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FUNCTIONALITY ADVANCEMENT OF POORLY SOLUBLE BIOVARIABLE ANTI HYPERTENSIVE DRUG BY SOPHISTICATED SD-FBP TECHNOLOGY AS PER ENHANCED QbD- A Research Article by Shivang Chaudhary & Amit Mukharya

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Lacidipine (LCDP) is a dihydropyridine derivative categorized as an Anti-hypertensive Ca+2 channel blocker belonging to BCS class IV drug with low solubility and low permeability which presents a challenge to the formulation scientists. The development of a solid dispersion by solvent evaporation is a practically viable method to enhance dissolution of LCDP from oral dosage form. Solvent evaporation by Fluidized Bed Process (FBP) was the method of choice for SD as it improves wettability with simultaneous increase in porosity of granules resulting enhanced surface area producing higher dissolution rate and bioavailability of poorly water-soluble drug. Thus, the main object of the present invention is to provide stable pharmaceutical dosage form of LCDP with desired dissolution rate i.e. at least 80% drug release within 45 minutes, without use of disintegrant(s) and/or surfactant(s) or without micronization of the active ingredient per se. One more object of this invention is to provide a sophisticated robust process for the preparation of said pharmaceutical dosage form by Quality by Design (QbD) concept focusing on thorough understanding of the product and process by which it is developed and manufactured along with a knowledge of the risks involved in manufacturing by IRMA & FMEA study of the product with process and how best to mitigate those risks by developing design space with DoE & MVDA with outlined control strategy. Keywords: Lacidipine (LCDP), Solid Dispersion (SD), Fluidized Bed Process (FBP), Critical Quality Attribute (CQA), CPP (Critical Process Parameter), Failure Mode Effective Analysis (FMEA), Design of Experiment (DoE), Quality by Design (QbD).
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International Journal of Research and Development in Pharmacy and Life Sciences
Available online at http//www.ijrdpl.com
June - July, 2012, Vol. 1, No.2, pp. 71-88


ISSN: 2278-0238

Research Article

FUNCTIONALITY ADVANCEMENT OF POORLY SOLUBLE BIOVARIABLE ANTI HYPERTENSIVE
DRUG BY SOPHISTICATED SD-FBP TECHNOLOGY AS PER ENHANCED QbD
Amit Mukharya*, Shivang Chaudhary, Niyaz Mansuri, Arun Kumar Misra
Formulation Development (F&D) Department, Regulated Market, CADILA Pharmaceuticals Limited,
1389, Trasad Road, Dholka, Ahmedabad, Pin: 387 810, Gujarat, India.
*Email for correspondence: amit.mukharya@cadilapharma.co.in
(Received: April 29, 2012; Accepted: May 18, 2012)

ABSTRACT


Lacidipine (LCDP) is a dihydropyridine derivative categorized as an Anti-hypertensive Ca+2 channel blocker belonging to BCS class IV drug with low
solubility and low permeability which presents a challenge to the formulation scientists. The development of a solid dispersion by solvent evaporation is a practically
viable method to enhance dissolution of LCDP from oral dosage form. Solvent evaporation by Fluidized Bed Process (FBP) was the method of choice for SD as it
improves wettability with simultaneous increase in porosity of granules resulting enhanced surface area producing higher dissolution rate and bioavailability of
poorly water-soluble drug. Thus, the main object of the present invention is to provide stable pharmaceutical dosage form of LCDP with desired dissolution rate i.e.
at least 80% drug release within 45 minutes, without use of disintegrant(s) and/or surfactant(s) or without micronization of the active ingredient per se. One more
object of this invention is to provide a sophisticated robust process for the preparation of said pharmaceutical dosage form by Quality by Design (QbD) concept
focusing on thorough understanding of the product and process by which it is developed and manufactured along with a knowledge of the risks involved in
manufacturing by IRMA & FMEA study of the product with process and how best to mitigate those risks by developing design space with DoE & MVDA with outlined
control strategy.

