01 Complete Thesis

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Introduction:
1. Introduction to Quality by Design
Quality by Design (QbD) refers to a holistic approach towards drug development. Quality by
design is a vital part of the modern approach to pharmaceutical quality. Quality by Design
(QbD) was first described by Joseph M. Juran, and applied heavily, particularly in the
automotive industry. The fundamental premise behind QbD is that quality can be designed
in to processes through systematic implementation of an optimization strategy to
establish a thorough understanding of the response of the system quality to given
variables, and the use of control strategies to continuously ensure quality. The FDA has
recently begun to advocate the QbD methodology for the pharmaceutical sector.[1]
Definition:
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.[2]
The overview of QbD is shown in figure 1.
Fig No 1.1 Overview of Quality by design [1]
FORMULATION AND EVALUATION OF SUSTAINED RELEASE FILM COATED

TABLETS USING QUALITY BY DESIGN (QbD) APPROACH
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1.1. Regulatory aspects:

In Aug 2009, ICH released a guideline Q8R(2) (Step 4) to guide the industry in the
implementation of quality by design (QbD) in Section 3.2.P.2 (Pharmaceutical
Development) for drug products as defined in the scope of Module 3 of the Common
Technical Document (ICH guideline M4). QbD (ICH Q8(R2)) is defined as 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. This is a more systematic approach to development which include, for
example, incorporation of prior knowledge, results of studies using design of
experiments, use of quality risk management (ICH Q9), and use of knowledge
management (ICH Q10) throughout the lifecycle of the product.[3]
Fig. 1.2 Regulatory Aspects: ICH Q8,Q9, Q10 guidelines [4]

1.2. Principle:
In all cases, the product should be designed to meet patients needs and the intended product
performance. Strategies for product development vary from company to company and from
product to product. The approach to, and extent of, development can also vary and should be
outlined in the submission. An applicant might choose either an empirical approach or a more
systematic approach to product development. A more systematic approach to development
also defined as quality by design) can include, for example, incorporation of prior knowledge,
results of studies using design of experiments, use of quality risk management, and use of
knowledge management (see ICH Q10) throughout the lifecycle of the product. Such a
systematic approach can enhance the process to achieve quality and help the regulators to

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better understand a companys strategy. Product and process understanding can be updated
with the knowledge gained over the product lifecycle.
A greater understanding of the product and its manufacturing process can create a basis for
more flexible regulatory approaches. The degree of regulatory flexibility is predicated on the
level of relevant scientific knowledge provided in the registration application. It is the
knowledge gained and submitted to the authorities, and not the volume of data collected, that
forms the basis for science-and risk-based submissions and regulatory evaluations.
Nevertheless, appropriate data demonstrating that this knowledge is based on sound scientific
principles should be presented with each application.[2]
1.3. Advantages of QbD [1]:
1. It provides a higher level of assurance of drug product quality.
2. It offers cost savings and efficiency for the pharmaceutical industry.
3. It increases the transparency of the sponsor understands the control strategy for the
drug product to obtain approval and ultimately commercialize.
4. It makes the scale-up, validation and commercialization transparent, rational and
predictable.
5. It facilitates innovation for unmet medical needs.
6. It increases efficiency of pharmaceutical manufacturing processes and reduces
manufacturing costs and product rejects.
7. It minimizes or eliminates potential compliance actions, costly penalties, and drug
recalls.
8. It offers opportunities for continual improvement.
9. It provides more efficiency for regulatory oversight:
10. It streamlines post approval manufacturing changes and regulatory processes.
11. It more focused post approval CGMP inspections
12. It enhances opportunities for first cycle approval.
13. It facilitates continuous improvement and reduces the CMC supplement.
14. It enhances the quality of CMC and reduces the CMC review time.
1.4. Steps in Quality by Design[5]

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Fig. 1.3 Steps in Quality by Design

1.5. The Target Product Quality Profile (TPQP): [6]
The quality target product profile (QTPP) is a prospective summary of the quality
characteristics of a drug product that ideally will be achieved to ensure the desired quality,
taking into account safety and efficacy of the drug product Target Product Quality Profile
(TPQP) is a tool for setting the strategic foundation for drug development planning with
the end in mind.
Primary components of QTPP are as follows:
1. Description
2. Clinical Pharmacology
3. Indications and Usage
4. Contraindications
5. Warnings
6. Precautions
7. Adverse Reactions
8. Drug Abuse and Dependence
9. Over dosage
10. Dosage and Administration
11. Animal Pharmacology and/or Animal Toxicology Clinical Studies
The TPP can play a central role in the entire drug discovery and development process such as:
effective optimization of a drug candidate, decision-making within an organization, design of
clinical research strategies, and constructive communication with regulatory authorities. TPP
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is currently primarily expressed in clinical terms such as clinical pharmacology, indications

and usage, contraindications, warnings, precautions, adverse reactions, drug abuse and
dependence, over dosage, etc. Thus, it is organized according to key sections in the products
label. TPP therefore links drug development activities to specific statements intended for
inclusion in the drugs label. Target Product Quality Profile (TPQP) is a term that is a natural
extension of TPP for product quality. The TPQP of a generic drug can be readily determined
from the reference listed drugs (RLD). Along with other available information from the
scientific literature and possibly the pharmacopeia, the TPQP can be used to define product
specifications to some extent even before the product is developed.
When ICH Q8 says that pharmaceutical development should include ...identification of
those attributes that are critical to the quality of the drug product, taking into consideration
intended usage and route of administration, the consideration of the intended usage and
route of administration would be through the TPP.
Many aspects of the TPP constrain or determine the actions of formulation and process
development scientists. These can include the route of administration, dosage form and size,
maximum and minimum doses, pharmaceutical elegance (appearance), and target patient
population (paediatric formulations may require chewable tablets or a suspension). Common
aspects of drug product quality are implicitly in the TPP.[6]
Based on the clinical and pharmacokinetic (PK) characteristics as well as the in vitro
dissolution and physicochemical characteristics of the RLD, a quality target product profile
(QTPP) is defined.
1.6. Critical Quality Attributes:[2, 5]

A CQA is a physical, chemical, biological, or microbiological property or characteristic that
should be within an appropriate limit, range, or distribution to ensure the desired
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product
quality.
CQAs are generally associated with the drug substance, excipients,
intermediates (in-process materials) and drug product.

CQAs of solid oral dosage forms are typically those aspects affecting product purity, strength,
drug release and stability. CQAs for other delivery systems can additionally include more
product specific aspects, such as aerodynamic properties for inhaled products, sterility
for parenterals, and adhesion properties for transdermal patches.
For drug substances, raw materials and intermediates, the CQAs can additionally
include those properties (e.g., particle size distribution, bulk density) that affect drug product
CQAs.
Potential drug product CQAs derived from the quality target product profile and/or
prior knowledge are used to guide the product and process development. The list of potential
CQAs can be modified when the formulation and manufacturing process are selected and as
product knowledge and process understanding increase. Quality risk management can be
used to prioritize the list of potential CQAs for subsequent evaluation. Relevant CQAs
can be identified by an iterative process of quality risk management and experimentation
that assesses the extent to which their variation can have an impact on the quality of the
drug product.
Process parameters and material attributes are critical when a realistic change can result in
failure for the product to meet the QTPP or a CQA that is outside an acceptable range.
Process parameters are not critical when there is no trend to failure and there is no evidence
of significant interactions within the proven acceptable range.
CQA has been used by some to describe elements of the TPQP (such as dissolution) while
others have used CQA to describe mechanistic factors (such as particle size and hardness)
that determine product performance. Thus CQA is used to describe both aspects of product
performance and determinants of product performance. The 2004 Q8 draft put CQA and
performance tests into the same pile of physiochemical and biological properties: The
physicochemical and biological properties relevant to the performance or manufacturability
of the drug product should be identified and discussed. These could include formulation
attributes such as pH, dissolution, particle size distribution, particle shape, polymorphism,
rheological properties, and biological activity or potency, and/or immunological activity. [5]
1.7. Critical Process Parameters:
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Critical process parameter is a process parameter whose variability has an impact on a critical
quality attribute and therefore should be monitored or controlled to ensure the process
produces the desired quality.
In this view, every item would be a process parameter. We propose that process parameter be
understood as referring to the input operating parameters (mixing speed, flow rate) and
process state variables (temperature, pressure) of a process or unit operation.[2]
1.8. Risk Assessment [7]:
Low: Broadly acceptable risk. No further investigation is needed
Medium: Risk is acceptable. Further investigation may be needed in order to reduce the risk.
High: Risk is unacceptable. Further investigation is needed to reduce the risk
Overview of typical quality risk management [9]
Fig. 1.4 Quality risk management

1.9.1. Methods of Risk Assessment:
1.9.1. A. Ishikawa (fishbone) diagram:
It is a very effective tool to capture a brainstormed list of potential process inputs impacting
variation. Mapping the manufacturing process using a process flow diagram (PFD) is helpful
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to define the scope of the risk assessment and to identify possible process inputs. API
mapping may include unit operation, chemistry pathways, and an impurities cascade. [8]
Example of Ishikawa (Fish bone) diagram is shown in figure 2:
Figure 1.5 - Ishikawa fishbone diagram

1.9.1. B. FMEA (failure modes and effects analysis): or use of a prioritization matrix
(cause and effect matrix) is helpful in identifying the process inputs that impact on quality
attributes. In some cases, a deeper dive into the driving forces at critical control points in the
manufacturing process can yield a more fundamental understanding of sources of variation.
Before embarking on extensive experimentation, a critical next step is to make sure that
critical measurements are made using fit for purpose methodology. A comprehensive risk
assessment should identify those measurements that are suspect. A simple frequency plot of
the data with specification limits will provide an indication of when variation is a potential
problem. [8]
FMEA provides for an evaluation of potential failure modes for processes and their likely
effect on outcomes and/or product performance.
Steps: [11]
1.
Selection of the process
2.
Review of the process

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3.
Brainstorm potential failure modes
4.
List of potential effects of each failure mode
5.
Assign a severity rating for each effect
6.
Assign an occurrence rating for each failure mode
7.
Assign a detection rating for each failure mode and effect
8.
Calculation of the risk priority number (RPN) for each effect: (RPNs) = ODS
9.
Prioritize the failure modes for action
10.
Taken action to eliminate or reduce the high risk failure modes
11.
Improvement index (II): II = (RPN before improvement) / (RPN after improvement)
1.9.1. C. Fault tree analysis

1. Assumes failure of the functionality of a product or process.
2. Identifies all potential root causes of an assumed failure or problem that it is thought
to be important to prevent.
3. Evaluates system or sub system failure one at a time.
4. Can combine multiple causes by identifying casual chains. [8]
1.9.2. Success factors in Risk Management: [1]
Risk management should
1.
2.
3.
4.
5.
6.
Create value
Be an integral part of organizational processes
Be part of decision making
Explicitly address uncertainty
Be systematic and structured
Be based on the best available information
The two primary principles should be considered when implementing quality risk
management: [12]
1. The evaluation of the risk to quality should be based on scientific knowledge and
ultimately link to the protection of the patient; and
2. The level of effort, formality and documentation of the quality risk management
process should be commensurate with the level of risk.
1.10. Design Space: [5]
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ICH Q8 (R1) defines design space as, the multidimensional combination and interaction of
input variables (e.g., material attributes) and process parameters that have been demonstrated
to provide assurance of quality. This definition evolved from early ICH Q8 drafts where
design space was defined as the established range of process parameters that has been
demonstrated to provide assurance of quality. The schematic representation of design space
is shown in figure 3:
Fig. No.1.6 Schematic representation of Design Space

Design space is proposed by the applicant and is subject to regulatory assessment and
approval. Because design space is potentially scale and equipment-dependent, the design
space determined at the laboratory scale may not be relevant to the process at the commercial
scale. Therefore, design-space verification at the commercial scale becomes essential unless it
is demonstrated that the design space is scale-independent.
1.10.1. Steps for the Design Space: [8]
Identify the unclassified parameters.

Applying design of experiment on some of unclassified parameters with the other
unclassified parameters fixed.

