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Formulation by design: An approach to designing better drug delivery systems

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 Article

Formulation by Design: An approach to designing

better Drug Delivery Systems
Subhashis Debnath*, M.N.L. Aishwarya, M.Niranajan Babu
Department of Pharmaceutics, Seven Hills College of Pharmacy, Tirupati.

Abstract:
Formulation by design (FbD) is a holistic concept of formulation development aiming to design more efficacious, safe,
economical and patient-compliant Drug Delivery System (DDS). With the recent regulatory quality initiatives, implementation
of FbD has now become an integral part of drug industry and academic research. This review article describes these
principles of design of experiment (DoE) and quality by design (QbD) as applicable to drug delivery development using a
more apt expression, that is, ‘formulation by design’. It also involves the various applications of QbD, FbD methodology,
Design of Experiments with its types along with optimization of factors and software designs respectively.
Key Words: Patient-compliant, Formulation by Design (FbD), Quality by Design (QbD), Design of Experiment (DoE).

Introduction essentially involves studying the influence of one variable at a

Over the past few decades, the domain of drug formulations
has metamorphosed from the conventional tablets and capsules to
advanced and intricate drug delivery systems (DDS), both temporal
and spatial. Formulation development of the oral DDS cannot be
adequately accomplished using the traditional ‘trial and error’
approaches of one variable at a time. This calls for the adoption of
rational, systematized, efficient and cost-efficient strategies using
‘design of experiments (DoE)’. The recent regulatory guidelines
issued by the key federal agencies to practice ‘quality by design
(QbD)’ paradigms have coerced researchers in industrial milieu,
in particular, to use experimental designs during drug product
development [1].
The pharmaceutical Quality by Design (QbD) is a systematic
approach to development that begins with predefined objectives
and emphasizes product and process understanding and process
control, based on sound science and quality risk management.
Quality by Design (QbD) is emerging to enhance the assurance of
safe, effective drug supply to the consumer and also offers promise
to significantly improve manufacturing quality performance. Hence,
QbD is related to product performance [1, 2].
The traditional approach of optimizing a formulation or process
time (OVAT), while keeping all others as constant. Using this OVAT
approach, the solution of a specific challenging property can be
achieved somehow, but attainment of the true optimal composi-
tion or process can never be guaranteed [2]. This may ostensibly be
ascribed to the presence of interactions, that is, the influence of
one or more variableson others. The final product though may be
satisfactory, but mostly sub-optimal, as a better formulation might
still prevail for the studied conditions. Design of experiments (DoE),
on the other hand, is an optimization technique meant for products
and/or processes, developed to evaluate all the potential factors
simultaneously, systematically and speedily. Its implementation
invariably encompasses the use of statistical experimental designs,
generation of mathematical equations and graphic outcomes,
portraying a complete picture of variation of the response(s) as a
function of the factor(s), which can never be obtained using the
traditional OVAT approach [3-7]. Table 1 succinctly enumerates the
merits of FbD over the OVAT methodology.
FbD Terminology:
Specific terminology, both technical and otherwise, is usually
used during FbD practice. To facilitate better clarity of precepts of
FbD of oral DDS, important terms have been compiled in Table 2

Table 1: Comparison of OVAT and FbD methodology

Attribute OVAT FbD
Choice of optimum May result only in sub-optimal Yields the best possible formulation
formulation solutions
Interaction among Inept to reveal possible interactions Estimates any synergistic or antagonistic interaction among
the ingredients constituents
Scale-up and post- Very difficult to design formulation Changes in the optimized formulation can easily be incorporated, as
approval changes slightly differing from the desired all response variables are quantitatively governed by a set of input
formulation, especially beyond Level II variables
Resource economics Highly resource-intensive, as it leads to Economical, as it furnishes information on product/process
unnecessary runs and batches performance using minimal trials
Time economics Highly time-consuming, as each Can simulate the product or process behavior using model
product is individually evaluated for its equations
performance