Keywords: Lacidipine (LCDP), Solid Dispersion (SD), Fluidized Bed Process (FBP), Critical Quality Attribute (CQA), CPP (Critical Process Parameter),
Failure Mode Effective Analysis (FMEA), Design of Experiment (DoE), Quality by Design (QbD).

INTRODUCTION
Lacidipine (LCDP) is chemically a "1, 4 - Dihydropyridine
pharmaceutics (BCS) class IV drug with low solubility and low
derivative", which is pharmacologically a "Calcium channel
permeability3. The formulation of poorly soluble drugs for
blocker" used as an anti-hypertensive drug. LCDP works by
oral delivery presents a challenge to the formulation
blocking 'calcium channels' in the muscle cells those are found
scientists. When an active agent is administered orally, it
in the arterial walls. Calcium is needed by muscle cells in
must first dissolve in gastric and/or intestinal fluids before it
order for them to contract; so by depriving them of calcium,
permeate the membranes of the GI tract to reach systemic
LCDP causes the muscle cells to relax. Relaxing and widening
circulation. Therefore, a drug with poor aqueous solubility
of the small arteries decreases the resistance that the heart
will typically exhibit dissolution rate limited absorption, and
has to push against in order to pump the blood around the
a drug with poor membrane permeability will typically
body, which reduces the pressure within the blood vessels1.
exhibit permeation rate limited absorption. In case of poorly
LCDP is completely absorbed from the GIT providing its
water soluble drugs, dissolution may be the rate-limiting step
complete dissolution2. But the quandary is that LCDP is a Bio-
in the process of drug absorption. Drug with poor water -
(c)SRDE Group, All Rights Reserved. Int. J. Res. Dev. Pharm. L. Sci. 71



Amit Mukharya et. al., June-July, 2012, 1(2), 71-88

solubility have been shown to be unpredictably and slowly
size reduction. In case of solid dispersion, drug is dispersed in
absorbed compared with drugs of higher solubility4. Among
the hydrophilic matrix with enhanced wettability & porosity7.
the relevant prior arts in this field, WO1995/08987
When the solid dispersion is exposed to aqueous media, the
discloses compositions comprising one or more 1, 4
carrier dissolves and the drug releases as fine colloidal
dihydropyridine derivatives; a carrier such as water-soluble
particles. The resulting enhanced surface area produces
derivatives of saccharides; a "disintegrant" selected from
higher dissolution rate and bioavailability of poorly water-
polacrilin potassium, sodium starch glycolate and/or cross-
soluble drugs8-10. The main object of the present invention is
linked carboxy methylcellulose and "surfactant" selected
to provide pharmaceutical dosage form of lacidipine with
from sodium lauryl sulfate, poloxamers and/or higher fatty
desired dissolution rate (at least 80% drug release within
acids
polyoxyethylene
sorbitan
ester5.
Whereas,
45 minutes), without the use of disintegrant(s) and/or
WO2006/113309
discloses
the
preparation
of
surfactant(s) or without micronization of the active ingredient
agglomerated particles of LCDP having smaller particle
per se. Another object of this invention is to provide a
size6. All the above mentioned prior art disclosed
sophisticated robust process for the preparation of said
pharmaceutical composition comprising of lacidipine by using
pharmaceutical dosage form with Quality by Design (QbD)
surfactant(s) and/or disintegrant(s) or micronized lacidipine.
concept focusing on thorough understanding of the product
Thus, it would be significant improvement in the art to
and process by which it is developed and manufactured
provide pharmaceutical dosage form of lacidipine without
along with a knowledge of the risks involved in
the use of surfactant(s) and/or disintegrant(s) or without
manufacturing the product and how best to mitigate those
micronization of Lacidipine per se. The development of solid
risks related to product quality and/or performance.
dispersion is a practically viable method to enhance

bioavailability of poorly water-soluble drug without salt

formation, solubilization by co-solvents



MATERIALS & METHODS

Materials

Intragranular Ingredients [Manufacturer/supplier]

Application
Lacidipine BP

[Cadila Pharmaceuticals limited, India]
Active Pharmaceutical Ingredient (API)