End is a regulatory situation with some space for the selected parameters but no
flexibility for other parameter.
1.10.2. Implications of Design Space: [13]
Increased process and product understanding.
Increased assurance to regulators i.e. regulatory flexibility.
In some cases boundaries will be identified that are known to be an edge of failure. In these
situations, it may be important to set boundaries at acceptable tolerance intervals around the

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edge of failure to better mitigate the risks near such edges. Application of tolerance interval is
not necessary when the edges of failure are not in play at design space boundaries.
1.11. Control strategy [6]
A planned set of controls, derived from current product and process understanding that
ensures process performance and product quality.
The Control Strategy should establish the necessary controls - based on patient requirements to be applied throughout the whole product lifecycle from product and process design
through to final product, including API and Drug Product manufacture, packaging and
distribution.
The controls can include parameters and attributes related to:
Drug substance,
Drug-product materials and components,
Facility and equipment operating conditions,
In-process controls,
Finished-product specifications,
The associated methods and
Frequency of monitoring and control. (ICH Q10)
Specifically, the control strategy may include control of input material attributes (e.g., drug
substance, excipients, and primary packaging materials) based on an understanding of their
impact on process-ability or product quality, Product specifications, Practical controls,
Facility controls, such as utilities, environmental systems and operating conditions, Controls
for unit etc. Implementing Control Strategy will require the application of process models
(multivariate prediction models) that either predicts CQAs or CPPs or a combination of both.
1.11.1 Developing the control strategy: [1]

Development of a Control Strategy requires a structured process, involving a multidisciplinary team of experts, linking pharmaceutical development to the manufacturing
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process, and engineering controls of process equipment. The PQLI Control Strategy Team has
proposed a Control Strategy Model that facilitates understanding and that may be used a
cross-functional communication tool. Personnel at all levels should be able to understand the
way control strategy links from CQAs to operational aspects to ensure, for example that:
1. Chemists understand in-process controls are established to keep the process inside the
design
2. Space and seek opportunities for simplification of controls, as knowledge is gained.
3. Engineers know how equipment operating conditions impact product quality.
4. Quality Assurance professionals know where the highest risks are in the process.
Although the primary driver for development of a control strategy will be assurance of
product safety, efficacy and quality, the Control Strategy may also ensure the meeting of
other business objectives such as operator health and safety, protection of the
environment, manufacturability and supplies related issues, efficiency, and profitability.
5. Development of a Control Strategy for a product will therefore be a structured activity
involving a multidisciplinary team of experts. This team may include representatives
from formulation development, drug substance development, process development,
analytical development, QC, QA, Regulatory Affairs, manufacturing, engineering, and
specialists in Process Analytical Technology (PAT) and chemo-metrics. A Control
Strategy and a product release strategy are not the same, but demonstration of adherence
to the Control Strategy would support the product or batch release strategy.
1.12. Tools of Quality by Design
1.12.1 Design of Experiments (DOE) [14, 37]
Design of experiments (DOE) is a structured and organized method to determine the
relationship among factors that influence outputs of a process.
Application of DOE in QbD helps in gaining maximum information from a minimum number
of experiments. When DOE is applied to a pharmaceutical process, factors are the raw
material attributes (e.g., particle size) and process parameters (e.g., speed and time), while
outputs are the critical quality attributes such as blend uniformity, tablet hardness, thickness,
and friability. As each unit operation has many input and output variables as well as process
parameters, it is impossible to experimentally investigate all of them. Scientists have to use
prior knowledge and risk management to identify the key input and output variables and
process parameters to be investigated by DOE. DOE results can help identify optimal

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conditions, the critical factors that most influence CQAs and those who do not, as well as
details such as the existence of interactions and synergies between factors.
DOE provides an enhanced knowledge of product performance over a wider range of
material attributes, processing options and process parameters. This proves a higher degree of
process understanding. Scientific understanding is important to provide a design space, which
is an important part of quality by design, and can be gained by formal design of experiments.
Types of Designs:
Factorial design: In a factorial design the influences of all experimental variables,
factors, and interaction effects on the response or responses are investigated. If the
combinations of k factors are investigated at two levels, a factorial design will consist of 2 k
experiments.
Fractional factorial design: To investigate the effects of k variables in a full factorial design,
2k experiments are needed. Then, the main effects as well as all interaction effects can be
estimated. To investigate seven experimental variables, 128 experiment will be needed; for 10
variables, 1024 experiments have to be performed; with 15 variables, 32,768 experiments
will be necessary. It is obvious that the limit for the number of experiments it is possible to
perform will easily be exceeded, when the number of variables increases. In most
investigations it is reasonable to assume that the influence of the interactions of third order or
higher are very small or negligible and can then be excluded from the polynomial model.
This means that 128 experiments are too many to estimate the mean value, seven main effects
and 21 second order interaction effects, all together 29 parameters. To achieve this, exactly 29
experiments are enough. To determine main effects, it is sufficient to perform less no of
experiments. Depending on the size of fraction, and number of variables, a lesser no. of
experiments are possible using fractional factorial design.
Optimization:
Two strategies can be applied: Simplex optimization and response surface methodology.
Simplex optimization: A simplex is a geometric figure with (k+1) corners where k is equal to
the number of variables in a k dimensional experimental domain. When the number of
variables is equal to two the simplex is a triangle.
Response surface methodology: Response surfaces are used to determine an optimum. In
addition, it is a good way to graphically illustrate the relation between different experimental
variables and the responses. To be able to determine an optimum it is necessary that the
polynomial function contains quadratic terms.
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Central composite design: A full central composite design consists of the following parts:
A full factorial or fractional factorial design.

Experiment at centre.
Experiments where points are situated on the axis in a coordinate system and are axial
points.
Mixture designs: In mixture experiment, it is not the actual amount of a single ingredient that
matters, but rather its proportion in relation to other ingredients. The sum of all the
ingredients is a constant total T, which is equal to 100% or 1. The constant total T represents
a constraint on mixture experiments that implies independence between all mixture factors.
1.12.2. Process Analytical Technology (PAT): [15]
PAT has been defined as A system for designing, analysing, and controlling manufacturing
through measurements, during processing of critical quality and performance attributes of
raw and in-process materials and processes, with the goal of ensuring final product quality.
The goal of PAT is to enhance understanding and control the manufacturing process, which
is consistent with our current drug quality system: quality cannot be tested into products; it
should be built-in or should be by design. The design space is defined by the key and critical
process parameters identified from process characterization studies and their acceptable
ranges. These parameters are the primary focus of on-, in- or at-line PAT applications. In
principle, real-time PAT assessments could provide the basis for continuous feedback and
result in improved process robustness. NIR act as a tool for PAT and useful in the RTRT (Real
Time Release Testing) as it monitors the particle size, blend uniformity, granulation, content
uniformity, polymorphism, dissolution and monitoring the process online, at the line and
offline, thus it reduces the release testing of the product.
1.13. Introduction to sustained release:

The basic goal of therapy is to achieve a steady state blood level that is therapeutically
effective and non-toxic for an extended period of time. The design of proper dosage regimens
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is an important element in accomplishing this goal. Sustained release (SR) dosage forms
continue to draw attention in the search for improved compliance and decrease the incidence
of adverse drug reactions [16]. A sustained release system includes any delivery system that
achieves slow release of the drug over an extended period of time.
Sustained release, sustained action, prolonged action, controlled release, extended action,
timed release, depot and repository dosage forms are terms used to identify drug delivery
systems that are designed to achieve a prolonged therapeutic effect by continuously
releasing medication over an extended period of time after administration of single dose
[17]. In the case of orally administered dosage forms, this period is measured in hours and
critically depends on the residence time of the dosage form in the gastrointestinal tract. The
term controlled release has become associated with those systems from which therapeutic
agents may be automatically delivered at predetermined rates over a long period of time [18].
The system attempts to control drug concentrations in the target tissues or cells.
Sustained release systems are any drug delivery system that achieves slow release of drug
over an extended period of time. If the system is successful in maintaining constant drug
levels in the blood or target tissue, it is considered as a controlled-release system. If it is
unsuccessful at this but nevertheless extends the duration of action over that achieved by
conventional delivery, it is considered as a prolonged release system.
In recent years, in association with progress and innovation in the field of pharmaceutical
technology, there has been an increasing effort to develop sustained release dosage forms for
many drugs. The primary objective of this system is to ensure safety and to improve efficacy
of the drugs as well as patient compliance. This is achieved by better control of plasma drug
levels and less frequent dosing. Pharmacokinetic theory suggests that the ultimate method for
reducing the plasma maximum concentration (Cmax) to plasma minimum concentration
(Cmin) ratio is to have zero-order absorption. Once steady state is achieved under these
conditions, drug concentration in plasma is constant as long as absorption persists. Successful
commercialization of an extended release formulation is usually challenging and involves
consideration of many factors such as physiochemical properties of the drug, physiological
factors, and manufacturing variables.
1.14 Advantages of controlled release dosage forms [19]:

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The frequency of drug administration is reduced.

Compliance can be improved.
Drug administration can be made more convenient as well.
The blood level oscillation characteristic of multiple dosing of conventional dosage
forms is reduced.
Better control of drug absorption can be attained, since the high blood level peaks that
may be observed after administration of a dose of a high availability drug can be
reduced.
The characteristic blood level variations due to multiple dosing of conventional
dosage forms can be reduced.

The total amount of drug administered can be reduced, thus:
Maximizing availability with minimum dose;
Minimize or eliminate local side effects;
Minimize or eliminate systemic side effects;
Minimize drug accumulation with chronic dosing.
Safety margin of high potency drugs can be increased and the incidence of both local
and systemic adverse side effects can be reduced in sensitive patients.

Improve efficiency in treatment.
Cure or control condition more promptly;
Improve control of condition i.e., reduce fluctuation in drug level;
Improve bioavailability of some drugs;
Make use of special effects
Economy.
1.15
Disadvantages of controlled release formulations:
Administration of controlled release medication does not permit the prompt
termination of therapy.
Flexibility in adjustment of dosage regimen is limited.
Controlled release forms are designed for normal population i.e. on the basis of
average drug biologic half-lives.

Economic factors must also be assessed, since more costly process and equipment are
involved in manufacturing of many controlled release dosage forms.
1.16
Physico-chemical factors influencing oral controlled release dosage form [15]:
a. Dose size:

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For orally administered systems, there is an upper limit to the bulk size of the dose
to be administered. In general a single dose of 0.5 to 1 gm is considered maximal.
b. Ionization, pKa and aqueous solubility:
The pH partition hypothesis simply states that the unchanged form of a drug species
will be preferentially absorbed through many body tissues therefore it is important to
note the relationship between pKa of the compound and its absorptive environment.
For many compounds the site of maximum absorption will also be the area in which the drug
is least soluble. For conventional dosage forms the drug can generally fully dissolve in the
stomach and then be absorbed in the alkaline pH of the intestine. For dissolution of diffusion
controlled forms, much of the drug will arrive in the small intestine in solid form.
This means that the solubility of the drug is likely to change several orders of
magnitude during its release.
c. Partition coefficient:
The compounds with a relatively high partition coefficient are predominantly lipid soluble
and easily penetrate membranes resulting high bioavailability. Compounds with very low
partition coefficient will have difficulty in penetrating membranes resulting in poor
bioavailability. Furthermore partitioning effects apply equally to diffusion through polymer
membranes.
d. Drug Stability:
Drugs that are unstable in the stomach can be placed in a slowly soluble form or have their
release delayed until they reach the small intestine However, such a strategy would be
detrimental for drugs that either are unstable in the small intestine or undergo extensive gut
wall
metabolism,
as
pointed
out
in
the
decreased
bioavailability
of
some
anticholinergic drugs from controlled /sustained release formulations.

e. Protein Binding:
It is well known that many drugs bind to plasma proteins with a concomitant
influence on the duration of drug action. Since blood proteins are for the most part
recirculated and not eliminated, drug protein binding can serve as a depot for drug
producing a prolonged release profile, especially if a high degree of drug binding occurs.
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Levine has shown that quaternary ammonium compounds bind to mucin in the GIT. Drug
bound to mucin may act as depot and act as a sustained release product.
1.17 Biological factors influencing oral sustained release dosage form:
a. Biological Half Life:
Therapeutic compounds with short half-lives are excellent candidates for controlled release
preparations. Drug with very short half-life will require excessively large amounts of drug in
each dosage unit to maintain controlled effects, thus forcing the dosage form itself to become
too large to be administered. Compounds with relatively long half lives, generally greater
than 8 hours are generally not used in controlled release dosage forms since their effect is
already sustained and also GI transit time is 8-12 hrs. Drugs with short half-lives require
frequent
dosing
in
order
to
minimize fluctuations in blood levels accompanying
conventional oral dosage regimens. Therefore controlled release dosage forms would appear
very desirable for drugs.
b. Absorption:
The characteristics of absorption of a drug can greatly affect its suitability as a
controlled release product. Assuming the transit time of most drugs and devices in the
absorptive regions before release is complete. The absorption rate constant is an apparent rate
constant. It should in actuality be the release rate constant of the drug from dosage form.
c. Metabolism:
Drugs that are significantly metabolized especially in the region of the small intestine can
show decreased bioavailability from slower releasing dosage forms. This is due to saturation
of intestinal wall enzyme systems.
2.3 Technique for preparation of sustained release formulation:
A. Film Coating:
Pharmaceutical coatings are an essential tool to achieve the desired formulation of
pharmaceutical dosage forms.
Coatings are applied to achieve superior property of a dosage form.
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Modified drug release

Colour
Texture
Mouth feel and taste masking [21]
When coating composition is applied to a batch of tablets in a coating pan, the tablet surfaces
become covered with a tacky polymeric film. Before the tablet surface dries, the applied
coating changes from a sticky liquid to tacky semisolid, and eventually to a nonsticky dry
Surface pans. The entire coating process is conducted in a series of mechanically operated
acorn-shaped coating pans of galvanized iron stainless steel or copper. The smaller pans are
used for experimental, developmental, and pilot plant operations, the larger pans for industrial
production.
Basic principles involved in tablet coating:
1. Tablet coating is the application of coating composition to moving bed of tablets with
concurrent use of heated air to facilitate evaporation of solvent.
2. Solution in which influences the release pattern as little as possible and does
not markedly change the appearance.
3. Modified release with specific requirement and release mechanism adapted to
body function in the digestive tract.
4. Colour coating which provides insulation.
5. To incorporate another drug or formula adjuvant in the coating to avoid
chemical incompatibilities or to provide sequential drug release.
6. To improve the pharmaceutical elegance by use of special colours and contrasting
printing.
Primary components involved in tablet coating
1.
2.
3.
4.
5.
6.
Tablet properties
Coating process
Coating equipments
Parameters of the coating process
Facility and ancillary equipments
Automation in coating processes.
Coating Process Design & Control [21]