*E-mail: shcp7@yahoo.com

Pharma Times - Vol. 50 - No. 08 - August 2018 9

 Table 2: Vital terminology used during FbD of drug delivery
Optimize Make as perfect, effective or functional
as possible
Optimization Implementation of systematic approaches
to achieve ‘the best’ combination of
product and/or process characteristics
under a given set of conditions using FbD
and computers
Independent Input variables, which are directly under
variables the control of the product development
scientist
Quantitative Variables that can take numeric values
variables
Categorical Qualitative variables which cannot be
variables quantified
Runs or trials Experiments conducted according to the
selected experimental design
Factors Independent variables, which tend
to influence the product/process
characteristics or output of the process
Design matrix Layout of experimental runs in matrix form
as per experimental design
Knowledge space Scientific elements to be considered
and explored on the basis of previous
knowledge as product attributes and
process parameters
Design space Multidimensional combination and
interaction of input variables and process
parameters, demonstrated to provide
quality assurance
Control space Domain of design space selected for
detailed controlled strategy
Levels Values assigned to a factor
Constraints Restrictions imposed on the factor levels
Response Characteristics of the finished drug
variables product or the in-process material
Critical quality Parameters ranging within appropriate
attributes limits, which ensure the desired product
quality
Critical process Independent process parameters most
parameters likely to affect the quality attributes of a
product or intermediates
Critical Formulation parameters affecting critical
formulation quality attributes
attributes
Effect The magnitude of the change in response
caused by varying the factor level(s)
Main effect The effect of a factor averaged over all the
levels of other factors
Interaction Lack of additivity of factor effects
Antagonism Undesired negative change due to
interaction among factors
Synergism Desired positive change due to interaction
between factors
Pharma Times - Vol. 50 - No. 08 - August 2018 10
Nuisance factors Uncontrollable factors which complicate
the estimation of main effect or interac-
tions
Orthogonality A condition where the estimated effects
are due to the main factor of interest, but
independent of interactions
Confounding Lack of orthogonality
Resolution The measure of the degree of
confounding
Coding (or Process of transforming a natural variable
normalization) into a non-dimensional coded variable
Factor space Dimensional space defined by the coded
variables
Experimental Part of the factor space, investigated
domain experimentally for optimization
Blocks A set of relatively homogenous experimen-
tal conditions, wherein every level of the
primary factor occurs the same number of
times with each level of nuisance factor
Response surface Graphical depiction of the mathematical
relationship
Empirical model Mathematical model describing factor-
response relation using polynomial
equations
Response surface 3D graphical representation of a response
plot plotted between two independent variables
and one response variable
Contour plot Geometric illustration of a response
obtained by plotting one independent
variable against another, while holding
the magnitude of response and other
variables as constant
Application of QbD in Pharmaceutical industry:
Quality refers to product free of contamination and delivers
the therapeutic benefit promised in the label to the consumer.
The quality of the pharmaceutical product can be evaluated by in
vivo or in vitro performance tests “QbD” assures in vitro product
performance and in vitro product performance provides assurance
of in vivo product performance. Hence, QbD is related to Product
Performance.
Benefits for Industry
• Better understanding of the process.
• Less batch failure.
• More efficient and effective control of change.
• Return on investment/cost savings.
• Provides opportunities for more flexible regulatory
approaches.
• Manufacturing changes within the approved design space
without further regulatory review.
• Reduction of post-approval submissions.
• Better innovation due to the ability to improve processes without
resubmission to the FDA when remaining in the Design Space [8,9].
Critical Quality attributes:
a) It will be vital to recognize the quality characteristics that will
be basic, i.e. those characterizing strength and surrogate for
 Bioavailability Criticality and so forth. It is based on the effect of subsequently generated to guide the drug delivery scientist.
value property/parameter on the security, adequacy & quality The drug delivery formulations are experimentally prepared
(manufacturability) of the product. according to the chosen experimental design, and the chosen
b) Establish a connection between CPP & CQAs: Identification of response variables are evaluated meticulously.
property or parameters that can be utilized as a surrogate for • In Step IV, a suitable numeric model is proposed on the
clinical security & adequacy (critical to patient) (Figure 3). basis of experimental data thus generated, and its statistical
c) Manufacturability will likewise be a credit (critical to business) significance is discerned. Response surface methodology
that is basic to quality. (RSM) is used to relate a response variableto the levels of input
variables. Optimum formulation compositions are searched
d) The level of criticality might contrast for an API producing
within the experimental domain, using graphical or numerical
process relative to a drug product assembling methodology.
techniques.
e) API is one part of a medication item and one stage further
• Step V, is the ultimate phase of the FbD exercise, involving
away from the persistent continuum of Criticality. Few levels of
validation of response predictive ability of the proposed
criticality may be utilized to potray different levels of danger.
design model. Drug delivery performance of some studies,
f) As trait or parameter limits methodology edges of disappointment, taken as the confirmatory runs, is assessed in relation to that
the level of discriminatingly expanded with the risk. predicted using RSM, and the results are critically compared.
g) Certain Key Aspects of QBD The optimum formulation is scaled-up and set forth ultimately
h) The Target Product Quality Profile (TPQP) is a apparatus for setting for the production cycle.
the key establishment for drug improvement — “arranging with
the end in personality.” More as of late, an extended utilization
of the TPP being developed arranging, clinical also business
choice making, administrative organization communications,
and danger administration has begun to develop.
i) To consistently achieve the drug-product quality specified in the
label, the drug substance needs to be thoroughly characterized
with respect to its physical, chemical, biological, and mechanical
properties such as solubility, polymorphism, stability, particle
size and flow properties. [7-9]