Plasdone(R) K29/32 (Polyvinyl Pyrrolidone)
[ISP Technologies, ]
Carrier cum Binder


Pharmatose(R) 200M (Lactose Monohydrate)
[DMV International]


Diluent cum substrate

Absolute Alcohol (Ethanol 99.6%v/v)


Solvent cum
[CVKUSML, India]

Granulating Agent


Extragranular Ingredients

Pharmatose(R) DCL11 (Lactose Spray Dried)

[DMV International]
Diluent cum flow promoter cum disintegrant

Magnesium Stearate (Vegetable grade)

EXPERIMENTAL METHODS
Lubricant
[Ferro Synpro]
drugs overcoming the limitations of previous approaches such
Formulation development (Solid Dispersion)
as
F ilsa
m l t
C foor
atm
inagti on, solubilization by co-solvents and particle

Opadry White (A premix powder of Hydroxy Propyl Methyl

HExp
PM e
C r im
as en
a tfa
il l
m M
f et
or h
mo
i d
n s
g
Cellulose (HPMC) Polyethylene glycol & Titanium Dioxide (TiO2))
agent & TiO2 as a opacifying agent
[Colorcon Asia limited]

(c)SRDE Group, All Rights Reserved. Int. J. Res. Dev. Pharm. L. Sci. 72



Amit Mukharya et. al., June-July, 2012, 1(2), 71-88


Figure 1 Schematic representation of SD-FBP Technology
Formulation development (Solid Dispersion)
The term Solid Dispersion (SD) is defined as "the dispersion
formulators. In this solvent-based spray drying process, PVP
of one or more active ingredients in an inert carrier or matrix
was selected as a carrier for SD, as it forms homogenous
(hydrophilic) at solid state, prepared by the melting (fusion),
glass solution, a glassy system in which a solute dissolves in a
solvent evaporation or melting-solvent method". Solid
glassy solvent. The glassy or vitreous state is usually obtained
dispersion refers to a group of solid products consisting of at
by an abrupt quenching of melt, which is characterized by
least two different components, generally a hydrophilic
transparency & brittleness below the glass transition
matrix and a hydrophobic drug. Among all methods, solvent
temperature Tg. i.e. a function of homogenously mixed SD
evaporation by Fluidized Bed Process (FBP) was the method
composition12. The next challenge was to mix both drug &
of choice for SD as it improves wettability with simultaneous
carrier in one common solvent, which is difficult when they
increase in porosity of granules. Because of the simplicity of
differ in polarity. Use of water to dissolve both drug &
manufacturing and scale up processes, the popularity of the
carrier requires evaporation of tremendous amounts of
solid dispersion systems to solve difficult bioavailability issues
solvent during Fluidized Bed Process; making the process
with respect to poorly water-soluble drugs will grow rapidly.
expensive, time consuming & impractical. Chloroform13
Moreover it also decreases the crystalline structure of drug &
(Betageri & Makarla, 1995) & Dichloromethane14 (Damian
promotes its conversion in to more soluble amorphous form11.
et al. 2002) may be used to dissolve both drug & carrier
The first step in this method includes the formation of clear
PVP simultaneously, but according to ICH guidelines (Q3C)15,
solution containing mixture of the drug i.e. LCDP and carrier
these are classified under class I (most toxic) solvents.
i.e. Poly Vinyl Pyrrolidone (PVP), dissolved in a common
Therefore, use of these solvents is unacceptable &
solvent and second step involves the removal of solvent
impractical because the amount of residual solvent present in
resulting the formation of solid dispersion. This enables to
SD after drying has to be below 1500 ppm. Thus, in this
produce a solid solution of the drug in the highly water
study Ethanol (commonly available ICH Class III solvent) 16
soluble carrier. Selection of carrier for SD matrix & common
was selected as it shows higher solubility of drug as well as
solvent for drug & carrier were two challenges in front of
carrier for solid dispersion.
(c)SRDE Group, All Rights Reserved. Int. J. Res. Dev. Pharm. L. Sci. 73



