Formulation Development and InVitro Evaluation of an Antiepilepsy

Solid Oral Dosage Form

Academic Guide
Dr.S.K.Ghosal
Professor in
Pharmaceutics

I.G.I.P.S.,Bhubaneswar

PRESENTED BY:A. KRUSHNA

KUMAR
M.PHARM (PHARMACEUTICS)

Industrial Guide
Mr.Om Prakash Sharma
Senior Manager,F&D,
KOPRAN RESEARCH Lab.

AIM & OBJECTIVE

Formulation Development and In-Vitro Evaluation
of an Antiepilepsy Solid Oral Dosage Form

TOPICS COVERED

INTRODUCTION

LITERATURE REVIEW

DRUG PROFILE

PLAN OF WORK

EXPERIMENTAL

REFERENCE

INTRODUCTION

INTRODUCTION:
IMMEDIATE RELEASE DOSAGE FORM

The mechanisms for release of drug from modified-release dosage forms

are more complex and variable than those associated with immediaterelease dosage forms.
According to BCS (Biopharmaceutics classification system), there are
three major factors that govern the rate and extent of drug absorption of
immediate release (IR) solid oral dosage forms:
Dissolution rate
Solubility
Intestinal permeability.
For IR dosage forms containing active pharmaceutical ingredients (APIs)
Showing high solubility
High intestinal permeability

A waiver from performing bioequivalence studies (biowaiver) can be

scientifically justified.
EPILEPSY:
These are the group of disorders of CNS characterized by paroxysmal
cerebraldysrhythmia, loss of consciousness, with or with out
characteristics of body movement (convulsion), sensory or psychiatric
phenomenon.
CLASIFICATION OF EPILEPSY:
It can be classified as two types of. (a)Generalized seizure
(b)Partial seizure

LITERATURE REVIEW

LITERATURE SURVEY:
The complexity of treatments for persons with epilepsy by Katherine
A.yeager et.al.
Development and Validation of a HPLC Method for a Dissolution Test
of Lamotrigine tablets & its Application to Drug Qulity Control Studies by
sripalakit pattana et.al.& srichaiya Arunee et.al.
Transbuccal delivery of lamotrigine across porcine buccal mucosa:in
vitro determination of routes of buccal transport by Mashru rajashree et
al.
Solubility of Lamotrigine at a diff pH by Vijaya sutariya et.al.
Official Dissolution Methods of Lamotrigine from U.S.FDA.
Sustained Release Formulations Comprising Lamotrigine from
European Patent Specification.
Accelerated aging: Prediction of chemical stability of pharmaceuticals
by KennethC.Waterman, rogerC.Adami et.al.

A dosing algorithm for converting from valproate monotherapy to

lamotrigine
Monotherapy in patients with epilepsy,by MarkE.sale,& Shankar
Natrajan et .al.
The potential role of lamotrigine in Schizophrenia by Charles
H.Large.Elizabeth L.Webster et.al.
Preparation Characterization &Biological Evalution of LamotrigineDextran conjugate by S.K.Srivastab et al.
Clinical Pharmacodynamics & Pharmacokinetics of Antimanic& MoodStabilizing Medication Paul E. keck, Jr, M..D. et.al.

OBJECTIVE

OBJECTIVE:
The primary object of the present project is to address the
aforementioned need in the art and provide for an immediate release
formulation for the administration of Drug from Anti-epileptic category.
The research investigated in the present study is an attempt towards
developing a formulation of Anti-epileptic drug, which has in-vitro dissolution
profile similar to that of Innovator formulation. The patents for uses and
dosage form of Drug A will expire in late future so our target was to develop
a dosage form as that of Innovator product to file an ANDA application
So the present project involves the development of a NON-INFRINGING
formula for an orally administrable immediate release tablet of Anti-epileptic
drug with reproducible and robust process

PLAN OF WORK

PLAN OF WORK:

To achieve this objective, the following plan of work was made.

1) Literature survey.
2) Analysis of innovator-LAMICTAL tablet
3) Preformulation study.
Compatibility study
API characterization
4) Formulation of tablet.
5) Evaluation of tablet
I. Pre-compression Parameters
Loss on drying.
Density analysis.
Compressibility Index and Hausers ratio.
Sieve analysis.

