APPLYING QBD PRINCIPLES

FOR THE DEVELOPMENT OF A

PHARMACEUTICAL DOSAGE
FORM Presented by
Sneha V. Kadu

Under guidance of
Harshal Pawar
CONTENT

AIM

OBJECTIVE

RATIONALE

EXPERIMENTAL WORK

RESULT AND DISCUSSION

 AIM
To prepare Carica papaya leaf extract granules using
QbD approach.
 Objective
• To identify the potential herb useful in dengue &
procurement of its extract.
• To carry out preformulation study.
• To identify CQA and perform risk assessment
• To prepare and optimize CPL extract granules using 3 2

design as a QbD tool

• To evaluate the prepared Granules using standard testing
procedure.
• To carry out stability study of the optimized formulation as
per ICH guidelines.
 Rationale
• QbD is a systemic approach to pharmaceutical development. It means
designing and developing formulations and manufacturing processes to
ensure predefined product quality.
• Dengue is the most common mosquito-borne viral disease in the world. and
is increasing day by day due to climate changing.
• Currently the drugs available in the market have various drawbacks, there is
need to develop a herbal drug which will be less harmful than synthetic one.
• The leaves of Carica papaya (Family: Caricaceae) has been traditionally used
in the treatment of Dengue fever.
• Marketed tablet formulations has poor patient compliance, unpalatable
taste, high dose (3300mg/day) and low bioavailability.
• Granules offer advantages over tablet and powders good flow properties,
faster disintegration and dissolution, greater acceptability in pediatrics and
geriatrics, time and cost required for their manufacture is lesser.
• `
 EXPERIMENTAL WORK
1. Selection and procurement of herbal extract
2. Preformulation
3. Identification of CQA and Risk assessment
4. Preparation and optimiztion of granules using
QbD tool
5. Evaluation of CPL granules
6. Stability studies
 RESULT AND DISCUSSION

Organoleptic Observation Organoleptic

characteristics characteristics
Color Brown colored Color
1. Odor Characteristic
Selection and procurementand Odor extract:-
of herbal
unpleasant
Papaya
Taste plant was selected
Bitter as an antidengue
Taste drug.
2. Organoleptic evaluation:-
 Solvents Solubility
Methanol Sparingly soluble
3.Preformulation:-
Ethanol Slightly soluble
1) Solubility:-
Water Soluble
Acetone Insoluble
Hydroalcoholic solution(ethanol: Freely soluble
Distilled water)1:2

Flow properties Result

Angle of repose 33.12
Bulk density 0.476 gm/ml
2) Flow property :-
Tapped Density 0.555 gm/ml
Compressibility Index 14.23
Hausner’ratio 1.165
 3) pH:-pH of 1%(w/v) solution of CPL extract in water was
found to be 5.7
4) FTIR:-
Peak Assignment
90 (cm-1)
2359.04

2097.68
%T
3380.40 O-H stretch phenols, and

861.25
75 carboxylate acid

924.91

765.77
707.91
1203.63
2935.78 Aliphatic C-H stretch aldehyde,
1648.24

1415.81
1367.59
2909.74
2935.78

60 2359.04 O-C=O stretch aldehyde

1648.24 C=N stretch amide
1152.52

45 1415.81 Aromatic C=C stretch alkene

1078.25

1152.52 C-O stretch

3380.40

1025.21

30
4500 4000 3500 3000 2500 2000 1500 1000 500
1025.21 O-H bend (primary alcohol)
papaya 1/cm
Fig 1: FTIR spectrum of CPL extract
5) Compatability with excipients:-
The CPL extract and Excipients compatibility was determined by
FTIR spectroscopy. The peak obtained in the spectrum of physical
mixture correlates with the peaks of the Drug spectrum. It does not
shows any well defined interaction between CPL extract and the
excipients.
100

%T

7 6 9 .6 3
6 9 1 .5 1
8 8 5 .3 6
80

5 7 3 .8 5
1 2 1 6 .1 7
2 8 1 8 .1 2

1 7 1 9 .6 1
1 6 3 2 .8 1
2 8 8 7 .5 6

1 4 1 0 .9 9
2 9 9 7 .5 1
60

1 0 6 1 .8 6
1 0 3 2 .9 3
3 3 8 8 .1 1

40

4500 4000 3500 3000 2500 2000 1500 1000 500

CPL MIXTURE 9-3-18 1/cm

Figure 2: FTIR of physical mixture

6) UV-Spectroscopy:-

Fig 3-UV spectrum of Carica papaya leaf (CPL) extract

The λmax was found to be 278nm.