Amit Mukharya et. al., June-July, 2012, 1(2), 71-88

Table 1 Compression parameters
No
Compression parameters
In House Specification Limits
1
Target Weight.
300 mg
2
Thickness
5.1 mm 0.1 mm (5.0 mm to 5.2 mm)
3
Hardness
40 to 80 Newton
4
Friability
Not more than 0.5 % w/w
5
Disintegration Time
Not more than 15 minutes

For drug: carrier solution preparation; LCDP was
granular lactose & extra granular lactose was optimized to
dissolved in ethanol (99.6%v/v) with stirring at slow speed
attain desired disintegration & corresponding dissolution
until a clear solution was obtained. In this solution, PVP-
profile as mentioned in formulation No. F7 to F9. This
K29/32 was slowly added and stirring was continued until a
formulation was sticky in its physical nature due to higher
clear yellow colored solution was obtained. To carry out
proportion of PVP, thus level of lubricant in formulation was
solvent evaporation method, fluidized bed processor (Pam-
optimized depending upon desired flow property which
Glatt(R)) was utilized. In fluidized bed granulation, 40# sifted
would not affect desired dissolution profile as mentioned in
Lactose Monohydrate (Pharmatose-200M) was loaded in
Formulation No. F10 to F12. Film coating was required to
fluidized bed processor & granulated by spraying of drug
protect core tablet from direct exposure of temperature,
carrier solution for moistening of lactose powder substrate
light & moisture. Finally, essential %weight gain per tablet
using top spray mechanics on fluidized bed as represented in
was optimized as per optimum film strength without affecting
Figure 1. Inlet, Product & outlet temperatures was set at
desired dissolution profile as mentioned in Formulation No.
5510C, 3510C & 3010C respectively; while Film
F13 to F15. All formulations optimization are summarized in
Coating was carried out for protection of core from heat,
Table 3. Peristaltic pump RPM, spray rate and atomization
light & moisture. For film-coating, Opadry(R) White was
air pressure were recorded intermittently in every 10
added in purified water with continuously stirring for 45
minutes. After completion of Granulation, Fluidized bed
minutes until a uniform suspension is formed. Coating was
drying was performed in the same FBP at inlet temperature
carried out with this suspension in 24" Auto coater
of 40 to 55C, until desired LOD i.e 1.5 to 2.5% w/w at
(Ganscoater(R)) at parameters mentioned in Table 2 until
105C was achieved. Dried granules were sifted through
desired weight gain was achieved.
20# screen in mechanical sifter. Dried sifted granules were
In formulation optimization study, first LCDP to PVP
mixed in double cone blender for 5 minutes at 102 RPM
ratio was optimized for SD depending upon desired
with 40# pre-sifted spray dried Lactose (Pharmatose DCL-
solubility & dissolution profile as mentioned in formulation
11) & lubricated with 60# pre-sifted magnesium stearate.
No. F1 to F6 i.e. from 1:4 to 1:14. Intra granular lactose
Lubricated granules were compressed using 12.7 X 7.1 mm
(Pharmatose(R) 200M) functions as a diluent, while extra
oval shaped punches embossed with "C" & "P" on each side
granular lactose (Pharmatose(R) DCL 11) promotes
of break line with below mentioned parameters in Table 1 in
disintegration by wicking mechanism17. Thus, ratio of intra
16 station compression machine (RIMEK(R)), India
Table 2 Film Coating Parameters
No.
Coating Parameters
In House Specification Limits
1
Inlet temp
55 10C
2
Outlet temp
50 10C
3
Bed temperature
40 5C
4
Pan Speed
2-8 RPM
5
Peristaltic pump speed
2-10 RPM
6
Compressed air pressure
2 - 3 kg /cm2


(c)SRDE Group, All Rights Reserved. Int. J. Res. Dev. Pharm. L. Sci. 74



Amit Mukharya et. al., June-July, 2012, 1(2), 71-88


Table 3A. Drug : Carrier ratio optimization for LCDP formulation


F1
F2
F3
F4
F5
F6
Drug : Carrier Ratio
1:04
1:06
1:08
1:10
1:12
1:14
Intragranular (IG)
Lacidipine
4
4
4
4
4
4
Plasdone K29/32
16
24
32
40
48
56
Pharmatose 200M
280
272
264
256
248
240
Unit Weight of core tablet (in mg.)
300
300
300
300
300
300