Contd.

II. Post- compression parameters:

Physical appearance
Weight variation
Thickness
Friability
Disintegration test
In-vitro dissolution study
Drug content uniformity test.
7) Comparison with reference listed drug
8) Stability study of the formulation.

FLOW CHART OF PLAN OF WORK

DRUG PROFILE

DRUG PROFILE:
LAMOTRIGINE TABLETS

DRUG DESCRIPTION:

Lamotrigine an AED of the phenyltriazine class, is chemically

unrelated to existing AEDs. Its chemical name is 3,5-diamino-6(2,3-dichlorophenyl)-as-triazine, its molecular formula is C9H7N5Cl2,
and its molecular weight is 256.09. Lamotrigine is a white to pale
cream-colored powder and has a pKa of 5.7. Lamotrigine is very
slightly soluble in water (0.17 mg/mL at 25C) and slightly soluble in
0.1 M HCl (4.1 mg/mL at 25C).

DRUG NAME

Lamotrigine

CHEMICAL NAME

6-(2, 3-dichlorophenyl) 1, 2, 4-triazine-3,

5diamine

MOL.WT

256.09

MOL.FORMULA

C9H7N5Cl2

APPERANCE

A white to slightly yellowish crystalline

powder

SOLUBILITY

Sparingly soluble in DMF, slightly in

methanol &ACETONE, DMSO, very slightly
soluble in water.

LOD

NMT.0.5%W/W

METING POINT

215-219

TOTAL IMPURITY

NMT1.0(BY HPLC)

IDENTIFICATION
PKA.

By.u.v.spectrophototometer. HPLC.
5.7

Solubility of Lamotrigine at different pH

pH
4
Sollubility 1.05
(mg/ml)
Bioavailability
Protein binding
Metabolism
Half life
Excretion

5
0.85

6.8
0.56

7.4
0.48

8
0.4

9
0.37

Pharmacokinetic data
98%
55%
Hepatic (mostly UGT1A4-mediated)
2434 hours (healthy adults)
Renal

Pharmacokinetics
The pharmacokinetics of lamotrigine are quite complicated, with highly
varying half-life and blood plasma levels. Lamotrigine has fewer drug
interactions than many anticonvulsant drugs, although pharmacokinetic
interactions with Sodium Valproate in particular is an indication for blood
monitoring.

Mechanism of action
One proposed mechanism of action for lamotrigine involves an effect on
sodium channels, although this remains to be established in humans. In
vitro pharmacological studies suggest that lamotrigine inhibits voltagesensitive sodium channels, thereby stabilizing neuronal membranes and
consequently modulating presynaptic transmitter release of excitatory
amino acids (for example glutamate and aspartate)

Side effects
Lamotrigine prescribing information has a black box warning about life
threatening skin reactions, including Stevens-Johnson Syndrome and
Toxic Epidermal Necrolysis.

Therapeutic uses:
Epilepsy and seizures
Lamotrigine is approved in the US for the treatment of partial seizures.
Lamotrigine is one of a small number of FDA-approved therapies for
seizures associated with Lennox-Gastaut syndrome, a severe form of
epilepsy.
Lamotrigine is also used as first line therapy for childhood absence
epilepsy.
It use as adjunctive therapy for partial seizures in pediatric patients as
young as 2 years of age.
Lamotrigine approved for maintenance treatment of Bipolar I disorder.
Lamotrigine use as monotherapy for treatment of partial seizures in adult
patients when converting from the anti-epileptic drug valproate (including
valproic acid (Depakene); sodium valproate (Epilim) and divalproex sodium
(Depakote).

Market scenario:
1. Range of similar products available in the Market :- Not Available
2.Orange book details
Active ingredients

; Lamotrigine.

Dosage form , Route ; Tablet , Oral

Proprietory name
Strength

; Glaxo smith klein

; EQ 25 mg ,50mg,
100mg,200mg,Base.

Aplication No.

; NDA 23516

Product No.