FbD Methodology:
FbD hits the bull’s eye using five key strengths, that is, apt choice
of experimental designs, accurate computer aided optimization,
meticulous drug product development, precise definition of design
and control space and identification of critical quality attributes
(CQAs), critical formulation attributes(CFAs) and critical process
parameters(CPPs). Figure 1 illustrates the concept. The theme of
DoE optimization methodology provides complete information on
diverse DoE aspects organized in a five-step sequence. Figure 1: Five cardinal elements of FbD

• The FbD study begins with Step I, where an endeavor is made DoE (Design ofFigure Experiment) :
1: Five cardinal elements of FbD
to explicitly ascertain the drug delivery objective(s). Various It is a mathematical tool for systematically planning and
CQAs or response variables, which pragmatically epitomize the conducting scientific studies that change experimental variables
objective(s), are earmarked for the purpose. All the independent
DoE (Design together in order
of Experiment) : to determine their effect on a given response [14].
product/process variables are also listed. It makes
It is a mathematical controlled
tool for changes
systematically to input
planning variables scientific
and conducting in order studies
to gainthat change
experimental maximum
• In Step II, the response variables which directly represent amounts
variables together in oforder
information on cause
to determine theirand effect
effect on arelationships
given response [14]. It
the product quality (e.g., particle size for nanoparticles,
makes controlled withchanges
a minimumto inputsample sizeinfororder
variables optimizing the formulation.
to gain maximum amounts of information
emulsification time for self-emulsifying systems) are on selected.
cause and effect relationships with a minimum sample size for optimizing the formulation
There are mainly four steps associated with DOE:
Also, selection of a ‘prominent few’ influential factors among
There arethemainly four steps associated with DOE:
1. The design of the experiment (by using various models)
‘possible many’ input variables is conducted using experimental
1. The design of the experiment (By using various models)
2. The collection of the data
designs through a process, popularly termed as ‘screening’ [9]
.
2. The collection of the data
The formulators, at times, can even by pass the rigors of 3. The 3.
statistical The statistical
analysis of the analysis
data and of the data and
screening process to choose these factors, that is, CFAs 4. Theand/ 4. The
conclusions conclusions
reached reached andmade
and recommendations recommendations made as a
as a result of the experiment.
or CPPs by virtue of their experience, wisdom and previous result of the experiment.
knowledge. Factor influence studies are usually conducted later
In Optimization Method various types of Model used from preliminary screening of factors to
to quantify the effect of factors and determine the interactions,
select their Types
level and offorExperimental
finally study ofDesign:
their effect so it’s depend upon the formulator to choose
[9]
if any. Experimental studies are also undertaken to define themodel for
a suitable study and help in minimizing
There are various type of Experimental the experimenting
design .
timemethods are
broad range of factor levels. available out of which method we have to use depends upon the
• During Step III, a suitable experimental design is worked out resources we have and what we want to study.
to map the responses on the basis of the study objective(s),
responses being explored, number and the type of factors, 1. Screening Designs:
and factor levels, that is, high, medium or low. The important These are used to identify the important factor and their level
experimental designs along with their pros and cons are which affect the quality of formulation. Screening Designs generally
discussed in subsequent sections. A design matrix is support only the linear responses.