Table 3B. Intra to Extra-granular Lactose ratio optimization for LCDP formulation


F7
F8
F9
Drug : Carrier Ratio
1:10
1:10
1:10
Optimization of Intra to Extragranular
(90:10)
(80:20)
(70:30)
Lactose ratio
Intragranular (IG)
Lacidipine
4
4
4
Plasdone K29/32
40
40
40
Pharmatose 200M
230.4
204.8
179.2
Extragranular (EG)
Pharmatose DCL11
25.6
51.2
76.8
Unit Weight of core tablet (in mg.)
300
300
300




Table 3C. Lubricant level& % weight gain in coating optimization for LCDP formulation


F10
F11
F12
F13
F14
F15
Drug : Carrier Ratio
1:10
1:10
1:10
1:10
1:10
1:10
Intragranular to Extragranular Lactose ratio (80:20)
(80:20)
(80:20)
(80:20)
(80:20)
(80:20)
Optimization of Level of Lubricant
0.25%
0.50%
1.00%
0.25%
0.25%
0.25%
Intragranular (IG)
Lacidipine
4
4
4
4
4
4
Plasdone K29/32
40
40
40
40
40
40
Pharmatose 200M
204.8
204.8
204.8
204.8
204.8
204.8
Extragranular (EG)
Pharmatose DCL11
50.45
49.7
48.2
50.45
50.45
50.45
Magnesium Stearate
0.75
1.5
3
0.75
0.75
0.75
Unit Weight of core tablet (in mg.)
300
300
300
300
300
300
%Weight gain in film coating
1%
2%
3%
Unit Weight of coated tablet (in mg.)
303
306
309


(c)SRDE Group, All Rights Reserved. Int. J. Res. Dev. Pharm. L. Sci. 75



Amit Mukharya et. al., June-July, 2012, 1(2), 71-88

Table 4. Definition of QTTP with reference to DP CQAs
DP CQAs
Quality Target Product Profile (QTPP)
White to off white, oval shaped, coated tablets having embossed with "C" & "P" on one side with break
Appearance
line on both side.
Assay
95% to 105% of the label claim
Impurity A: NMT 0.5%; Impurity B: NMT 2.0%;
Impurities
Any Other Impurity: NMT 0.5%;
Total Impurities: 2.5%
Acceptance Value: NMT 15.0
Content Uniformity
RSD : NMT 5.0%
Disintegration
Not more than 15 minutes
Dissolution
Not less than 75% (Q) of the labeled amount dissolved in 45 minutes

Process Optimization (Fluidized Bed Granulation) by QbD
product with robust process by enhanced QbD approach
According to ICH Q8 Guideline "Quality cannot be tested
included following steps in succession:
into products; quality should be built-in by design". In all
Definition of Quality Target Product Profile (QTPP):
cases, the product should be designed to meet patients'
First, Quality Target Product Profile (QTPP) was identified as
needs and the intended product performance. A more
it relates to quality, safety and efficacy, considering e.g., the
systematic enhanced QbD approach to development includes
route of administration, dosage forms, bioavailability and
incorporation of prior knowledge, results of studies using
stability
as
represented
in
Table
4.
design of experiments (ICH Q8)18, use of quality risk
Identification of API & Formulation Critical quality Attribute
management (ICH Q9)19 and use of knowledge management
(CQAs): Potential drug product CQAs derived from QTPP &
(ICH Q10)20 throughout the lifecycle of the product. A
prior knowledge were used for product and process
greater understanding of the product and its manufacturing
development. Thus, CQA of the AP) and Excipients having an
process created a basis for more flexible regulatory
impact on product quality were identified and summarized in
approaches. Thus, for pharmaceutical development of stable
Table 5 to study & control those product characteristic
Table 5 Identification of API & Excipient CQAs impact on DP CQAs