; 08954

Approval date

; DEC.1989

RLD

; Yes

Rx / OTC / DISCN

; Rx

EXPERIMENTAL DESIGN

Calibration Curve of Lamotrigine With 0.1N HCl at

210nm

Data for Calibration Curve

Concentrati
on
Absorban
(g/ml)
ce
0

0.109

0.215

0.609

10

1.002

20

2.01

30

2.916

FORMULATION DEVELOPMENT:Our formulation development process for this product

involved the following steps:
Innovator product characterization.

Selection/Characterization of API.

Selection of excipients.

Drug-Excipient Compatibility study.

Manufacturing prototype development (small scale

development trial and finalizing the formula).

Packing development & Stability study of developed

batch.

Optimization of process.

PREFORMULATION STUDIES:
Preformulation testing is the first step in the rational development of dosage form. It
can be defined as an investigation of physical and chemical properties of a drug substance
alone and when combined with excipients. The overall objective of preformulation studies is
to generate a stable and acceptable formulation of Quetiapine tablet for oral use.
The follwings mainly evaluated
Physical observation
Moisture content
Assay
Impurity Quantity

Drug Excipients compatibility study:

Drug excipients compatibility study was carried out by keeping
Lamotrigine alone and along with the excipients in clear transparent glass
vials stoppered with LDPE plugs. The samples were kept at 40C /75% RH
for 4 weeks and evaluated for impurity and appearance at 2 nd week and 4th
week. HPLC method used for analysis was tentative; hence total impurities
are taken into consideration for evaluation. Compatability study by HPLC
was done only for Non innovator listed excipient.

Evaluation criteria:
Lamotrigine is considered compatible with the respective excipients if the total
impurity is less than or equal to 3 folds of API impurities in respective condition.
Condition
S.No

1
2
3
4
5

Drug+ Excipients
L
L + Lactose MH
L + MCC 102

L + Starch RX 1500

L + Mg. stearate

L + SLS

L + Yellow Ferric Oxide

Ratio

Initial Value

40C/75% RH
2nd Week

4th Week

1.0

0.55

0.55

0.55

Appearance

1:5

0.55

0.55

0.55

Appearance

1:5

0.55

0.55

0.55

Appearance

1:0.5

0.55

0.55

0.55

Appearance

1:5

0.55

0.55

0.55

Appearance

1:1

0.55

0.55

0.55

Appearance

1:0.05

0.55

0.55

0.55

Appearance

Water Content Analysis:-

Vial No.

Initial

2nd Week

4th Week

Lamotrigine
(API)

0.09%

0.09%

0.09%

Lamotrigine
(Blend)

2.73%

2.73%

2.73%

Comparative composition of all formulations

Comparative composition of all the designed formulations are shown in the tables
below:
Ingredient

Quantity/ Tablet(mg)

Quantity/ Batch(gm)

Lamotrigine

200.9

100.45

Lactose monohydrate

50

25

MCC BP

133.1

66.5

PVP K30

12

SSG

Magnesium stearate

Total

410

205

Manufacturing Procedure For Various Trials:Procedure:

Calculate &Weigh Lamotrigine based on its potency.

Dispense all other ingredients as per batch formula and sift Lamotrigine,
MCC BP , Lactose monohydrate through # 40
Prepare binder solution using PVP K- 30 in warm water
Prepared granule in RMG by using above shifted mix and binder solution
Dry the above granule at 60 C in dryer and then pass it in 20 # mesh.
Pass the Extragranullar Blend (#40) & Mix to the granules above obtained
for 20min in blender.
Finally SSG, Mg.Sterate(#60) was mixed for 5min.
Compression is carried out using 14x8mm oval shape both side plane
Punch.

Drug Release:Then sample send to ADL for analysis of uncoated tablet.

Different Media used for Dissolution
Time
(min.)

0.1N HCl

0.01N
HCl

pH 4.5
Buffer

pH5.5
Buffer

pH6.8
Buffer

Water

95.57

97.15

87.37

69.05

60.92

66.52

10

95.9

97.83

96.75

86.95

78.42

82.87

15

96.0

97.95

97.38

94.63

87.03

86.38

20

95.93

97.8

97.52

98.43

91.97

89.02

30

95.25

97.85

97.68

100.12

95.63

91.83

45

96.3

98.05

97.47

100.8

97.65

93.25

REFERENCE

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THANK YOU