Pharma Times - Vol. 50 - No. 08 - August 2018 11

2. Response Surface Designs:
These are used when we required exact image of response,
estimating interaction and even quadratic effects. Response
surface designs generally support non linear and quadratic
response and capable of detecting curvatures
much on the quantity of each substance present but on their
proportions. The sum total of the proportions of all the excipients
is unity, and none of the fractions can be negative. Therefore, the
levels of different components can be varied with the restriction
that the sum total should not exceed one.

3. Factorial Designs :
Factorial designs (FDs) are very frequently used response
surface designs. A factorial experiment is one in which all levels
of a given factor are combined with all levels of every other factor
in the experiment. These are generally based upon first-degree
mathematical models. Full FDs involve studying the effect of all the
factors (k) at various levels (x), including the interactions among
them, with the total number of experiments being xk. If the number
of levels is the same for each factor in the optimization study, the
FDs are said to be symmetric, whereas in cases of a different
number of levels for different factors, FDs are termed asymmetric.’’
When we study three factors at two level 23 the total Number of run
will be=8 & When we study two factors at three level 32 the total
Number of run will be=9.

4. Fractional Factorial Design (FFD) :

Fractional factorial design is generally used for screening of
factor. This design has low resolution due to less number of run.
Although, these designs are economical in terms of number of
experiments, the ability to distinguish some of the factor effects is
partly sacrificed by reduction in the number of experiments.