API CQAs
Particle
Moisture
Solvent
Crystal
Salt
DP CQAs
Solubility
Stability
Purity
size
content
content
linity
form
Appearance
Low
Low
Low
Low
Low
Low
Low
Low
Assay
Low
Low
Low
Low
Low
Low
High
High
Impurities
Low
High
High
Low
Low
Low
High
High
Content Uniformity
High
Low
Low
Low
Low
Low
Low
Low
Disintegration
High
Low
Low
High
High
High
Low
Low
Dissolution
High
Low
Low
High
High
High
Low
Low


EXCIPIENT CQAs
Plasdone(R)
Pharmatose(R)
Absolute
Pharmatose(R)
Magnesium
K29/32 -
200M
Alcohol -
DCL11
Stearate -
Opadry
DP CQAs
Polyvinyl
-Lactose
Ethanol
-Lactose Spray
Vegetable
White
Pyrrolidone
Monohydrate
99.6%v/v
Dried
grade)
Appearance
Low
Low
Low
High
High
High
Assay
Low
Low
Low
Low
Low
Low
Impurities
Low
Low
High
Low
Low
Low
Content Uniformity
Low
High
Low
Low
Low
Low
Disintegration
High
Low
Low
High
High
Low
Dissolution
High
Low
Low
High
High
Low



(c)SRDE Group, All Rights Reserved. Int. J. Res. Dev. Pharm. L. Sci. 76



Amit Mukharya et. al., June-July, 2012, 1(2), 71-88



Quality Risk analysis of CPPs by IRMA & FMEA: Risk
summarized in Table 6A & Failure mode effective analysis as
assessment is a valuable science-based process used in
summarized in Table 6B were concisely used to identify and
Quality Risk Management (QRM) (ICH Q9) that aided in
rank parameters with potential to have an impact on DP
identifying which material attributes and process parameters
CQAs, based on prior knowledge and initial experimental
potentially had an effect on product CQAs. Risk assessment
data. This list was refined further through experimentation to
was typically performed early in the development stage &
determine the significance of individual variables and
was repeated as more information & greater knowledge
potential interactions through a combination of DOEs,
was obtained. Risk assessment tools i.e. matrix analysis as
mathematical models or studies that lead to mechanistic
understanding to achieve a higher level of process

mechanistic understanding.
Table 6A. Initial Risk based Matrix Analysis for CPPs (IRMA)

UNIT OPERATIONS RELATING TO CPPS
DP CQAs
FB Process
Sizing
Blending
Compression
Film Coating
Appearance
Low
High
Low
High
High
Assay
High
Low
Low
Low
Low
Impurities
High
Low
Low
Low
High
Content
High
High
Low
Low
Low
Uniformity
Disintegration
High
Low
High
High
Low
Dissolution
High
Low
High
High
Low



questions. In doing an effective risk assessment, the
As an aid to clearly defining the risk(s) for risk assessment
robustness of the data set is important because it determines
purposes, three fundamental questions are often helpful:
the quality of the output. Revealing assumptions and
1.
What might go wrong?
reasonable sources of uncertainty will enhance confidence in
2.
What is the likelihood (probability) it will go wrong?
this output and/or help identify its limitations. Uncertainty is
3.
What are the consequences (severity)?
due to combination of incomplete knowledge about a
Risk identification is a systematic use of information to
process and its expected or unexpected variability. Typical
identify hazards referring to the risk question or problem
sources of uncertainty include gaps in knowledge gaps in
description. Information can include historical data,
pharmaceutical science and process understanding, sources
theoretical analysis, informed opinions, and the concerns of
of harm (e.g., failure modes of a process, sources of
stakeholders. Risk identification addresses the "What might
variability), and probability of detection of problems. The
go wrong?" question, including identifying the possible
output of a risk assessment is either a quantitative estimate
consequences. This provides the basis for further steps in the
of risk or a qualitative description of a range of risk. When
quality risk management process. Risk analysis is the
risk is expressed quantitatively, a numerical probability is
estimation of the risk associated with the identified hazards.
used. Alternatively, risk can be expressed using qualitative
It is the qualitative or quantitative process of linking the
descriptors, such as "high", "medium", or "low", which should
likelihood of occurrence and severity of harms. In some risk
be defined in as much detail as possible. Sometimes a "risk
management tools, the ability to detect the harm
score" is used to further define descriptors in risk ranking. In
(detectability) also factors in the estimation of risk. Risk
quantitative risk assessments, a risk estimate provides the
evaluation compares the identified and analyzed risk
likelihood of a specific consequence, given a set of risk-
against given risk criteria. Risk evaluations consider the
generating circumstances. Thus, quantitative risk estimation is
strength of evidence for all three of the fundamental -
useful for one particular consequence at a time.