In most coating methods, the coating solutions are sprayed onto the tablets as the tablets are
being agitated in a pan, fluid bed, etc. As the solution is being sprayed, a thin film is formed
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that adheres directly to each tablet. The coating may be formed by a single application or may
be built up in layers through the use of multiple spraying cycles.
Rotating coating pans are often used in the pharmaceutical industry. Uncoated tablets are
placed in the pan, which is typically tilted at an angle from the horizontal, and the liquid
coating solution is introduced into the pan while the tablets are tumbling. The liquid portion
of the coating solution is then evaporated by passing air over the surface of the tumbling
tablets. In contrast, a fluid bed coater operates by passing air through a bed of tablets at a
velocity sufficient to support and separate the tablets as individual units. Once separated, the
tablets are sprayed with the coating composition.
The coating process is usually a batch driven task consisting of the following phases:
Batch identification and Recipe selection (film or sugar coating)

Loading/Dispensing (accurate dosing of all required raw materials)
Warming
Spraying (application and rolling are carried out simultaneously)
Drying
Cooling
Unloading
Coating equipment
A modern tablet coating system combines several components:
A coating pan
A spraying system
An air handling unit
A dust collector
Advantages of tablet coating [21]

1. Tablet coatings must be stable and strong enough to survive the handling of the tablet, must
not make tablets stick together during the coating process, and must follow the fine contours
of embossed characters or logos on tablets.
2. Coatings can also facilitate printing on tablets, if required. Coatings are necessary for
tablets that have an unpleasant taste, and a smoother finish makes large tablets easier to
swallow.
Chapter 1
INTRODUCTIO
N
21
Disadvantages of tablet coating [21]

1) Disadvantages of sugar coating such as relatively high cost, long coating time and high
bulk have led to the use of other coating materials.
2) However the process of coating is tedious and time-consuming and it requires the expertise
of highly skilled technician. The process is tedious and time-consuming and it requires the
expertise of highly skilled technician.
Sustained release can also be achieved by following mechanisms:
Embedding the drug in slowly dissolving or erodible matrix (monolith).
In such systems the drug is homogeneously dispersed throughout a rate controlling medium
and employs waxes such as bees wax, carnauba wax, hydrogenated castor oil etc. Dissolution
of drug is controlled by controlling the rate of penetration of dissolution fluid into the matrix
by altering the porosity of tablet, decreasing its wet ability or by itself getting dissolved at
slower rate. The drug release is often followed by first order kinetics from such matrices. A
major disadvantage of matrix system is that drug release rate continuously decreases with
time due to increased diffusional distance and decreased surface area at the penetrating
solvent front. Consequently, to achieve zero order release, it is necessary to select geometry
that compensates the increase in diffusional distance with the corresponding increase in
surface areas for the dissolution.
To achieve zero order drug release a novel approach is proposed by incorporating nonuniform drug distribution in a matrix material, encapsulation or coating with slowly
dissolving or erodible substances (Reservoir devices).[22]
These systems generally employ coating of drug particles or granules with slowly dissolving
materials. Time required for the dissolution of the coat is a function of thickness of coat and
its aqueous solubility. One can obtain controlled action by employing a wide spectrum of
coated particles of varying coat thickness. Coating can be achieved by one of the several
micro encapsulation techniques with slowly dissolving materials like cellulose. [23]
Diffusion controlled release system
Matrix diffusion controlled systems [21, 24]
Chapter 1
INTRODUCTIO
N
22
In these systems the dug is dispersed in an insoluble matrix of rigid non-swellable

hydrophobic materials or swellable hydrophilic substances. For rigid matrix insoluble plastics
such as PVC and fatty materials like bees wax, stearic acid etc. are used. While for the
swellable matrix hydrophilic gums of natural origin (tragacanth, guar gum), semi synthetic
(HPMC, Xanthan gums, CMC), or synthetic (polyacrylamides) can be used.
Reservoir Devices
In these systems an inner core of drug is surrounded by a water insoluble polymeric
membrane. The polymer can be applied by coating or microencapsulation techniques.
Commonly used polymers are HPC, Ethyl cellulose and polyvinyl acetate. The drug release
mechanism across the membrane involves its partitioning into the membrane with subsequent
release into the surrounding fluid by diffusion.
Dissolution and Diffusion controlled Release system
In such system, the drug core is enclosed in partially soluble coating. Pores are formed due to
dissolution of parts of the membrane which can permit entry of dissolution fluid into the core
and hence drug dissolution and allow diffusion of dissolved drug out of the system.
Sr.
No.
Author/
Organisation
Quality By Design
International
Conference On
1.
Harmonisation
(ICH) [2]
Title
Conclusion/ Description
Pharmaceutical
Describes in detail basic principles of
Development Q8R(2) Quality by Design
2.
Sandipan Roy [25]
Quality by design: A
Gives the details of role of OGD to
holistic concept of
integrate QbD into its ANDA drug filing
building quality in
by using a question based review.
pharmaceuticals
3.
CMC IM Working
Group [26]
Pharmaceutical
Development: Case
study: ACE tablets
Case study explaining each step of

Quality by design approach used for
ACE tablets along with in vivo testing
Sustained Release Formulation

Chapter 1
INTRODUCTIO
N
Sr.
No.
Author/
Organisation
Title
4.
Formulation and
Evaluation of
Dinanath Gaikwad et Sustained Release
al [22]
Tablet of
Aceclofenac by Film
Coating
5.
Bhavani Boddeda et
al [27]
Formulation and
evaluation of
glipizide sustained
release tablets
Venlafaxine Hydrochloride
Development and
Optimization of
Venlafaxine
Shital Bhavin Butani Hydrochloride
6.
[28]
Sustained Release
Triple Layer Tablets
Adopting Quality by
Design Approach
Formulation
development and
evaluation of
Venlafaxine HCl
sustained
Release matrix tablet
23
SR tablets were prepared by using

HPMC E5 LV. Diffusion disso controlled
prolonged and gradual release was
obtained.
Of 2 hydrophobic polymers and 2
hydrophilic gum resins, Olibanum was
found to exchibit better SR
characteristics
Triple layer tablets were developed by

varying amount of important variables
and using quality by design approach.
Xanthan gum as well as polyethylene
oxide was used to formulate matrix
tablets with comparable drug release to
EffexorXR 150 mg capsules.
Optimum concentration of Carbopol
971P and Ethyl cellulose based
formulations was found to provide the
desired release (95.47%) with a
reduced frequency of administration.
7.
Rahul Thorat et al
[29]
8.
Development and
validation of UV
spectrophotomeric The method was validated with
Method for the
respect to linearity, precision, accuracy,
Sundaraganapathy R.
determination of
selectivity and sensitivity according to
[30]
Venlafaxine
ICH guideline and
Hydrocholoride in
definition.
bulk and solid dosage
forms
Coating
9.
Susanne Tobiska,
Peter Kleinebudde
[31]
Coating uniformity
and coating
efficiency in a Bohle
Lab-Coater using
oval tablets
Pan speed has a big influence on the

quality of the film tablets the mass
variance of the tablets, disintegration and
dissolution behaviour

Chapter 1
INTRODUCTIO
N
Sr.
No.
10.
24
Author/
Organisation
Title
Daniela Brock et al
[32]
Evaluation of critical
process parameters
for inter-tablet
coating uniformity of
active-coated GITS
using Terahertz
Pulsed Imaging
Coating uniformity was assessed by

calculating the coefficient of variation
(CV) of coating thickness, and the CV of
API content measured by high
performance liquid chromatography
(HPLC).

Chapter 3
NEED OF WORK
25
Need of work: [57]

Currently, most of the pharmaceutical products in the market are of good quality. End product
quality for them is not an issue. However, there is a huge scope for improvement at
Development and manufacturing level.
The improvement may be in terms of:
Minimisation of batch failures and reworks.

Minimisation of long cycle times.
Transforming traditional Frozen process into a flexible process.
Implying newer technologies to generate opportunities for improvement.
In current state, the problem is uncontrolled variability, which may be in terms of variability
in quality of raw material, or manufacturing processes.
Fig. 3.1 Difference between current manufacturing process and Quality by Design
Objective:
Primary objective:
To study and implement Quality by Design Approach for formulation development and
process optimization.
Secondary objective:
1. Formulation development of sustained release tablet by film coating using Quality by
Design approach

Chapter 4
PLAN OF WORK
26
PLAN OF WORK
Sr. No.
WORK TO BE DONE
1.
Literature survey
2.
Selection of drug
3.
Selection and Procurement of Excipients and Polymers
4.
Study of Quality Target Product profile for formulation
5.
6.
Study of Critical Quality attributes of formulation and coating process

Marketed product dissolution study
7.
Study of components of drug product

1 Drug
2
Polymers
Drug excipient compatibility studies
11.
Initial risk assessment for tablet formulation using FMEA
12.
Tablet Formulation development
13.
Coating process development

1
Coating formula development
Release optimization
3. Optimization of coating process parameters

11.
Study quality attributes of final batch
12.
Updated risk assessment for coating process
13.
Conclude design space and control strategy for

1
Raw material attributes

2
Tablet compression
Coating
14.
Stability Studies
15.
Conclusion

Chapter 5
MATERIALS AND EQUIPMENTS
27
MATERIALS AND EQUIPMENTS

Drugs and excipients
Drugs/ excipients
Provided by
Venlafaxine Hydrochloride
Cipla Pharmaceuticals, Mumbai
Eudragit RLPO, RSPO
Evonik Degussa,
Microcrystalline cellulose
Loba Chemie, Mumbai
Lactose
Loba Chemie, Mumbai
Talc
Loba Chemie, Mumbai
Magnesium Stearate
Loba Chemie, Mumbai
Acetone
Loba Chemie, Mumbai
Isopropyl alcohol
Loba Chemie, Mumbai
Table no. 5.1: List of drugs and excipients

Equipments
Instrument/Apparatus
Make and model
Planetary mixer
Gem pharma machineries
Tablet compression machine
Rimek minipress II, 12station
R and D coater
R and D coater, Ideal Cures
UV Visible Spectrophotometer
JASCO V-530
FT-IR Spectrometer
JASCO 460 plus
Tablet Dissolution Test Apparatus
Electrolab
Friability tester
Electrolab
Stability chamber
(Thermo lab, TH 200S).
Table no. 5.2: List of equipments

Chapter 6
DRUG AND EXCIPIENT PROFILE
28
DRUG AND EXCIPIENTS PROFILE

DRUG PROFILE
Venlafaxine Hydrochloride [43, 44, 45]
Sr.
No.
1.
Property
Description
Chemical
Structure
Venlafaxine is structurally and pharmacologically related to the

atypical opioid analgesic tramadol, and more distantly to the
newly released opioid tapentadol, but not to any of the
conventional antidepressant drugs, including tricyclic
antidepressants, SSRIs, MAOIs, or RIMAs.
(R/S)-1-[2-(dimethylamino)-1-(4 methoxyphenyl)ethyl]
cyclohexanol hydrochloride or ()-1-[a [a(dimethylamino)methyl] p-methoxybenzyl] cyclohexanol
hydrochloride.
C17H27NO2.HCl
3.
Chemical Name
4.
5.
Empirical
formula
Appearance
6.
Melting point
215-217 C
7.
Water solubility
572 mg/ml (Hydrochloride salt)
8.
Mode of action
Venlafaxine is usually categorized as a serotonin-norepinephrine

reuptake inhibitor (SNRI), but it has been referred to as a
serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI).
It works by blocking the transporter "reuptake" proteins for key
neurotransmitters affecting mood, thereby leaving more active
neurotransmitters in the synapse. The neurotransmitters affected
are serotonin and norepinephrine. Additionally, in high doses it
weakly inhibits the reuptake of dopamine, with recent evidence
showing that the norepinephrine transporter also transports some
dopamine as well, since dopamine is inactivated by
norepinephrine reuptake in the frontal cortex. The frontal cortex
largely lacks dopamine transporters, therefore venlafaxine can
It is a white to off-white crystalline solid.
FORMULATION AND EVALUATION OF SUSTAINED RELEASE FILM