5. Plackett-Burman Designs (Hadamard designs) :

Plackett-Burman designs (PBD) are special two-level FFDs used
Fig 2: Various screening and Response surface designs
generally for screening of factors. This design is generally used Fig 2: Various screening and Response surface designs
when we want to screen high number of factors [15]
if we want to
Optimization of important factors:
study the effect of 7 factors then we have to show four dummy
factors. The interpretations of results in FFD, Plackett-Burman Optimization Model Development:
of important factors:
Designs & Taguchi design are drawn with the help of Pareto chart Model Development:A model is an expression defining the quantitative dependence
and Half normal plot. A model is an expression defining the quantitative dependence of a response variable on the
of a response variable on the independent variables. Usually, it is a
independent variables. Usually, it is a set of polynomials of a given order or Degree. From this
set of polynomials of a given order or Degree. From this polynomial
6. Central Composite Design (Box-Wilson design) : polynomial equation we calculate the coefficient with the help of Principal of MLRA (Multiple
equation we calculate the coefficient with the help of Principal of
Linear Regression Analysis). By the help of software we can also study here the effect of
For non linear responses requiring second-order models, central MLRA (Multiple Linear Regression Analysis). By the help of software
excipients, their interaction study, 3D Response plot, Contour Plot etc.
composite designs (CCDs) are the most frequently employed. A two- we can also study here the effect of excipients, their interaction
In screening design with the help of half normal plot and Pareto chart we can find out easily the
factor CCD is identical to a 3 FD with rectangular experimental mainstudy,
2
3Dtheir
factor and Response
level plot, Contour Plot etc.
domain at α = ±1, On the other hand, the experimental domain
In screening, design with the help of half normal plot and Pareto
is spherical in shape for α = √2= 1.414. The CCD is quite popular
chart we can find out easily the main factor and their level
in response surface optimization during pharmaceutical product
development. From the models thus selected, optimization of one response
or the simultaneous optimization of multiple responses needs to
7. Box-Behnken Designs : be optimized graphically, numerically and by using Brute force
A specially made design, the Box-Behnken design (BBD), search technology [9].
requires only three levels for each factor -l, 0 and +1. It employs 15
experiments run with three factors at three levels. It is economical (a) Graphical Optimization:
then CCD because it requires less number of Trial. Graphical optimization deals with selecting the best possible
formulation out of a feasible factor space region. To do this, the
8. Taguchi Design : desirable limits of response variables are set, and the factor levels
Taguchi refers to experimental design as “off-line quality are screened accordingly by the help of overlay plot.
control” because it is a method of ensuring good performance
in the development of products or processes.” It is also used (b) Brute-force search (Feasibility and Grid search) :
for screening of factors and it provides 8 experimental run for Brute-force search technique is the simple and exhaustive
7 factors. search optimization technique. It checks each and every single
point in the function space. Herein, the formulations that can be
9. Mixture Design: prepared by almost every possible combination of independent
Mixture designs are used when the characteristics of the factors and screened for their response variables. Subsequently,
finished product (Drug delivery system) usually depend not so the acceptable limits are set for these responses, and an exhaustive

Pharma Times - Vol. 50 - No. 08 - August 2018 12

Table 3: A few of recent literature instances of FbD optimization of various oral drug delivery systems, process optimization and
designs used in screening studies.
DDS Drug Factors Design
Screening studies
Nanocapsules Benzocaine Size, polydispersion index, zeta potential, drug loading FFD
Solid lipid nanoparticles Buspirone HCl Lipid type, surfactant percentage, speed of homogenizer, Taguchi
acetone:DCM ratio
Orodispersible tablet Ondansetron HCl Concentrations of glycine, chitosan and drug and tablet crushing PBD
strength
Product optimization
Nanosuspension Simvastatin Amounts of polymers and solvents CCD
Nanostructured liquid Valproic acid Concentrations of aqueous and organic phases, and relative Taguchi
carrier ratios of solvents
Colon-targeted systems Mesalamine Amounts of polymers in compression coating, coating mass and BBD
coating force
Floating-bioadhesive Tramadol Amounts of constituents polymers CCD
tablets
Process optimization
Pellets Lithium carbonate Rotor speed, slit air flow rate, spray air rate FD
Osmotic pump Propranolol HCl Rotation speed, ionic strength, pH SSD
SR tablets Ketoprofen pH, dissolution medium volume, stirring speed PBD

search is again conducted by further narrowing down the feasible

region. The optimized formulation is searched from the final feasible
space (termed as grid search), which fulfills the maximum criteria
set during experimentation.

(c) Numerical Optimization :

It deals with selecting the best possible formulation out of a
suitable factor. To do this, the desirable limits of response variables
are set, and the factor levels are displayed by the software. Other
techniques used for optimizing multiple responses are canonical
analysis, ANNs and mathematical optimization.
Softwares for design and optimization:
Many commercial software packages are available which are
either dedicated to experimental design alone or are of a more
general statistical type.
Software’s dedicated to experimental designs
• Design Expert
• ECHIP
• Multi-Simplex
• NEMRODW
• Software for general statistical nature
• SAS
• Minitab
• SYSTAT
• Graphpad Prism

Overall FbD strategy for Drug Delivery Development: Fig 3: Overall FbD strategy during drug delivery development.
The overall approach for conduct of an FbD study in oral DDS
can be described by a holistic plan [6,8]. The salient steps involved experimental design is selected and the number of experimental
in this FbD strategy include: runs calculated.