• 7) Calibration curve:-
• The calibration curve was plotted using different
concentration values of CPL extract (50 µg/ml - 400 µg/ml)
versus their respective absorbances.
0.7
calibration curve of cpl at 278 nm Conc(µg/ml) Abs
0.6
f(x) = 0 x + 0.01 50 0.087
R² = 1
0.5
100 0.156
0.4
150 0.229
Abs 0.3

0.2
200 0.289
0.1
250 0.405
0
0 50 100 150 200 250 300 350 400 450
300 0.445
350 0.528
Conc
400 0.604
Figure 4: Calibration curve of CPL extract
4. Identification of CQA and Risk assessment:-
QTPP Elements Target Justification
Dosage form Granules Better flow, enhance content
uniformity, easy to
administrate
Dosage design Immediate release Immediate effect
Route of administration Oral Easy to administration for
pediatric & geriatric ,stable
Dosage strength 1100mg As per marketed formulation
reported
Stability At least 1-month shelf- To check potency , helps in the
life at room temperature development of formulation
Drug Physical Attributes Pharmaceutical equivalence requirement: Must meet the
product Identification same compendial or other applicable (quality) standards
quality Assay (i.e., identity, assay, purity, and quality).
attribute Content Uniformity
s Dissolution
Water Content
Microbial Limits
Alternative methods of None None are listed in the
administration reference listed drug
Critical Quality Attributes (CQAs)
Quality Attributes Justification
of the Drug Product
Assay Assay variability will affect safety and efficacy.
Process variables may affect the assay of the drug
product.

Content Uniformity Variability in content uniformity will affect safety

(CU) and efficacy. Both formulation and process
variables impact content uniformity.

Dissolution Failure to meet the dissolution specification can

impact bioavailability. Both formulation and
process variables affect the dissolution profile.

Palatability Palatability influence decisively the patient

compliance and should be appropriate for target
patient population.
5.Preparation of granules
Weighing

40 sieve

Mixing
Binder

Blending (lumpy mass)

16 sieve

Drying
18 sieve

lubrication
Preparation of granules:-
Ingredients Quantity(mg) % Ingredient Role/uses
Drug Extract 1100 22% API
Starch 750 15% Diluent/Disintegrant
Mannitol 500 10% Diluent/ sweetner
Lactose 750 15% Diluent
Dibasic calcium phosphate 1250 25% Diluent
Citric acid 500 10% Taste masker
Methyl paraben 9 0.18% Preservative
Propyl paraben 1 0.02% Preservative
Sucralose 40 0.8% Sweetener
Orange flavour 50 1% Flavour
Magnesium stearate 50 1% lubricant
PVP K 30 in IPA 5% ≈3 ml Binder
Determination of Drug content by uv spectroscopy

• Granule
• Solution:- Hydroalcoholic (1:2)
λ max abs
278 nm 0.5532

• Placebo granule:-
λ max Abs
278 nm 0.1615

Observation:- placebo interference is High.

• Calibration curve of CPL extract
Solution :- 0.1N HCl Conc (ppm) Abs
0.9
0.8 50 0.1002
f(x) = 0 x − 0.02
0.7
0.6
R² = 0.99 100 0.2103
0.5 150 0.3159
0.4
Abs
0.3 200 0.4799
0.2
0.1 250 0.5488
0
0 50 100 150 200 250 300 350 400
300 0.6604
Conc 350 0.809

• Drug content of Cpl granule in 0.1N HCl

λ max Abs
278 nm 0.5128
• Placebo granule
λ max Abs
278 nm 0.0754

Observation:- placebo interference is LOW

• pH dependent solubility
pH Abs
1.2 0.3122
2.1 0.1910
4.5 0.1945
5.5 0.2094
6.8 0.448
7.4 0.2064
 Preparation of granule using QbD tool
• Initial Risk Assessment of the Drug Product Manufacturing Process
Drug Product Process Steps
CQAs
Siffing Mixing Drying Lubrication

Assay Medium Medium High Medium

Content Medium High Medium Medium
Uniformity
Dissolution Low Medium Medium Low
Palatability Low Medium Low Low
Flow Medium Low Medium High

• From the study it was investigated the CQAs of the drug product
Assay
Content uniformity
Dissolution
 