COATED TABLETS USING QUALITY BY DESIGN (QbD) APPROACH
Chapter 6
Sr.
No.
9.
Property
Pharmacokinetics
10. Volume of
distribution
11. Contraindications
12. Drug interactions
13. Side effects
29
Description
increase dopamine neurotransmission in this part of the brain.
Venlafaxine interacts with opioid receptors (mu-, kappa1- kappa3and delta-opioid receptor subtypes) as well as the alpha2adrenergic receptor.
Venlafaxine is well absorbed, with at least 92% of an oral dose
being absorbed into systemic circulation. It is extensively
metabolized in the liver via the CYP2D6 isoenzyme to
desvenlafaxine (O-desmethylvenlafaxine), which is just as potent
a SNRI as the parent compound.Steady-state concentrations of
venlafaxine and its metabolite are attained in the blood within 3
days. Therapeutic effects are usually achieved within 3 to 4
weeks. The primary route of excretion of venlafaxine and its
metabolites is via the kidneys.The half-life of venlafaxine is
relatively short, so patients are directed to adhere to a strict
medication routine, avoiding missing a dose.
7.5 3.7 L/kg [venlafaxine]
5.7 1.8 L/kg [O-desmethylvenlafaxine(active metabolite)]
Paediatric age group
Allergic to the inactive ingredients, like gelatin, cellulose,
ethylcellulose, iron oxide, titanium dioxide and hypromellose.
Monoamine oxidase inhibitor (MAOI), as it can cause
potentially fatal serotonin syndrome
Glaucoma
Pregnant women
St John's wort.
Lowers seizure threshold with bupropion and tramadol
positive phencyclidine (PCP) results caused by large doses of
Venlafaxine.
Skin rash or hives; difficulty breathing; swelling of your face,
lips, tongue, or throat.
Mood or behavior changes, anxiety, panic attacks, trouble
sleeping, or if you feel impulsive, irritable, agitated, hostile,
aggressive, restless, hyperactive (mentally or physically), more
depressed, or have thoughts about suicide or hurting yourself.
blurred vision, tunnel vision, eye pain or swelling, or seeing halos
around lights; easy bruising; high levels of serotonin in the body agitation, hallucinations, fever, fast heart rate, overactive reflexes,
nausea, vomiting, diarrhea, loss of coordination, fainting;
low levels of sodium in the body - headache, confusion, slurred
speech, severe weakness, vomiting, loss of coordination, feeling
unsteady; or
severe nervous system reaction - very stiff (rigid) muscles, high

Chapter 6
Sr.
No.
Property
14. Dose
30
Description
fever, sweating, confusion, fast or uneven heartbeats, tremors,
feeling like you might pass out.
A.Usual Adult Dose for Depression
(a) Immediate release:
Initial dose: 37.5 mg orally twice a day or 25 mg orally 3 times a
day
Maintenance dose: May increase in daily increments of up to 75
mg at intervals of no less than 4 days
Maximum dose: (moderately depressed outpatients): 225 mg/day
Maximum dose (severely depressed inpatients): 375 mg/day
Daily dosage may be divided in 2 or 3 doses/day
(b) Extended release:
Initial dose: 75 mg orally once daily
Maintenance dose: May increase in daily increments of up to 75
Maximum dose (moderately depressed outpatients): 225 mg/day
Maximum dose (severely depressed inpatients): 375 mg/day
B. Usual Adult Dose for Anxiety:
Extended release:
Initial dose: 75 mg orally once daily
Maintenance dose: May increase in daily increments of 75 mg at
intervals of no less than 4 days
Maximum dose: 225 mg/day
C. Usual Adult Dose for Panic Disorder:
Extended-release:
Initial dose: 37.5 mg once a day
Maintenance dose: May increase dose in daily increments of 75
Maximum dose: 225 mg/day
PROFILES OF THE POLYMER [46, 47]

Eudragit RLPO
EUDRAGIT RL PO
EUDRAGIT RL PO is a copolymer of ethyl acrylate, methyl methacrylate and a low
content of methacrylic acid ester with quaternary ammonium groups. The ammonium
groups are present as salts and make the polymers permeable.

Chapter 6
Sr. No.
1.
Property
Physical properties:
Description
It is a solid substance in form of white powder with a
faint amine-like odour.
2.
Chemical structure
3.
4.
Product Form
Targeted Drug Release
Area
CAS number
Chemical/IUPAC
name
INCI name
Monographs
Powder
Time controlled release, pH independent
Drug Master File

Weight average molar
mass
Alkali Value
Glass Transition
Temperature (Tg)
# 1242
approx. 32,000 g/mol
5.
6.
7.
8.
9.
10.
11.
12.
31
33434 24 1
Poly(ethyl acrylate-co-methyl methacrylate-co
trimethylammonioethyl methacrylate chloride) 1:2:0.2
Acrylates / Ammonium Methacrylate Copolymer
Ph. Eur.: Ammonio Methacrylate Copolymer,
Type A
USP/NF: Ammonio Methacrylate Copolymer,
Type A - NF
JPE: Aminoalkyl Methacrylate Copolymer RS
28,1 mg KOH/ g polymer

63C (+/- 5C)

Chapter 6
32
Eudragit RSPO
EUDRAGIT RS PO is a copolymer of ethyl acrylate, methyl methacrylate and a low
content of methacrylic acid ester with quaternary ammonium groups. The ammonium
groups are present as salts and make the polymers permeable.
Sr. No.
1.
Property
Physical properties:
Description
It is a solid substance in form of white powder with a
faint amine-like odour.
2.
Chemical structure
3.
4.
Product Form
Targeted Drug Release
Area
CAS number
Chemical/IUPAC
name
INCI name
Monographs
Powder
Time controlled release, pH independent
Drug Master File

Weight average molar
mass
Alkali Value
Glass Transition
Temperature (Tg)
# 1242
approx. 32,000 g/mol
5.
6.
7.
8.
9.
10.
11.
12.
33434 24 1
Poly(ethyl acrylate-co-methyl methacrylate-co
trimethylammonioethyl methacrylate chloride) 1:2:0.1
Acrylates / Ammonium Methacrylate Copolymer
Ph. Eur.: Ammonio Methacrylate Copolymer,
Type A
USP/NF: Ammonio Methacrylate Copolymer,
Type A - NF
JPE: Aminoalkyl Methacrylate Copolymer RS
28,1 mg KOH/ g polymer

63C (+/- 5C)

Chapter 6
33
PROFILE OF OTHER EXCIPIENTS

Lactose Monohydrate [53]
Sr.
No.
Property
Description
1.
Chamical Structure
2.
CAS No.
10039-26-6
3.
Chemical Name:
LACTOSE, MONOHYDRATE
4.
CBNumber:
CB8685418
5.
Molecular Formula:
C12H24O12
6.
Formula Weight:
360.31
7.
MOL File:
10039-26-6.mol
8.
Melting point
~215 C (dec.)
9.
Solubility :
H2O: 0.5 M at 20 C, clear, colorless
Microcrystalline cellulose: [52]

Sr. No.
1.
Property
Chemical
formula
Description
(C6H10O5)n

Chapter 6
Sr. No.
2.
34
Property
Chemical
structure
Description
3.
4.
CAS No.
Uses
5.
6.
Density
pH
94700-07-9
Microcrystalline cellulose is a term for refined wood pulp
and is used as a texturizer, an anti-caking agent, a fat
substitute, an emulsifier, an extender, and a bulking agent in
food production.The most common form is used in vitamin
supplements or tablets. It is also used in plaque assays for
counting viruses, as an alternative to
carboxymethylcellulose.[2]
Approved within the European Union as a thickener,
stabilizer or emulsifiers microcrystalline cellulose was
granted the E number E460(ii) with basic cellulose given the
number E460(i)[3]
1.76 g/cm3
5-7.5
Polyvinylpyrrolidone [48, 49]

Polyvinylpyrrolidone (PVP), also commonly called polyvidone or povidone, is a watersoluble polymer made from the monomer N-vinylpyrrolidone.
Sr. No.
1.
Property
Chemical structure
Description
2.
3.
4.
5.
6.
Molecular formula
Molar mass
Appearance
Density
Melting point
7.
Uses
(C6H9NO)n
2.500 2.500.000 gmol1
White to light yellow, hygroscopic, amorphous powder
1.2 g/cm3
150 to 180 C (302 to 356 F; 423 to 453 K) (glass
temperature)
PVP was used as a plasma volume expander for trauma

Chapter 6
Sr. No.
Property
35
Description
victims after the 1950s.
It is used as a binder in many pharmaceutical tablets;[2] it
simply passes through the body when taken orally.
However, autopsies have found that crospovidone (PVPP)
contributes to pulmonary vascular injury in substance
abusers who have injected pharmaceutical tablets intended
for oral consumption.[3] The long-term effects of
crospovidone or povidone within the lung are unknown.
PVP added to iodine forms a complex called povidoneiodine that possesses disinfectant properties.[4] This
complex is used in various products like solutions,
ointment, pessaries, liquid soaps and surgical scrubs. It is
known under the trade names Betadine and Pyodine among
a plethora of others.
It is used in pleurodesis (fusion of the pleura because of
incessant pleural effusions). For this purpose, povidone
iodine is equally effective and safe as talc, and may be
preferred because of easy availability and low cost.[5]
Talc [50, 51]

Talc is a common metamorphic mineral in metamorphic belts which contain ultramafic
rocks, such as soapstone (a high-talc rock), and within whiteschist and blueschist
metamorphic terranes. USP grade talc is used as an inert filler in tablets and as a lubricant /
glidant in tablet coatings. Pharmaceutical grade talcs are also widely used in medicated
foot powders, creams, lotions, ointments and as a release agent in tablet molds.
Sr.
No.
1.
Property
Description
Synonyms
Talcum powder.
2.
Chemical Name
Hydrated magnesium silicate
3.
CAS No.
14807-96-6
4.
Empirical formula
Mg3Si4O10(OH)2
5.
Category
Silicate mineral

Chapter 6
Sr.
No.
6.
36
Property
Description
Specific gravity
2.52.8
7.
colour
white to grey
8.
Applications:
In medicine talc is used as a pleurodesis agent to prevent

recurrent pleural effusion or pneumothorax. In the European
Union the additive number is E553b. Talc finds use as a
cosmetic (talcum powder), as a lubricant, and as a filler in
pharmacueticals and cosmetic manufacturing. . Because of
talcs crystalline platy structure and softness, talc is used as a
lubricant or glidant in the manufacturing of pharmaceutical
tablets. It is also commonly used as an in ingredient in enteric
(time release) tablet coating formulations. Talc has been shown
to
improve
direct
compression
of
tablet
formulation
disintegration properties and can be used in combination with

magnesium stearate to restore disintegration and dissolution
properties caused by the addition of magnesium stearate as a
lubricant. Smaller particle size talcs have also been shown to
improve lubricant efficiency. USP grade talc is often found in
9.
Solubility:
medicated foot powders.

Talc is not soluble in water, but it is slightly soluble in dilute
mineral acids.
Magnesium stearate [56]

Sr. No.
1.
2.
3.
Property
Synonyms
Molecular Weight
Description
Description
Stearic acid magnesium salt, Magnesium octadecanoate.
125
Magnesium stearate is a fine, white, precipitated, milled,
impalpable powder of low bulk density, having a faint,
characterstic odour and taste. The powder is greasy to
touch and readily adheres to skin.
4.
Pharmaceutical
Uses
Magnesium stearate is widely used in cosmetics, foods

and pharmaceutical formulations. It is primarily used as

Chapter 6
Sr. No.
Property
37
Description
lubricant
in
capsule
and
tablet
manufacturing
at
concentration between 0.25-5.0% w/w.

5.
Solubility
Practically insoluble in ethanol, ethanol (95%), ether and

water, slightly soluble in warm benzene and warm ethanol
(95%).

Chapter 7
EXPERIMENTAL WORK
38
7.1. Analysis of drug

7.1.a. Analysis of Venlafaxine hydrochloride:
The drug sample was used without further purification. Characterization of drug was done by
physicochemical methods.
7.1.b. Organoleptic properties and description
The sample of Venlafaxine hydrochloride was studied for organoleptic characters like
appearance, color, and odor.
7.1.c. Melting point
The melting point was determined using melting point apparatus.
7.1.d. Solubility
The solubility of Venlafaxine hydrochloride was determined by adding excess amount of drug
in the solvent at 370C. Solubility was determined by taking supernatant and analyzing it on
U.V Spectrophotometer (Jasco).
7.1.e. U.V. Spectroscopy [30]
A standard stock solution of Venlafaxine hydrochloride was prepared by dissolving
accurately weighed 10 mg of Venlafaxine hydrochloride in quantity of 10 ml of water, then
appropriate dilutions were prepared and max was determined.
ProcedureDetection wavelengthPrepare 10 g/ml solution by following method,
Dissolve 10mg Venlafaxine hydrochloride in 10ml distilled water. Dilute 1ml of this solution
to 10ml with distilled water (SOLUTION A i.e. 100 g/ml). From this solution further
dilutions are made as 2-14 g/ml are carried out. Measure the absorbance of above solution
and find out the detection wavelength.