(c)SRDE Group, All Rights Reserved. Int. J. Res. Dev. Pharm. L. Sci. 77



Amit Mukharya et. al., June-July, 2012, 1(2), 71-88

Table 6B. Failure Mode Effective Analysis (FMEA)
Unit Operations
Critical Process Critical
Effect on DP CQAs
S
e

P
D
(
R
r
e
R
i
Parameter
Event
with respect to QTPP
v
o
P
sk
e
b
t
e
c

N

(CPPs)
r
i

a
=
P
t
t
y
b
a
r

i
b
S
i
(
l
*P
o
S
i
t

i
l

r
)
y
i
i


*D
t
(
t
y

y
P


)
(
)
N

D

)
o


Very High
Higher rate of
Inlet/ Product/
degradation = Assay
Temperature
03 02 01
06
Exhaust
& Impurity profile
Temperature
affected
Fluidized Bed
Larger granules =
Process
Higher
Spraying rate
Disintegration &
03 03 03
27
(Granulation
Rate
Dissolution affected
& Drying)
Uneven distribution of
Atomizing air
Lower
Drug binder solution =
02 02 02
08
pressure
Pressure
Content Uniformity
affected
Total RPN for FBP
41
Increase in
Sifting
Larger granules =
02 02 01
04
Sieve No.
Dissolution affected
Sizing
Uneven PSD = Content
Increase in
Milling
Uniformity affected
02 02 01
04
Screen size
Total RPN for Sizing
08
Blender RPM
Higher RPM
Increase No. of total
01 02 01
02
Revolutions =
Blending
Disintegration &
Blending Time
Longer Time
Dissolution affected
01 02 01
02
Total RPN for Blending
04
High
Weight Variation =
Press Speed
02 02 02
04
Speed
Content Uniformity
Compression
Thickness
Higher
Disintegration=
03 03 02
18
adjustment
Hardness
Dissolution affected
Total RPN for Compression
22
Very High
Impurity profile
Temperature
01 02 01
02
Temperature
affected
Higher
Film Coating
Spraying rate
Appearance affected
02 02 01
04
Rate
Atomizing air
Lower pressure
Appearance affected
01 02 01
02
pressure
Total RPN for Film-Coating
08

Severity
Score
Probability
Score
Minor
01
Very Unlikely
01
Major
02
Remote
02
Critical
03
Occasional
03
Catastrophic
04
Probable
04
Frequent
05

Total Risk Priority Number (RPN) more than 10 seek critical attention for DoE for possible failure

(c)SRDE Group, All Rights Reserved. Int. J. Res. Dev. Pharm. L. Sci. 78



Amit Mukharya et. al., June-July, 2012, 1(2), 71-88



Selection of appropriate manufacturing process by DoE &
granule size & tablet hardness) were analyzed for
MVDA: Depending on IRMA & FMEA results, process
establishment of Design Space (DS) to design, analyze and
understanding experiments [Design of Experiments (DoE) &
control manufacturing through timely measurements of critical
Multi-Variate Data Analysis (MVDA)] were developed for
quality and performance attributes of raw and in-process
FBP & Compression having higher risk priorities i.e. more than
materials, which were modeled out with the goal of ensuring
10. The effect of CPPs on product quality (e.g. average
product quality.

