Product Development Report of Acetriptan Tablet
ABC Pharmaceuticals,
near Neelam Hospital,
Rajpura Punjab,India, 133001
Drug Profile
Product PArameter
Dosage Form
Background
description
Tablet 20mg
This tablet is developed for migraine, toothache, nerve pain. The
intent was to introduce a rapid onset therapy for symptomatic
relief.triptans are a family of drugs used majorly in migraine and
custer headaches. And target the 5-HT1B and 5HT-1D receptor
Molecule Type
Chemical Formula
Small Molecule
C14H21N3O2S
Conditions
Migraine, toothache, nerve pain
Pharmacokinetics
Mechanism of Action
Immediate release
target the 5-HT1B and 5HT-1D receptor cranial blood vessel
constrictor
2.7L/KG
Volume of Distribution
Half Life
1.7 hr for oral
Toxicity
LD50 = 338 mg/kg (oral, mouse); LD50 = 1944 mg/kg (oral, rat)
Protein binding
14-21%
Product Profile
This tablet is developed for migraine treatment.It provides rapid onset of therap for pain
relief.Single tablet per dose is itended.
Dosage Form
Tablet, 20mg
Potency
Tmax 2-4 hours
Dissolution dependent
Appearance
White, biconvex, round
Critical
excipients
Microcrystalline
Cellulose,lactose
monohydrate,croscarmellose
sodium,magnesium stearate,
talc
Impurities
ACE12345 NMT 0.5% other
critical
impurities 0.2% total NMT
1%
Water
NMT 1%
Not critical- not subjected to
hydrolysis
Content Uniformity
As per USP
C
HArdness
5kP- 12kP
NC- depends on dissolution
Friability
NMT 1%
NC
Dissolution
Immediate release(NLT 75%
Very C
30 min)
Disintegration
NMT – 15 minutes
NC
Microbiology
As per USP
Low C
3. Formulation and its Process Selection
Tmax of <2 hrs was decided and achieved using formulation control.Roller cmpaction
granulation was done. Factors like degradation on heat exposure, drying time, poor flow
properties if directly compressed(precluded), compaction time were critical.
Variables and Unit operation
Critical
Quality
Attribute
CQA
Appearance
Identity
Assay
impurity
Content
Uniformity
Formulation Blending1 Rolling
Milling Lubrication Compression
Composition
Compaction
Low
L
L
High
H
L
L
L
L
H
L
L
L
L
H
L
L
L
L
H
H
L
L
L
L
H
L
H
L
H
Dissolution
H
L
H
H
H
H
High risk areas are studied further in the development process for reduction or elimination.
Low risks are marked based on data form prior studies/knowledge.
Mfg. steps- of 200mg single dose tablet of acetriptan- preblending, roller copaction with
MCC,LM,CCS, then milling to make granules before blending with Mg stearate and talc
4.Impact of API attributes on drug
CQA
Part Salt Moistu
icle for re
Size m
Appearanc
e
Identity
Assay
Impurity
Content
H
Unifirmity
Dissolution H
Crystalli
nity
H
Stabili Solven Puri
ty
t
ty
quanti
ty
Solubil
ity
H
H
H
H
H
H
H
Excipient
MCC
LMH
CCS
Mg Stearate
Intra granular
Extra granular
Talc
Morphol
ogy
H
Mg per tablet
80
81.5
6-8
2-4
0.5
Function
Filler/ diluents
F/D
Disintegrant
Lubricant
10
Glidant
H
Dissolution Method- Acetriptan is BCS CLassII drug.solubility is <0.015 mg/mL. from
studies it was seen that aqueous buffers are not efficient in dissolution.(assessed along
buffer ph 1.2- 6.8). Tween media was inadequate due to insoluble excipient coning. Hence
SLS media conc. 0.25 to 5.5w/v was considered.
5. Summary of Formulation Component Studies
Acetriptan Particle Size
Acetriptan Conc.
Croscarmalose level
10- 35 micron
10%
3-4%
35- 40 micron
10%
3-4%
Mg Stearate level
Microcrystalline cellulose
Lactose monohydrate
TAlc
Formulaton process
1-2%
40%
38.75% - 48.75%
5%
1-1.75%
40%
39-40.75
5%
Te API is heat sensitive hence preclude wet granulation.tablet coating was precluded due to
chemical instability during drying.
Ishikawa fish bone diagram for blend uniformity
Production process
MCC,LMH,CCS,Mg
Stearate
Roller Compaction
Blend
+ API
Summary of Scale Up Process
Scale
Amount
Lab
Pilot
Plant
1
50
Blender
Capacity
L
5
200
Blend
Volume Fill
speed rpm Ratio
9
5
40
50
Mlling
Lubrication followed
by compression
Overall Risk Asessment Summary
CQA
Appearanc
e
Identity
Assay
Formulatio
n
Compositio
n
L
Blending
Roller
Compactio
n
Milling
Lubricatio
n
L
L
L
No. of
Control of
revolutions tablet
hardness
L
L
L
L
L
L
L
L
L
L
L
L
L
L
Blend
Uniformit
y
Controlle
d by NIR
L
No issue
within
studied
range
Granule
SA
controlle
d
L
Impurity
Excipient
compatibilit
y
Content
Choice,
Uniformity level and
particle size
of
excipients
Dissolution
Ribbon
Granule
density
SA
controlled controlle
by NIR
d
Control strategy to applied to mitigate highlighted risk
Compressio
n
L
Tablet
weight and
weight
uniformity
L
Tablet
weight and
weight
uniformity
No. of
Hardness
revolutions control
This table summarises the design for acetriptan.
Critical process steps
Unit Operation
Blending
Granulation
Tablt compression
Intermediate
attribtues
Homogenecity
Density
Tablt hardness
Container Closure system
Measurement
method
spectrometery
Spectrometery
5 tablet weight
control measurment
limits
% NMT 50.68-0.81 g/cm3
5-12 Kp
Mean of 12 tab
within 194 – 206 mg
These tablets are packed with 30cc HDPE bottles having cotton wading, heat induction seal
closd with polypropylene caps 10 tablets per bottle and blisters with push through foil
20g/cm2, 6 tablets per blister with a cardboard carton.
Final Specifications for Acetriptan Tablet 20mg
Test
Identification : acetriptan
free base
Impurities : ACE12345
Any other degradation
product
Crushing Resistance
dissolution
Bacteria
Fungi
E.coli
Acceptance Criteria
As per USP reference std
90-110%
Not more than 0.5%
Not more than 2%
5-12kP
80% in 30 min as per USP
acceptance table 1
No more than 10*3/g
Not more than 10*2/g
None
Analytical procedure
IR
HPLC
USP app 2, HPLC