Chapter 7
EXPERIMENTAL WORK
39
7.1.e.1. Linearity and rangeDilute aliquots of each A to 10ml with Distilled Water so as to get solutions of concentration
2, 4, 6, 8, 10, 12, 14g/ml and measure the absorbance of each of above dilution at detection
wavelength.
Find out the equation of line and regression coefficient (R2) from linearity graph.
7.1.e.2. PrecisionPrepare 6 replicates of SOLUTION of 12 g/ml and measure the absorbance of each. Find
out standard deviation and average. Find out %RSD as follows,
(S.D/AVG)* 100
It must be less than 2
7.1.f. Assay: (BP) [69]
Procedure: Dissolve 0.25 g in a mixture of 5 ml of 0.01 M hydrochloric acid and 50 ml of
ethanol (96%). Carry out a potentiometric titration using 0.1 M sodium hydroxide. Read the
volume added between 2 points of inflexion. Carry out a blank titration.
1ml of 0.1M NaOH is equivalent to 31.39 mg C17H28ClNO2.
7.1.g. Infra-red spectroscopy:
The IR spectrum of the pure drug was obtained to prove the chemical identity of the drug.
The drug was powdered and intimately mixed with dry powdered potassium bromide. IR
spectrum was recorded by scanning in the wavelength region of 400 to 4000 cm1 in a FTIR
Spectrophotometer (model 460 Plus, Jasco, Japan).
7.2. Excipient compatibility studies:
A compatibility study of drug with excipients is an early risk reduction strategy which
precludes the use of excipients which may interact with the drug substance.
Drug was triturated with individual excipients in 1:1 ratio. The samples were stored for 4
weeks and analyzed by IR spectroscopy.
Chapter 7
EXPERIMENTAL WORK
40
7.3. Dissolution study of marketed Venlafaxine Tablets:[70]

Venlafaxine sustained release matrix tablets are available in market. A dissolution study of
marketed tablets (Ventab XR 37.5) was carried out for 24 hrs. A USP dissolution type II
apparatus was used. Speed was adjusted at 50 rpm. Deaerated water was used as a dissolution
medium.
7.4. Quality by Design Protocols
7.4.a. Quality target product profile (QTPP) for Venlafaxine Hydrochloride sustained
release tablet:
taking into account safety and efficacy of the drug product.
The QTPP is an essential element of a QbD approach and forms the basis of design of the
generic product. For ANDAs, the target should be defined early in development based on the
properties of the drug substance (DS), characterization of the RLD product and consideration
of the RLD label and intended patient population. The QTPP includes all product attributes
that are needed to ensure equivalent safety and efficacy to the RLD. Based on the clinical and
pharmacokinetic (PK) characteristics as well as the in vitro dissolution and physicochemical
characteristics of the RLD, a quality target product profile (QTPP) was defined for
Venlafaxine Hydrochloride Tablets. It included following parameters:
Dosage form and type

Route of administration
Potency
Appearance
Identification
Assay
Impurities
Content Uniformity
Dissolution
Hardness, Friability
Pharmacokinetics

Chapter 7
EXPERIMENTAL WORK
41
% Coating Defects
Coating colour uniformity
7.4.b. Critical quality attributes:

Critical Quality attributes indicate the attributes which were classified as drug product critical
quality attributes (CQAs). CQAs are those that have the potential to be impacted by the
formulation and/or process variables and, therefore, were investigated and discussed in detail
in subsequent formulation and process development studies.
On the other hand, if CQAs include Dosage form and type, route of administration, potency,
appearance, identification which are unlikely to be impacted by formulation and/or process
variables were not discussed in detail in the pharmaceutical development report. However,
these CQAs are still target elements of the QTPP and are ensured through a good
pharmaceutical quality system and the control strategy.
7.4.c Risk assessment for Drug substance attributes:[9]
According to ICH Q9 Quality Risk Management, it is important to note that it is neither
always appropriate nor always necessary to use a formal risk management process (using
recognized tools and/or internal procedures e.g., standard operating procedures). The use of
informal risk management processes (using empirical tools and/or internal procedures) can
also be considered acceptable. Appropriate use of quality risk management can facilitate but
does not obviate industrys obligation to comply with regulatory requirements and does not
replace appropriate communications between industry and regulators.
The two primary principles considered when implementing quality risk management:
The evaluation of the risk to quality should be based on scientific knowledge and ultimately
link to the protection of the patient; and
The level of effort, formality and documentation of the quality risk management process
should be commensurate with the level of risk.
Based upon the physicochemical and biological properties of the drug substance, the initial
risk assessment of drug substance attributes on drug product CQAs was done.
Risk assessment using FMEA: FMEA provides for an evaluation of potential failure modes
for processes and their likely effect on outcomes and/or product performance.
Chapter 7
EXPERIMENTAL WORK
42
Steps: [11]
1. Selection of the process
2. Review of the process
3. Brainstorm potential failure modes
4. List of potential effects of each failure mode
5. Assign a severity rating for each effect
6. Assign an occurrence rating for each failure mode
7. Assign a detection rating for each failure mode and effect
8. Calculation of the risk priority number (RPN) for each effect: (RPNs) = ODS
9. Prioritize the failure modes for action
10. Taken action to eliminate or reduce the high risk failure modes
11. Improvement index (II): II = (RPN before improvement) / (RPN after improvement)
Score scale for frequency of occurrence
Failure
Very High: (Failure is almost
inviolable)
High: (Repeated failure)
Probability of failure
1 in 2
1 in 3
1 in 8
1 in 20
Moderate: (Occasional failure)
1 in 80
1 in 400
1 in 2000
Low: (Relatively few failure)
1 in 15000
1 in 150000
Remote: (Failure is unlikely)
1 in 1500000
Table No.7.1 Score scale for frequency of occurrence
Occurrence Ranking
10
9
8
7
6
5
4
3
2
1
Score scale for probability of detection

Detection
Criteria
Impossible to detect
Remote detection
Very slight detection
No known techniques available

Only unreliable technique available
Providing durability tests on products with system
Detectio
n
Ranking
10
9
8

Chapter 7
EXPERIMENTAL WORK
components installed
On product with prototypes with system
components installed
Low detection
On similar system components
Medium Detection
On preproduction system components
Moderate detection
On early prototype system elements
Good detection
Simulation and modeling in early stage
High chance of detection
Proven analysis available in early design stage
Certain to detect
Proven detection methods available in concept
stage
Table No.7.2 Score scale for probability of detection
Slight detection
43
7
6
5
4
3
2
1
Score scale for severity

Severity
Hazardous without
warning
Hazardous with warning
Very high
High
Moderate
Low
Very low
Minor device
Very minor
Effect
Without warning, people can get severely
wounded
May cause hazards, with warning
Loss of primary function
Highly reduced level of performance
Reduced level of performance
Slightly reduced level of performance
Defect noticed by most of the customers
Defect noticed by average customers
Defect noticed by discriminating
customers
None
Almost no effect
Table No.7.3 Score scale for severity
Severity Ranking
10
9
8
7
6
5
4
3
2
1
7.5. Formulation development:

Initial risk assessment was done and CQAs were identified. Focusing on coating process, a
formulation fulfilling all requirements of hardness, friability, size and shape was developed.
7.5.a. Preparation of tablets:
7.5.a.1. Selection of excipients:[49]
Various excipients were selected for good tabletting purpose. Lactose monohydrate was used
as filler. Microcrystalline starch cellulose was also used as filler, having additional binding
properties. PVP was used as binder (added later in the formula, when process was finalized).
Talc and Magnesium stearate which are hydrophobic in nature were used as glidant and
lubricant respectively.
Sr. No.
Excipient Name
% of Tablet Wt
Weight in mg

Chapter 7
EXPERIMENTAL WORK
1.
Lactose monohydrate
2.
Microcrystalline Cellulose
3.
PVP(solution)
4.
Magnesium Stearate
5.
Talc
Table No. 7.4 Formula for core tablets
-(q.s.)
5%
2.5%
1.5%
2%
44
qs
10
5
3
4
7.5.a.2. Selection of process for preparation of tablets: [71]

Tablet formulations were prepared by both direct compression and wet granulation technique.
Required quantities of drug and excipients were mixed thoroughly. Tablet blend was checked
for flow properties.
The granules were also prepared by same formula, and checked for flow properties.
(Lubricant: L, Glidant: G)
Batch
1.5
1.5
0.5
0.5
1.5
0.5
2.5
2.5
2.5
Table No. 7.5 Overview of levels of lubricant and glidant at different levels
The tablets were compressed using 8mm concave punches on a Rimek Mini Press-II tablet
compression machine.
7.6. Evaluation of preliminary batches: [68]
a) Hardness
The hardness was tested using Monsanto tester. Hardness factor, the average of the three
determinations, was determined.
b) Thickness
Thickness of the tablets was measured using vernier calipers.
c) Uniformity of weight
Twenty tablets were weighed individually. Average weight was calculated from the total
weight of all tablets. The individual weights were compared with the average weight. The
percentage difference in the weight variation should be within the acceptable limits
Chapter 7
EXPERIMENTAL WORK
45
(7.5%). The percent deviation was calculated using the following formula.
% Deviation = Individual weight Average weight
x 100
Average weight
Not more than two of the individual weights deviate from the average weight by more than
7.5% and none deviates by more than twice that percentage.
d) Friability Test
Roche Friabilator was used to measure the friability of the tablets. Ten tablets were weighed
collectively and placed in the chamber of the Friabilator. It was rotated at a rate of 25 rpm. In
the Friabilator, the tablets were exposed to rolling, resulting from free fall of tablets within
the chamber of the Friabilator. After 100 rotations (4 minutes), the tablets were taken
out from the Friabilator and intact tablets were again weighed collectively.
Permitted
friability limit was 1.0%. The percent friability was determined using the following formula.
(W1 W2)
Friability =
x 100
W1
Where, W1 = weight of the tablets before test, W2 = weight of the tablets after test
7.7. Coating Process Development:

CQAs were identified and risk assessment was done using FMEA.
7.7.a. Coating Formula Development

7.7a.1. Selection of solvents based on viscosity and drying time: [59]
Sr. No.
1.
Solvent
Ratio
Water: Ethanol
1:9

Chapter 7
EXPERIMENTAL WORK
Sr. No.
Solvent
Ratio
2.
Water: IPA
1:9
3.
Water: Acetone
1:9
4.
IPA: Acetone
4:6
46
Table No. 7.6: Solvent combinations and their ratios

Various solvents as described above were selected in varying ratios. The viscosities were
measured using Ostwalds viscometer. Selected ratios were further checked for drying time. A
ratio, in which drying time was lowest, was selected.
7.7.a.2. Selection of Plasticizer based on stickiness and folding endurance [58, 72]
Polyethylene glycol and triethyl citrate were chosen as plasticizers. Initial trials were taken at
a concentration of 0.2% of each. Further trials were taken with 0.4% and 0.6% concentration
of previously chosen plasticizer.
7.7.a.3. Effect of fillers on film roughness:
Fillers are said to increase film adherence and bulk. Their effect on roughness and folding
endurance was checked. Fillers like lactose, talc, microcrystalline starch were used for study.
7.7.a.4. Selection of ratio of sustained release polymer: [73]
The objective of this work was to prepare sustained release tablet of Venlafaxine
hydrochloride. The work thus involves use of Eudragit polymer for the SR formulation.
An initial coating using Eudragit RLPO and RSPO alone was done. Eudragit RSPO was used
in combination to Eudragit RLPO, which is a water impermeable polymer.
Various ratios of polymer were selected, as shown in table below and depending on which
ratio gives proper dissolution, a ratio was selected. Percentage weight gain was kept constant
(5%) initially.
In vitro Dissolution study:
In-vitro drug release study of the samples was carried out using USP type II dissolution
Chapter 7
EXPERIMENTAL WORK
47
apparatus (Peddle type). The dissolution medium, 900 ml of deaerated water, was placed
into the dissolution flask maintaining the temperature of 37 0.5 0C and rpm of 50.
Tablets were placed in each basket of the dissolution apparatus. The apparatus was allowed to
run for 24 hours. Samples measuring 5 ml were withdrawn after every 1 hour up to 24 hours
manually and samples were filtered. The fresh dissolution medium was replaced every
time with the same quantity of the sample withdrawn. Collected samples were analyzed
at 225 nm using water as blank. Percentage drug release was calculated.
Sr. No.
Eudragit RLPO
Eudragit RSPO
1.
2.
3.
4.
5.
Table No.7.7 Selection of ratio of sustained release polymer

7.7.a.5. Selection of % weight gain: [73]
Selected polymer ratio was used for this study. Coating at 7.5% and 10 % weight gain was
also achieved. Dissolution study (24 hrs) was carried out, and results were compared.
The value of % weight gain which gives complete and more sustained release over 24 hours
was selected.
7.7.b. Preparation of coating solution:

Accurately weighed quantities of polymers were dissolved in solvents. Selected amount of
triethyl citrate was added. Sunset yellow color was added. The resulting solution was stirred
for 15 min on a magnetic stirrer to ensure complete dissolution of polymer. It was then
filtered using Whatmann filter paper to remove undissolved particles of color, if any.
7.7.c. Optimization of process parameters
7.7.c.1. Selection of process parameters:
Initially, solid content was varied between 1%- 4%. Initial trial batches were taken by
Chapter 7
EXPERIMENTAL WORK
48
changing different process parameters like:
Temperature
Pan load
Pan Speed
Atomization pressure etc.
Polymer
Amount
Pan Load
(No. of
(% w/v)
tablets)
1.
2.
Study
Temperature
Atomization
(0 c)
Pan speed
(RPM)
50 tabs
300 c
30
5 lb/in2
50 tabs
400 c
30
5 lb/in2
3.
200 tabs
400 c
30
5 lb/in2
4.
200 tabs
600 c
40
5 lb/in2
5.
200 tabs
600 c
50
15 lb/in2
6.
200 tabs
600 c
30
10 lb/in2
7.
200 tabs
600 c
40
10 lb/in2
No.
pressure
(lb/in2)
Table No.7.8 Process parameters and polymer amount for preliminary batches
7.7.c.2. Evaluation of preliminary batches [74]
1
Percentage of weight gain: It is percentage the difference between weights of tablets
before and after coating.