Table 7. Design of Experiments (DoEs) & Multi-Variate Data Analysis (MVDA)


(a) For Fluidized Bed Process (b) for compression.

(a) DoE & MVDA for Fluidized Bed Process
Run Spraying rate
Atomizing Air Pressure (bar)
Average Granule size:
(in gm/min)
D50 (um)
1
3.00
1.50
375
2
4.00
1.50
395
3
5.00
1.50
710
4
3.00
2.00
360
5
4.00
2.00
380
6
5.00
2.00
630
7
3.00
2.50
350
8
4.00
2.50
370
9
5.00
2.50
615
(b) DoE & MVDA for Compression
Run Adjusted Thickness

Press Speed
Tablet Hardness

(in mm)
(in RPM)
(in Newton)
1
5.00
10
69
2
5.10
10
64
3
5.20
10
56
4
5.00
15
66
5
5.10
15
61
6
5.20
15
54
7
5.00
20
65
8
5.10
20
61
9
5.20
20
53



Outline of pertinent control strategy: Finally pertinent Control
bottle with child resistant closure containing cotton and silica
Strategies were outlined for ensuring consistent final product
gel 2) ALU-ALU 10's Blister; Final packed tablets were
quality & process robustness i.e. ability of process to tolerate
charged at different storage condition of Temperature (c)
variability of materials and changes of the process and
and Relative humidity (%RH) for long term (real time),
equipment without any negative impact on product quality.
Intermediate and Accelerated stability testing. Stability
Packaging Materialistic Study with Accelerated Stability
samples on pre-decided time points were withdrawn from
Optimized formulation prepared by optimized process
stability chamber and analyzed for Assay, Related
having desired QTPP was packed in two different types of
substances, Disintegration & Dissolution by methods specified
packaging material 1) HDPE (High Density Poly Ethylene)
in British Pharmacopoeia.



(c)SRDE Group, All Rights Reserved. Int. J. Res. Dev. Pharm. L. Sci. 79



Amit Mukharya et. al., June-July, 2012, 1(2), 71-88


RESULTS & DISCUSSION
Formulation Optimization with desired disintegration & dissolution profile
Table 8A. Drug: carrier ratio optimization in LCDP Formulation

F1
F2
F3
F4
F5
F6
Drug : Carrier Ratio
1:04
1:06
1:08
1:10
1:12
1:14
Assay
97.1
97.4
98.6
99.2
99.2
99.2
Related Substances (Impurities)
Impurity A
0.31
0.30
0.30
0.31
0.31
0.31
Impurity B
0.22
0.22
0.20
0.22
0.22
0.21
Unknown Max
0.23
0.23
0.23
0.20
0.20
0.19
Total Impurities
0.76
0.75
0.73
0.72
0.72
0.70
Disintgration Time
N=6 (Min:Sec)
30:00
23:10
17:50
12:00
11:30
11:10
Dissolution Profile (N=12) in BP official media
10 min
29
33
39
40
42
46
15 min
31
49
56
65
66
68
20 min
42
58
67
76
78
80
30 min
56
71
87
95
96
99
45 min
71
85
93
99
99
100
60 min
94
96
99
100
100
101

Table 8B. Intra to Extra-granular Lactose ratio optimization in LCDP Formulation

F7
F8
F9
Drug : Carrier Ratio
1:10
1:10
1:10
Optimization of
Intragranular to
Extragranular Lactose

(90:10)
(80:20)
(70:30)
Assay
99.2
99.2
98.8
Related Substances (Impurities)
Impurity A
0.30
0.31
0.31
Impurity B
0.20
0.22
0.27
Unknown Max
0.18
0.20
0.22
Total Impurities
0.70
0.72
0.90
Disintgration Time
N=6 (Min:Sec)
12:10
9:40
8:20
Dissolution Profile (N=12) in BP official media
10 min
39
41
44
15 min
62
66
68
20 min
73
76
77
30 min
93
96
98
45 min
96
98
100
60 min
99
101
100




(c)SRDE Group, All Rights Reserved. Int. J. Res. Dev. Pharm. L. Sci. 80


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