOGICAL FINDINGS
We took radiological investigations to support a finding of cerebellar atrophy if they reported
cerebellar atrophy; or there was prominence of the cerebellar folia or widening of the cerebellar
sulci or both; or an increase in size of the fourth ventricle.

Some patients underwent radiological investigations at the time of admission and at follow-up.

Two patients underwent carotid angiography, with normal results.

In 14 cases, patients had pneumoencephalograms after developing symptoms attributed to

phenytoin.

Five studies were normal or only slightly abnormal, four were reported to show enlargement of
the fourth ventricle, and five were reported to show cerebellar atrophy.
There were 35 cases with recorded CT scan results, six of which showed no cerebellar
abnormality.

In the 29 (85%) patients with abnormal scans, cerebellar atrophy, cerebellar degeneration, clearly
outlined cerebellar sulci or folia, or enlargement of the fourth ventricle, or a combination of these
findings, was observed.

One scan was interpreted to demonstrate cerebellar infarction.

Fifteen patients had MRI scans reported: one scan as normal, one as showing 'prominent
cerebellar folia,' and one both prominent folia and cerebellar atrophy.

Twelve MRI scans (80%) in total were reported to show cerebellar atrophy or 'shrinkage of
cerebellum.'

A further patient underwent MRI scanning, but the scan was not described.

Altogether, radiology by one or more modality was reported to show cerebellar atrophy in 37/62
patients (60%) and ventricular dilation or other changes without explicit mention of cerebellar
atrophy in 11/62 (18%); examinations in 14 patients showed no or 'minor' abnormalities.

Discussion: A total of 9 tablets were stored for 15 days in the stability chamber at 40 ± 2°C and
75 ± 5% relative humidity.

Three tablets each were stored in open petri dishes, heat sealed aluminum pouches, and induction
sealed HDPE bottles.

After 15 days two tablets from each packaging type was analyzed for disintegration time and one
tablet for tablet breaking force.

The tablets that were stored in aluminum pouches and HDPE bottles their disintegration time, as
well as tablet breaking force, was found to be lowered as compared to average reading for the
batch.

It can be inferred that Aluminum pouches are better packaging material.

When compared with the results of optimized batch readings, there is no major difference in
disintegration time and tablet breaking force for tablets stored in the pouches.

This suggests that Aluminum pouches provide a better barrier against humidity.

While for the tablets which were stored in open Petri plates its disintegration time was found to
be increased.
While there can be many reasons this contrary result two assumptions can be made for increased
disintegration time.

Storage of tablets at higher humidity conditions could have resulted in higher adsorption of
moisture on the surface and thereby moisture itself may be acting as a binder which might have
increased the disintegration time.

Since mannitol accounts for almost 60% of tablet weight its possible polymorphic transitions
might be the reason for the increase in disintegration time.
 CHAPTER VI
CONCLUSION

The goal of the current study was to develop and assess a sustained release matrix tablet
containing phenytoin sodium utilizing several polymers, including HPMC, CMC, and PVP
K90. While CMC and PVP-K90 with a drug to polymer ratio of 1:2 were able to regulate the
drug release up to 8 and 6 hours, respectively, HPMC-based matrix tablets with a 1:2 ratio
were able to maintain the release of phenytoin for up to 12 hours. The medication was stable
in matrix tablets with an HPMC basis, according to the stability study. Therefore, HPMC was
chosen as the ideal polymer to create a formulation for phenytoin that releases slowly over a
12-hour period.

The project's hunch is that pills from optimized batches would dissolve in 30 seconds or less.
Since the pills did dissolve in 30 seconds for each of the three batches, it can be said that the
data obtained are consistent with the stated hypothesis.
 CHAPTER VII
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THANK YOU
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