% Wt gain = [(Final wt Initial Weight)/Initial Weight] X 100
Coating Process Efficiency (CPE): CPE actual percent weight gain relative to the
theoretical percent. Coating process efficiency was determined by the following equation.
CPE = (%wga/%wgt) 100%
where wgt is the theoretical percent weight gain and wga is the actual percent weight
gain.
Tablet Surface roughness: It is not considered as individual defect, but overall surface
texture of the batch. Specialized tablet surface roughness equipments are available, but
for laboratory purpose, it is ranked as 1: Very smooth, 2: Slightly rough, 3: Very rough
Picking and sticking: The tablets show coating material pulled from the tablet surface
5
6
7
8
9
and/or coating material deposited on the surface.

Breakage: Tablets are broken during coating run.
Edge erosion: The edges of the tablets are worn away or damaged during the coating run.
Peeling: The coating peels away from the tablet surface.
Tablet to tablet colour variation: The colour of tablets is uneven within the batch.
Twinning: Two or more tablets are stuck together.
Chapter 7
EXPERIMENTAL WORK
49
10 Orange peel roughness: The entire surface of the tablet appears rough, like a surface of an
orange.
11 Colour variation: The colour of individual tablets is uneven or non-uniform.
7.7.c.3. Effect of temperature on quality of coating:[35]
For this study, three batches were coated with temperatures 300c, 400c and 600c whereas
concentration, load and pan speed were kept constant.
Concentrati
Temperatu
on
re
(% w/v)
Load
(No. of tablets)
Pan speed
(RPM)
300c
400c
50
40
600c
Table No. 7.9 Effect of temperature on quality of coating
7.7.c.4. Effect of pan load on Coating process efficiency:

Concentration
Temperature
Pan speed
(% w/v)
(0c)
(RPM)
600c
40
Load
50
200
300
415
Table No.7.10 Effect of pan load on coating process efficiency

7.7.c.5. Effect of Solid content, pan speed and atomization pressure on Process
efficiency, defects, and tablet roughness.

Chapter 7
EXPERIMENTAL WORK
50
Based on risk assessment using FMEA and initial trials, process parameters like solid content,
pan speed, atomization pressure which were identified as CQAs were varied.
Goal of present study was to select levels of above stated parameters and to study their
interactions.
Levels of parameters were set referring to those in initial studies. Experiment was designed
by Box-Behnken design using Stat-Ease Design Expert Software.
Independent variables
Solid Content (%)
Pan Speed
Atomization Pressure
Dependant variables
-1
0
+1
3
4.5
6
40
55
70
5
10
15
Process efficiency, no. of defects, and
tablet roughness.
Table No.7.11 Overview of Independent and dependent variables in the design of

experiments
Temperature and Pan load were kept constant.
Design layout
Sr.
no.
1.
Concentratio
n
(% w/v)
3
Pan
Speed
(RPM)
40
Atomization
Pressure
(lb/in2)
10
2.
55
3.
55
15
4.
70
10
5.
4.5
40
6.
4.5
40
15
7.
4.5
55
10
8.
4.5
55
10

Chapter 7
EXPERIMENTAL WORK
Sr.
no.
9.
Concentratio
n
(% w/v)
4.5
Pan
Speed
(RPM)
55
Atomization
Pressure
(lb/in2)
10
10.
4.5
55
10
11.
4.5
70
12.
4.5
70
15
13.
40
10
14.
55
15
15.
55
16.
70
10
51
Table No.7.12 Design layout Box-Behnken Design

7.8. Updated risk assessment of formulation and process variables:[9,11]
Acceptable ranges for the high risk formulation variables have been established and were
included in the control strategy. Based on the results of the formulation development studies,
risk assessment of the formulation and process variables was updated.
7.9. Defining Design Space: [2, 60]
ICH Q8 (R1) defines design space as, the multidimensional combination and interaction of
input variables (e.g., material attributes) and process parameters that have been demonstrated
to provide assurance of quality.
This definition evolved from early ICH Q8 drafts where design space was defined as the
established range of process parameters that has been demonstrated to provide assurance of
quality. The Design Space is linked to criticality through the results of risk assessment,
which determines the associated CQAs and process parameters. It describes the multivariate
functional relationships between CQAs and the process parameters that impact them. The
Design Space also contains the proven acceptable ranges (PAR) for process parameters and
acceptable values for their associated CQAs.

Chapter 7
EXPERIMENTAL WORK
52
By combining the results of all performed studies final design space were defined as per
quality target product profile.
7.10. Defining control strategy:[2]
The control strategy for Venlafaxine hydrochloride SR Tablets was built upon the outcome of
extensive product and process understanding studies. These studies investigated the material
attributes and process parameters that were deemed high risk to the CQAs of the drug product
during the initial risk assessment. Through these systematic studies, the CMAs and CPPs
were identified and the acceptable operating ranges were established. All variables ranked as
high risk in the initial risk assessment were included in the control strategy because the
conclusion of the experiments was dependent on the range(s) studied and the complex
multivariate relationship between variables. Thus, the control strategy is an integrated
overview of how quality is assured based on current process and product knowledge.
Controls can include parameters and attributes related to:
Drug substance
Excipients
Facility and equipment operating conditions
In-process controls
Finished product specifications

Chapter 8
RESULTS AND DISCUSSION
53
8.1. Analysis of drug:

8.1.a. Analysis of Venlafaxine hydrochloride:
The drug sample was used without further purification. Characterization of drug was done by
physicochemical methods.
8.1.b. Organoleptic properties and description:
Appearance: Amorphous powder
Color: White
Odor: Odorless
8.1.c. Melting point:
The melting point was determined by open capillary method. It was found to be 215 0c,
within given range of the reported results.
8.1.d. Solubility:
Venlafaxine is soluble in water, ethanol, methanol, acetone and isopropyl alcohol.
8.1.e. U.V. Spectroscopy:
ProcedureMaximum absorption wavelength was found at 225 nm.
8.1.e.1. Linearity and range:
Solution was found to be linear over given range.
R
0.995
Linearity Equation
y = 0.024x + 0.004
Table No. 8.1: R2 value and linearity equation

Chapter 8
54
0.4
0.35
f(x) = 0.02x + 0
R = 1
0.3
0.25
0.2
0.15
0.1
0.05
0
0
10
12
14
16
Fig. No. 8.1 Linearity of Venlafaxine

8.1.e.2. Precision:
System Precision: % RSD was found to be 0.0006%.
Intraday Precision: % RSD was found to be 1.22%.
Interday Precision: % RSD was found to be 1.299%.
8.1.f. Assay: (BP)
% purity of Venlafaxine was found to be 100.208 % w/w.
8.1.g. Infra-red spectroscopy:
Fig. No.8.2: Infrared Spectrum for Venlafaxine Hydrochloride

Chapter 8
Functional Group
Range
Observations
Hydoxyl
3300-3400 cm-1
3321.42 cm-1
Benzyl
1500-1600 cm-1
1514.12 cm-1
Aliphatic CH
2800-3000 cm-1
2943.37 cm-1
C-O-C
1000-1200 cm-1
1039.63 cm-1
55
Table No.8.2 IR Functional Group ranges and observations

Functional groups like hydroxyl, benzyl, aliphatic CH, ether and their ranges were observed
Fig. No.8.3: IR Spectrum of Eudragit RLPO
Fig. No.8.4: IR spectrum of Eudragit RSPO

8.2. Excipient compatibility studies:
IR spectra of drug with excipients showed characteristic peaks for the drugs. This shows that
there is no interaction of the drug with excipients.

Chapter 8
56
Fig. No.8.5: Overlay spectra of pure drug(black) with a mixture of drug and Lactose
Fig. No. 8.6 Overlay spectra of pure drug with a mixture of drug and Microcrystalline
Cellulose(black)
Fig. No. 8.7: Overlay spectra of pure drug with a mixture of drug and Talc(black)

Chapter 8
57
Fig. No. 8.8 Overlay spectra of pure drug with a mixture of drug and Magnesium
Stearate(black)
8.3. Dissolution study of marketed Venlafaxine Tablets:

Dissolution study was carried out for tablets Ventab XL (37.5 mg), manufactured by Intas
Pharmaceuticals. Manufacturing date was June 2014, and expiry date was May 2017.
Tablets showed 21.84% release in 2 hrs, 58.40% in 6 hrs, 70.34% in 8 hrs, 90.34% in10 hrs,
92% release in 12 hrs, and 99.66% release in 24 hrs. This gave a reference profile for
developing sustained release tablets by film coating approach.
% Release
%
R
e
l
e
a
s
e
100
80
60
% Release
40
20
0
-1
14
19
24
Time in hrs
Fig. No. 8.9: Dissolution study of marketed tablets

Chapter 8
58
8.4. Quality by Design Protocols

8.4.a. Quality target product profile (QTPP) for Venlafaxine Hydrochloride sustained
release tablet
taking into account safety and efficacy of the drug product.
QTPP
Dosage form and type
TPP
Sustained release film
coated tablet.
TPQP
Sustained release
over 24 hrs
Route of
administration
Potency
Appearance
Identification
Assay
Oral
Justification
Sustained release over
24 hrs, ease of
administration
Ease of administration
37.5 mg
Round, convex tablets
Venlafaxine tablets
98-102 % w/w of
label claim
Minimal impurities
Assay
IR, UV spectra
-
Efficacy
Patient compliance
Efficacy
Efficacy
Individual : NMT
0.2%
Total : NMT 0.5%
-
Efficacy
5kP
Stability during
transport and shelf life
Stability during
transport and shelf life
Bioequivalence
Impurities
Dissolution
Hardness
Equivalent to or better
than RLD
Sufficient
Friability
Minimum
NMT 1 %
Pharmacokinetics
PK parameters AUC
and C max fall within
BE limits
Good performance
and minimal defects
Uniform color
C max = 150ng/ml
% Coating Defects
Coating colour
uniformity
< 5%
Uniform color
Therapeutic effect
Efficacy and patient

compliance
Efficacy and patient
compliance
Table No.8.3 Quality Target Product Profile

8.4.b. Critical quality attributes:
Quality attributes of Venlafaxine Hydrochloride tablets and indicates which attributes were
classified as drug product critical quality attributes (CQAs). For this product Dissolution,
Assay, No. of defective tablets, tablet surface roughness, coating process efficiency were
identified as the CQAs that have the potential to be impacted by the formulation and/or
Chapter 8
59
process variables and, therefore, will be investigated and discussed in detail in subsequent
formulation and process development studies.
On the other hand, if CQAs include Dosage form and type, route of administration, potency,
appearance, identification, coating color uniformity, which were unlikely to be impacted by
formulation and/or process variables will not be discussed in detail in the pharmaceutical
development report. However, these CQAs were still target elements of the QTPP and were
ensured through a good pharmaceutical quality system and the control strategy.
Various Attributes affecting tablet properties
(++high effect, + moderate effect, - low effect)
Quality
Attributes
Salt form
Appearance
Identification
Microbiology
Dissolution
Hardness
Assay
Flow
Taste
Degradation
Impurities
+
+
++
-
Effect of API on product quality

Particle
Solubility
Purity
Residual
size
solvent
++
++
++
++
++
++
Table No.8.4: API Attributes
Moisture
+
+
++
It can be seen from table no. 8.4 that quality attributes that are affected by API attributes are
dissolution, flow, taste, and impurity profile.
Effect of Excipient on product quality
Magnesium
Talc
Eudragit RLPO/
Quality Attributes Lactose
(Diluent)
Stearate
(Glidant)
RSPO (Polymer)
(Lubricant)
Appearance
+
+
+
Identification
Microbiology
Dissolution
++
Hardness
Assay
Flow
+
+
++
Taste
Degradation
Impurities
Table No.8.5 Excipient Attributes
Chapter 8
60
It can be seen from table no. 8.5 that quality attributes affected by excipient attributes are
dissolution, and flow.
Quality Attributes
% CPE
No. of Defective
Tablets
Tablet Moisture
Surface Roughness
Dissolution
Moisture
Effect of coating material parameters on product quality

Solution Viscosity Amount of coating
Type of solvent
solution
++
++
+
++
+
+
++
Table No.8.6: Coating Material Attributes
++
++
++
It can be seen from table no. 8.6 that all quality attributes affected by coating material
attributes.
Quality Attributes
Appearance
Identification
Dissolution
Hardness
Assay
Flow
Taste
Degradation
Impurities
Effect of process parameters on product quality

Mixing
Granulation
Lubrication
Compression
+
++
++
++
+
++
++
++
Table No.8.7: Tablet Compression Process Parameters
Dissolution, assay, hardness and flow are affected by tabletting process parameters.
Quality Attributes
Effect of coating process parameters on product quality

Pan Speed
Pan load
Spray
Temperature
Pressure
CPE
++
No. of Defective Tablets
++
++
++
+
Tablet Moisture
+
Surface Roughness
+
+
Dissolution
Table No.8.8: Coating Process Parameters
No. of defective tablets, Coating process efficiency are affected by coating process
parameters.