 Process optimization
Mixing Drying
Batch Time(min) time(min) Assay% C.U.%
Factor -2,
1 5 60 90.62 96.22
2 10 90 100.43 108.94
Level – 3,
3 5 30 96.1 97.45 Design -32 (general
4 15 90 100.2 106.65 factorial)
5 15 30 106.13 111.9 Response –Assay , C.U.
6 10 30 99.5 100.66
7 5 90 94.44 98.55
8 10 60 103.73 121.55
9 15 60 93.01 110.19

Batch B.D. T.D. Hausner ratio remark Carr's index remark

1 0.472 0.531 1.125 Good 11.11 Good
2 0.4451 0.4945 1.110 Excellent 09.98 Excellent
3 0.4104 0.4515 1.100 Excellent 09.10 Excellent
4 0.4359 0.4843 1.111 Excellent 09.99 Excellent
5 0.3704 0.4445 1.200 Good 16.67 Fair
6 0.4372 0.4857 1.110 Excellent 04.85 Excellent
7 0.4356 0.4612 1.058 Excellent 05.55 Excellent
8 0.4651 0.491 1.055 Excellent 05.27 Excellent
9 0.4445 0.4938 1.110 Excellent 04.93 Excellent
 Formulation optimization
Table . Initial risk assessment of the formulation variables

Drug Formulation Variables

Product Drug Starch Mannitol Lactose Dibasic Citric Sucralos Magnesium Binder
CQA Sub. calcium acid e Stearate (PVP10
phosphat %)
e
Assay High Low Low Low Low Low Low Low Low
CU High Medium Medium Medium Medium Medium Medium Medium Medium
Dissolutio High High High High High High High High High
n
 Formulation optimization
Batch disintegrant(mg) binder(%) Assay(%) C.U.(%)
1 1000 7.5 90.98 91.57 Factor -2,
2 500 2.5 92.47 91.51 Level – 3,
3 500 5 95.49 94.5 Design -32 (general
4 1000 2.5 99.07 100.07 factorial)
5 1000 5 98.55 97.56 Responce –Assay , C.U.
6 750 5 94.94 95.52
7 500 7.5 96.24 95.52
8 750 7.5 97.21 96.94
9 750 2.5 98.54 99.13
 Dissolution in 0.1N HCL
Disintegrant Binder 5 10 15 30 45 60
Batch (mg) (%) min min min min min min
1 1000 7.5 68.17 74.14 77.75 91.87 96.25 98.11
2 500 2.5 61.83 72.59 75.05 82.09 91.29 98.17
3 500 5 69.96 75.23 75.85 79.93 84.76 94.53
4 1000 2.5 75.35 77.95 81.53 85.08 98.65 99.54
5 1000 5 61.48 67.7 77.99 79.9 82.89 91.26
6 750 5 61.24 72.37 77.3 83.92 87.97 94.11
7 500 7.5 67 70.37 78.5 86.12 87 90.5
8 750 7.5 50.18 51.77 54.1 63.89 71.6 84.7
9 750 2.5 72.89 74 76.6 77.59 78.83 83.29

120 dissolution in 0.1N HCL

100
%CR

80

60

40

20

0
0 10 20 30 40 50 60 70
Min
6.Evaluation of optimized granules:-

Flow properties Result Specified limit Inference

Angle of repose
29.82 25-30 Excellent
Bulk density
0.526gm/ml - -
Tapped Density
0.625gm/ml - -
1) Compressibility
Flow property:- Index
15.84 12-16 Good
Hausner’ratio
1.18 1.12-1.18 Good

Test Result
Drug content 99.06%
Content Uniformity 100.6%
Granular friability 16.66%
2) Evaluation parameters of CPL extract chewable tablet
 3) In Vitro Dissolution Studies in 0.1 N Hydrochloric Acid (HCl).

Time (min) %CR

Dissolution
5 75.35
120

10 77.95 100

15 81.53 80

30 85.08

%CR
60

45 98.65 40

60 99.54 20

0
0 10 20 30 40 50 60 70
Min
Work in progress
• Stability study
• DSC
 Conclusion
• In the present study the Granules of CPL extract were
formulated successfully. The study showed that CPL
Granules can be the promising approach to overcome the
disadvantages of the conventional tablet dosage
formulation currently available in the market. The results
of the evaluation tests for the optimized batch of CPL
Granule batch were found satisfactory.
 REFERNCES
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 Acknowledgment

Its my immense pleasure to thank all those who have contributed

to complete my project.
I would like to thank our Principal Mr. Paraag Gide sir, my guide
Dr. Harshal Pawar,teachers,non teaching staff, my colleagues for
valuable advice and constant support throughout the thesis work.