Problem definition: The FbD problem is clearly comprehended
and defined.
Selection of factors and factor levels: The independent factors
are identified amongst the quantifiable and easily controllable
variables.
Design of experimental protocol: Based on the choice of
independent factors and the response variables, a suitable
Formulating and evaluating the dosage form: Various drug
delivery formulations are prepared as per the chosen design and
evaluated for the desired response(s).
Prediction of optimum formulation: The experimental data
are used for generation of a mathematical model and an
optimum formulation is located using graphical and/or numeric
methods.
Pharma Times - Vol. 50 - No. 08 - August 2018 13
 Validation of optimization: The predicted optimal formulation
is prepared and the responses evaluated. Results, if validated, are
carried further to the production cycle via pilot plant operations
and scale-up techniques.
Overall, Flow chart 2 depicts the various salient steps involved
during an FbD strategy as a whole.
Conclusion:
FbD is a thirst area of Research now a day in every industry.
Experimental design is a tried and tested approach to formulation
optimisation that really works. Experimentation is cost effective.
Hence, Experimental design can be used to explore the potential for
formulation optimisation against desired criteria before committing
a modified formulation to production. In addition, the process
is conducive to creative thinking as preconceptions inevitably
get challenged when the scope for formulation is considered in
mapping the possible formulation. Mostly, orally administered DDS
are optimized by FbD. Not only oral DDS but FbD have also been
ideal for development of ‘optimized’ DDS of all other kinds. In this
article, an overview of FbD was given.
References:
1. Bhupinder Singh, Rishi K, Mousumi N & Naveen A. Available at: https://
www.researchgate.net/publication/51522336.
2. Singh B, Kumar R, Ahuja N.Crit Rev TherDrugCarrierSyst 2005,22:27-
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3. Dhawan S, Kapil R, Singh B.J Pharm Pharmacol 2011,63:342-51.
4. Singh B, Mehta G, Kumar R.Curr Drug Deliv2005,2:143-53.
5. Huang J, Goolcharran C, Ghosh K. Eur J Pharm Biopharm. 2011,78:141-
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6. Rahul Kumar Garg, Indrajeet Singhvi. Asian journal Of Pharmaceutical
research.2015,5:217-212.
7. Hemangi Pandit Bendale, Akshada A. Bakliwal, Swati G. World Journal
of Pharmaceutical Research.2015,4:402-422, 2015.
8. Verma S, Lan Y, Gokhale R. Int J Pharm. 2009,377:185-98
9. Patel MM, Amin AF. J Pharm Sci,2011,100:1760-1772.

IRF Life Time Achievement Award 2018

IPA Fellowship Award 2018
IPA Eminent Pharmacist Award 2018
The Indian Pharmaceutical Association and Shri Ramanbhai B. Patel Foundation (IRF) established in the
year 2004, is dedicated to the memory of Late Shri Ramanbhai Patel, Former President of IPA and Founder
Chairman of Zydus Cadila.
The Foundation every year recognizes Commitment and Excellence made by a person throughout his / her life
in the field of Pharmacy Profession by giving Life Time Achievement Award.
Any member of IPA can nominate a person for this award who has made outstanding contributions in the field
of pharmacy profession and healthcare / pharmaceutical sciences and powered its growth through vision and
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Please forward the nomination of an eligible candidate in the prescribed format so as to reach the Hon. Gen.
Secretary, IPA, Kalina, Santacruz (East), Mumbai – 400098, positively on or before 30th September, 2018. You
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Please forward the nomination of an eligible candidate in the prescribed format so as to reach the Hon. Gen.
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The Eminent Pharmacist Award is the highest award of IPA. The Eminent Pharmacist Award is given
to a person who has distinguished him/herself by his/her significant contributions in the field of pharmacy
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All members of the Central Executive Council and Presidents of State and Local Branches of IPA are requested
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For detail guidelines and prescribed format, please refer to IPA Website www.ipapharma.org or
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