Chapter 8
CQAs
Appearance
Identification
Dissolution
Hardness
Assay
Flow
Taste
Degradation
Impurities
% CPE
No. of Defective
Tablets
Tablet Moisture
Surface Roughness
61
Variables and Process Parameters

Excipient
Tabletting
Coating Process
Attributes
process
Low
High
High
Low
Low
Low
High
High
High
High
High
Low
Low
High
Low
High
High
Low
Moderate
Low
High
Low
Low
Low
Low
Low
Low
Low
Low
High
Low
Low
High
API
Attributes
Low
Low
High
Low
High
Low
High
Low
Low
Low
Low
Low
Low
Low
Low
Low
Low
High
High
Table No.8.9: Identification of CQAs using Initial Risk Assessment
Sr. No.
1
2
3
4
5
6
CQAs
Dissolution
Hardness
Friability
No. of defective tablets
Coated Tablet Roughness
Coating Process Efficiency
Critical Process parameters

Coating Polymer/s, Ratio
Process of tabletting (Direct
compression/Granulation)
Process variables:
Temperature, Pan load,
Pan Speed, Atomization Pressure
Table No.8.10: Critical Quality Attributes

8.4.c Risk assessment for Drug substance attributes:
Failure Mode and effects:
(S- Severity ranking, O- Probability of Occurrence, D- Probability of detection, RPN- Risk
priority number)
Sr.
No.
1.
Failure
Mode
Receiving
incorrect
material
Failure
Effect
Contamina
tion, cross
contaminat
ion in raw
material
Failure Cause
Incorrect check
during receiving
of raw material
Control
Measure
Approved
Vendor
D RPN
1 16

Chapter 8
Sr.
No.
2.
Failure
Effect
Non
uniformity
Improper
mixing
Failure Cause
4.
Mixing speed
Improper
mixing
5.
Mixing load
Improper
mixing
6.
Compression
7.
Compression
8.
Compression
9.
Coating
10.
Spraying
11.
Coating
12.
Coating
13.
Coating
Non
uniform
release of
dose
Non
uniform
release of
dose
Weight
variation
Poor film
formation
Development of
droplets
Poor film
formation
Breakage,
picking,
sticking,
color
variation
Twinning,
picking
and
sticking
Mistake in sieve
no.
Equipment
problem, time not
followed as per
BMR
Equipment
problem, speed
not followed as
per BMR
Load excess or
less than
equipment
capacity
Improper
compression
force
3.
Failure
Mode
Improper
mixing
Mixing time
62
D RPN
Control
Measure
Proper checking,
follow BMR
Follow BMR
Follow BMR
1 12
Follow BMR
1 10
Follow BMR
1 14
Unspecified
diameter and
thickness
Follow BMR for

die and punch
specification
1 12
Flow property of
granules
Lack of
experience
Lack of
experience
Improve flow
properties
Change the
solution
Adjustment of
spray gun
1 42
Pan load
1 48
Pan speed
Adjustment of
pan load
Adjustment of
pan speed
Atomization
pressure
Adjustment of
atomization
pressure
1 56
8
6
6
5
1 21
1 12
5 240
3 90
4 160
Table no. 8.11 Failure mode, effect, cause, measure with RPN calculation

Chapter 8
63
Severity Ranking
When severity ranking is 8, it states loss of primary function. Thus this ranking is given to:
Receiving incorrect raw material: Loss of primary function i.e. effect of active
ingredient
Coating (improper spraying, poor film formation and defects) Loss of primary
function i.e. sustained release over long time.
When severity ranking is 7, it states highly reduced level of performance. Thus this ranking is
given to:
Improper mixing (mistake in sieve number): It will affect uniformity of blend and
flow.
Improper compression force: It will affect hardness and thickness resulting in
improper release.
When severity ranking is 6, it states reduced level of performance. Thus this ranking is given
to:
Improper mixing (Mixing time, mixing speed): It will affect uniformity of blend.
Compression (Weight variation): The batch may fail due to more tablets falling
outside the limits.

Improper spraying (Development of droplets): There may be delay due to improper
spray pattern.
When severity ranking is 5, it states slightly reduced level of performance. Thus this ranking
is given to:
Improper mixing (Improper mixing load): There may be some problem with capacity
of mixing equipment, and result in delay in manufacturing time.
Occurrence Ranking
When occurrence ranking is 7, it states repeated failure. Thus this ranking is given to:
Improper compression due to variable flow property. This may affect weight
variation. Thus IPQC checks should include weight variation testing.

Chapter 8
64
Improper coating due to variable atomization pressure. This may happen due to
variability in pump pressure. Thus IPQC checks should include atomization pressure
testing at frequent time points.
When occurrence ranking is 6 and 5, it states occasional failure. Thus this ranking is given to:
Improper coating due to poor film formation. This depends on operators skill and
knowledge about parameters like solution properties, spray pattern and pan speed.
Thus failure is occasional.
When occurrence ranking is 3 and 2, it states relatively few failures. Thus this ranking is
given to:
Incorrect check during receiving of raw material

Mistake in sieve no.
Improper time and speed
Load excess or less than equipment capacity
Improper compression force, unspecified diameter and thickness
All of the above types of failures depend on following BMR. Thus these types of failures are
relatively few.
Detection Ranking
When detection ranking is 5, it states detection on preproduction system components. Thus
this ranking is given to:
Poor film formation due to different coating solution: Changes in coating solution can
be detected before starting of coating process.
When detection ranking is 4, it states moderate detection. Thus this ranking is given to:
Various coating defects: These types of failures are detectable on early prototype
system elements.
When detection ranking is 3, it states good detection. Thus this ranking is given to:

Chapter 8
65
Poor film formation: These types of failures show good detection at simulation and
modelling in early stage.
When detection ranking is 1, it states certain to detect, i.e. proven detection methods available
in concept stage. Thus this ranking is given to:
Receiving incorrect material

Improper mixing
Compression
Coating
Different proven analytical methods are available for detection of these types of failure.
8.5. Formulation development:
Initial risk assessment is done and CQAs were identified. Focusing on coating process, a
formulation fulfilling all requirements of hardness, friability, size and shape is developed.
8.5.a. Preparation of tablets:
8.5 a.2. Selection of process for preparation of tablets:
Flow properties of powder blend
Batch
Housners
Ratio
Carrs
index
1
1.332
2
1.466
3
1.394
4
1.461
5
1.461
6
1.394
7
1.428
8
1.62
9
1.032
25
31.7
28.2
31.57
31.57
28.2
30
38.46
35
Table no. 8.12 Flow properties of powder blend

Flow properties of granules
Batch
Housners
Ratio
Carrs
index
1
1.09
2
1.09
3
1.1
4
1.09
5
1.1
6
1.095
7
1.1
8
1.09
9
1.15
8.69
8.69
9.09
8.33
9.09
8.69
9.09
8.69
13.04
Table no. 8.13 Flow properties of granules

Chapter 8
66
In case of dry blend, out of various batches batch no. 9 shows excellent housners ratio, but
Carrs index was very poor. This may be due to In case of batch 1, Carrs index and
Housners ratio was only passable. This may be due to a high difference in bulk and tapped
density. On the other hand, in case of granules all batches show good to excellent Housners
ratio and Carrs index, since interparticle interactions lessen due to granulation technique.
Overall dry blend flow properties were not satisfactory; hence granulation was used as a
tabletting method.
8.6. Evaluation of preliminary batches

Hardness of all batches was found to be within limits. Thickness was measured with the help
of vernier calipers. All batches pass test for uniformity of weight. Friability results were much
below the limit, i.e. 1%, for all batches.
Batch
Hardness
5.5
5.5
5.5
Thickness
2.44
0.03
2.44
0.05
2.44
0.06
2.44
0.04
2.44
0.05
2.44
0.04
2.44
0.03
2.44
0.03
2.44
0.03
Uniformity
of weight
Passe
s
Passes Passes Passes
Passes
Passes
Passes
Passes
Passes
Friability
Test
0.15
0.18
0.12
0.16
0.12
0.22
0.26
0.15
0.13
Table no.8.14: Results of evaluation of preliminary batches

Assay was done for selected batch and was found to be 99.92%
8.7. Coating Process Development:
CQAs were identified and risk assessment was done using FMEA.
8.7.a. Coating Formula Development

Chapter 8
67
8.7a.1. Selection of solvents based on viscosity and drying time:

Solvent
Water: Ethanol
Water: IPA
Water: Acetone
IPA: Acetone
Ratio
1:9
1:9
1:9
4:6
Viscosity (cp)
1.0501
2.1986
0.417
0.8483
Table no.: 8.15: Viscosities of solvents

Water: Acetone (1:9) and IPA: Acetone (4:6) was found to have lower (0.417 and 0.8483 cp
respectively) viscosities.
They were further checked for drying time. The drying time for water acetone combination
was high because of presence of moisture; it was lesser in case of acetone-IPA mixture, since
both are volatile liquids. In order to ensure high speed of coating, IPA: Acetone combination
was selected for further studies.
8.7.a.2. Selection of Plasticizer based on stickiness and folding endurance
Film prepared by using polyethylene glycol (PEG) was sticky, so PEG was not selected for
further studies. Triethyl citrate gave non sticky film, but folding endurance was less.
Increasing concentrations of TEC were tried; of 0.6% concentration gave folding endurance
around 210. As concentration of plasticizer increases, folding endurance increases since
plasticizer is responsible for decreasing tackiness of film. This concentration was selected for
further studies.
Sr. No.
Plasticizer
Folding endurance
Stickiness
1.
PEG: 0.2%
Sticky
2.
TEC:0.2%
473
Non sticky
3.
0.4%
985
Non sticky
4.
0.6%
2106
Non sticky
Table no. 8.16 Effect of plasticizers: Stickiness and folding endurance
8.7.a.3. Effect of fillers on film roughness:

These fillers gave rough films and folding endurance was less When film was casted, the
Chapter 8
68
fillers settled at the bottom of Petri plates, giving uneven surfaces. Apart from this, taking
into consideration the difficulty in spraying a suspension and constant stirring to be provided
at laboratory scale, fillers were not added in coating formula.
Fillers
MCC
Talc
Lactose
Folding Endurance
55
46
50
Roughness
Very Rough
Rough
Rough
Stickiness
Nonsticky
Nonsticky
Nonsticky
Table no. 8.17 Effect of fillers: Folding endurance, roughness, stickiness

8.7.a.4. Selection of ratio of sustained release polymer:
Polymers in selected ratios were used to coat tablets. Dissolution study was then carried out.
The ratio which gives a release profile similar to marketed formulation was selected for
further studies.
Time
(hrs)
2
4
6
8
10
12
14
16
18
20
22
24
RSPO:RL
PO
(1:1)
18.54
56.69
78.71
92.03
92.92
93.39
94.43
96.15
98.45
99.17
99.16
99.17
RSPO:RL
PO
(1:2)
17.44
45.68
78.87
92.81
94.36
95.25
95.92
97.79
98.95
99.69
99.69
99.67
RSPO:RL
PO
(2:1)
6.86
38.73
65.04
75.36
89.92
92.38
93.66
94.81
97.02
97.92
99.22
99.22
Fig no. 8.18: % Release for various polymer ratios

Chapter 8
69
Fig. No. 8.10: Comparative Dissolution Study of various polymer ratio coatings
Tablets coated with Eudragit RLPO alone shows complete release in 8 hrs, hence this coating
type was not selected for comparison. Tablets coated Eudragit RSPO alone shows only 29.9%
release in 8 hrs, hence this type of coating also was not considered for comparison. Eudragit
RSPO polymer is a water impermeable polymer; Eudragit RLPO is water permeable polymer.
When drug is very soluble in given medium, it is desirable to use water impermeable polymer
in higher proportion. When its concentration is less than or equal to that of Eudragit RLPO,
Venlafaxine (being highly water soluble), shows higher release. Depending on drug release,
ratio of Eudragit RSPO: RLPO (2:1) is selected for further studies.
8.7.a.5. Selection of % weight gain:
Coating thicknesses 7.5% and 10% show release similar to that of 5%, but lesser amount of
drug is released as thickness increases. This may be due to fact that the amount of Eudragit
RSPO (responsible for impermeability to water) increases with increasing coating thickness,
2 times more than Eudragit RLPO (water permeable polymer).

Chapter 8
Time
(Hrs)
2
4
6
8
10
12
5%
7.50%
10%
6.86
38.73
65.04
75.36
89.92
92.38
3.56
21.87
41.37
55.36
69.44
75.22
0
8.92
22.56
38.05
49.98
60.84
Time
(Hrs)
14
16
18
20
22
24
5%
7.50%
10%
93.66
94.81
97.02
97.92
99.22
99.22
76.41
76.02
80.15
84.52
85.61
86.31
62.14
63.71
65.46
71.86
74.11
75.84
70
Table no. 8.19: % release at various coating thickness
Fig No. 8.11: Dissolution Study at various percentages of wt gain

8.7.c. Optimization of process parameters
8.7.c.2. Evaluation results of preliminary batches
Batch No.
Polymer
Pan load
50
50
200
200
200
200
200
Temperature
300 c
Pan speed
30
amount
Pressure
Process
400 c
30
5
9.31
400 c
30
5
10.55
600 c
40
5
23.51
600 c
50
5
29.55
600 c
30
600 c
40
15
10
30.51
26.15
10
35.42%

Chapter 8
Batch No.
efficiency
Picking and 10
71
sticking
Breakage
Edge
Peeling
Colour
Orange peel 3
erosion
variation
Twinning
effect
Table no.8.20: Evaluation results of preliminary batches
In some batches, pan load, temperature and pan speed were low. Hence the problems due to
sticking and picking are high. For batches where pan load was less, problems like tablet to
tablet colour variation were high, as pan load increased, no. of such defects decreased. If pan
speed is too low, defects like twinning, colour variation increase. Problems like peeling, edge
erosion were not observed in batches.
8.7.c.3. Effect of temperature on quality of coating:
Temperature Concentration
Load
Pan speed
300c
Defects
12
400c
50
40
600c
8
3
Table no. 8.21: Effect of temperature on no. of defects

At lower temperature, the sprayed solution takes longer time to dry, making tablets stick to
each other. At higher temperature, curing process is faster as compared to lower temperature.
8.7.c.4. Effect of pan load on Coating process efficiency:
Load
Concentration
Temperature
Pan speed
%CPE
50
600c
40
14.76%

Chapter 8
200
35.51%
300
52.21%
415
72
Table no. 8.22: Effect of pan load on coating process efficiency

Coating efficiency was shown to be affected by pan load. As pan load increases, the spray
falls on tablet bed, instead of falling on pan surface. This decreases wastage of spray solution,
resulting in greater weight gain, thus increasing overall process efficiency.
8.7.c.5. Effect of Solid content, pan speed and atomization pressure on Process
efficiency, defects, and tablet roughness.
Coated tablets were evaluated for Process efficiency, defects, and tablet roughness.
Sr.
no.
1.
2.
3.
Concentratio
n
3
3
3
Pan
Speed
40
55
55
Atomization
Pressure
10
5
15
Process
efficiency
13.26
15.03
19.66
Defects
Roughness
4
2
2
1
1
1

Chapter 8
Sr.
no.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
Concentratio
n
3
4.5
4.5
4.5
4.5
4.5
6
6
6
6
Pan
Speed
70
40
40
55
70
70
40
55
55
70
Atomization
Pressure
10
5
15
10
5
15
10
15
5
10
Process
efficiency
21.13
8
11
13.04
12.88
12.48
8.75
7.15
11.56
9.31
73
Defects
Roughness
2
4
2
4
3
2
5
2
5
4
1
3
2
2
2
2
3
2
3
2
Table no. 8.23: Results of optimization batches
Response I- Coating process efficiency
25
CPE
20
15
10
5
70
64
58
B
:S
peed
52
46
40
3.6
4.2
4.8
5.4
A
:C
oncentration

Chapter 8
74
25
CPE
20
15
10
5
15
40
13
46
11
52
58
C
: Pressure
64
B: Speed
70
25
CPE
20
15
10
5
15
13
11
C
: Pressure
9
7
5
3.6
4.2
4.8
5.4
A: C
oncentration
Fig. No. 8.12 3D Surface plot showing effect of Independent Parameters on CPE
Coating Process Efficiency = 13.04-4.03875 * A+ 1.84875 * B +0.3525* C -1.8275* AB
-2.26 * AC -0.85 * BC+ 1.16625 * A2 -1.09375 * B2 -0.85625 * C2
Equation states that Concentration has negative effect on process efficiency; Pan Speed has a
positive, whereas atomization pressure has a positive effect on process efficiency. Effect of
concentration was the most significant.
As concentration increases, solution solid content increases. For given batch size (50
Chapter 8
75
tablets), loss of coating solution on coating pan increases. Hence, relative % weight gain
decreases, resulting in lower coating process efficiency.
As pan speed increases, it improves distribution of coating solution onto tablet bed.
Sussane Tobiska et al (Coating uniformity and coating efficiency in a Bohle Lab-Coater using
oval tablets, Europian journal of pharmaceutics and biopharmaceutics, 2003) show that with
increasing pan speed less polymer has to be applied to coating, that is efficiency of given
process increases.[31]
As Atomization Pressure increases, droplet velocity increases and droplet size decreases,
drying time decreases and efficiency increases.
J. Wang et al (International Journal of Pharmaceutics 427, 2012) stated a direct relationship
between atomization pressure (i. e. pattern air flow rate) and coating process efficiency.
Response II- Defects

Chapter 8
76
D e fe c t
6
5
4
3
2
70
6
64
5.4
58
4.8
52
4.2
B: Speed
46
3.6
40
A: C
oncentration
D e fe c t
6
5
4
3
2
5
7
3
9
C
: Pressure
3.6
4.2
11
4.8
13
5.4
15
A: C
oncentration

Chapter 8
77
D e fe c t
6
5
70
4
3
64
2
58
1
52
15
B: Speed
13
11
46
9
7
5
40
C
: Pressure
Fig. 8.13: 3D Surface plot showing effect of Independent Parameters on No. of defects
Defect = 4+ 0.75 * A -0.5 * B -0.75 * C + 0.25 * AB -0.75 * AC + 0.25 * BC -0.125 * A2
-0.125* B2 -1.125 * C2
Equation states that Concentration has positive effect on coating defects; Pan Speed and
atomization pressure have a negative effect on coating defects. Concentration and
atomization Pressure have opposite effects of same magnitude.
High content of solid and low atomization pressure result in larger droplet size, which takes
more time to dry, and may result in increased no. of defects.
High solid concentration increases viscosity of solution; pan speed is also low, this takes
longer time to dry, resulting in wetting of surface, and problems like sticking-picking, tablet
color variation, spray drying ( logo filling) etc.
Colorcon film coating troubleshooting chart provides solutions to these problems; like
increasing pan speed, atomization pressure, decreasing solution viscosity.

Chapter 8
78
R oughness
Response III- Surface Roughness
3
2.5
2
1.5
1
0.5
3.6
A
:C
oncentration
4.2
4.8
5.4
40
46
52
58
64
70
B
:S
peed

R oughness
Chapter 8
79
3
2.5
2
1.5
1
0.5
5
7
40
46
52
11
C
: Pressure
58
13
64
R oughness
15
B: Speed
70
3
2.5
2
1.5
1
0.5
15
13
6
11
5.4
C: P
ressure
4.8
4.2
3.6
5
A: C
oncentration
Fig. 8.14: Surface plot showing effect of Independent Parameters on S roughness

Roughness = 1.75 + 0.75 * A-0.25* B -0.25 * C -0.25 * AB -0.25 * AC + 0.25 * BC -0.25 *
A2
0.25 * B2+0.25 * C2
Equation states that Concentration has positive effect on surface roughness; Pan Speed has a
negative, whereas atomization pressure also has negative effect on Surface Roughness. Effect
of concentration is more than other variables.
Chapter 8
80
Sanjay Patel et al (formulation, process parameters optimization and evaluation of delayed

release tablets of rabeprazole sodium, International journal of pharmacy and pharmaceutical
sciences, 2010) also stated that higher solid content and lower atomization pressure increase
surface roughness. [32]
Optimization Studies:
The results of experiments were entered in the software and numerical optimization solutions
were obtained. These experiments were repeated as per the given solutions and evaluated.
Independent variables were set to in range a value, i.e. experimental ranges. Goal for
coating process efficiency was set to maximize value. Goal for defects was set to minimize
value. Goal for coating process efficiency was set to minimize value.
Three solutions were selected according to desirability and experimental conditions.
Predicted and observed values were compared. (C: concentration, S: Speed, A: Atomization
Pressure, CPE: Coating process efficiency, RE: Residual error)
Predicted
Solution
No.
1
46
65
Solution
No.
1
46
65
3.000
3.000
3.506
63.228
70.000
63.014
CPE
14.193
21.130
9.101
20.483
14.588
18.113
Observed
Defect
Roughness
Desirability
2.000
2.169
2.000
1
1
1
0.992
0.956
0.871
CPE
RE
Defect
RE
Roughness
RE
20.982 0.13
19.845 0.58
18.187 0.64
0.148
0.638
0.074
1
2
2
1
1
1
Table no. 8.24: Predicted vs observed values for optimization
8.8. Updated risk assessment of formulation and process variables:

Steps
Receiving
Mixing
Failure mode
Receiving incorrect material
Improper mixing
Mixing time
RPN I
16
21
12
RPN II
8
7
6
Risk priority Index

2
3
2

Chapter 8
Compression
Spraying
Mixing speed
Mixing load
Compression
Compression
Compression
Coating
Spraying
Coating
Coating
Coating
12
10
14
12
42
240
90
48
160
56
5
10
14
12
12
80
90
32
32
24
81
2.4
1
1
1
3.5
3
1
1.5
5
2.33
Table no.8.25: Updated risk assessment
Fig No. 8.15: FMEA analysis of manufacturing process
8.9. Defining Design Space:

Design Space for Materials and process parameters
Formulation
Design space
Response
Attributes

Chapter 8
Drug
Fine powder
Assay
Assay -98-102 %
Dissolution
82
Volume- 37.5 mg
Polymer level
Eudragit RSPO: Eudragit RLPO ratio Dissolution

2:1
Talcum level
2- 2.5%
Physical Characteristic
Mg.St. Level
1-1.5%
Physical Characteristic, flow
Mixing
Mixing frequency: 30-100 times, so Blend uniformity

that %RSD is lowest.
Compression
Weight of tab 200mg 5 %

Hardness 5Kg/cm2 0.5 5Kg/cm2
Coating
parameters
process Concentration: 3-6

Pan speed: 40-70
Assay, Content Uniformity,

Dissolution Time
Coating process efficiency,
Defects, Surface roughness
Atomization Pressure: 5-15

Table no. 8.26: Design Space
Graphical Representation of Design space for coating process

Chapter 8
83

Chapter 8
De sign -Ex pe rt So ftwa re
De sign -Ex pe rt Sof twa re
Fa ctor Co din g:A ctu al

Ov erla yP lot
D esi gn- Exp ert S oft war e
Fa ctor Co din g:A ctu al

Ov erla yP lot
CP E
De fect
Ro ugh nes s
D esi gn Poin ts
F act orC od ing: Ac tua l

O ver lay Plo t
CP E
De fect
Ro ugh nes s
D esi gnP oin ts
X1 =A :C onc ent rati on

X2 =B :S pe d
C PE
D ef ct
R ugo hn es
D esi gn Poi nts
X1 =A :C onc ent ratio n

X2 =B :S pe d
Ac tual Fa cto r
C: Pre su re =5
X 1= A: Co nce ntra tio n

X 2= B: Sp ed
Ac tual Fa cto r
C: Pre su re= 10
A ctu alF ac tor

C :P res sur e= 15
OverlayPlot
70
OverlayPlot
70
64
64
58
58
52
Roughness: 3
40
58
52
52
46
46
40
4.2
4.8
5.4
CPE:7.15
Defect:5
46
3.6
OverlayPlot
70
64
Roughness:1
84
X1: A: Concentration
X2: B: Speed
40
3
3.6
4.2
4.8
5.4
X2: B: Speed
3.6
4.2
4.8
5.4
X2: B: Speed
b
Fig No. 8.16: a Graphical Representation of design space
b. Control Space
In above given red area covers extreme variable points, known as points of failure. Here,
concentration ranges from 0 to 8%, and pan speed ranges from 10-90 RPM.
The yellow area is knowledge space, which gives results according to quadratic model in
DOE.
The green area is covered by ranges tested in DOE, also called as design space, the
movement in which is not considered as a change in process.
Fig b represents solution given by Design expert, which known as Control Space.
All six plots show design space where X1= Concentration, X2= Speed and Pressure= 5, 10,
15 respectively for both a and b.
8.10. Defining control strategy:

Chapter 8
Sr. No.
1.
Attributes/ Steps
Drug
85
Control Measures
Pass through #24 mesh size
Assay 98 -102 %
Pass through #24 mesh size
2.
Excipients
3.
Coating polymer
4.
Raw material dispensing
5.
Weighing
6.
Sifting
Check labeling properly.

Check date of retesting.
Approved Vendor
Check labeling properly.
Ensure balance is in proper position
Weigh in controlled environment
Pass ingredients through #24 sieve
7.
Blending
Mortar Pestle rotate between 30-100 times
8.
Granulation
9.
Lubrication
Ensure proper drying (500c)

Granules pass through #18 and are retained on #20
Pass Through #44 mesh size
10.
Compression
11.
Coating
12.
Dissolution
Punch- 8mm, concave, Compression force 5 kg/cm2

Single Punch Used
IPQC Checks: Hardness, Weight variation
Ensure that Spray Pattern is proper
Ensure tablet load and temperature is proper
Apparatus - USP type II Paddle Apparatus
Speed 50 RPM
Medium 900ml Deaerated Water
Temperature 370c
Analysis on UV spectrophotometer - 225 nm
Table no. 8.27 Control strategy
Scale up for processes: Checklist

Following points should be considered when the process is to be applied and optimized at
pilot/ production scale.
Process
Sifting
Blending
Granulation
Lubrication
Compressio
n
Parameter
Pilot scale/ Production
Batch size
Equipment
Equipment
Equipment
End point
No. of stations
College level
experiments
20 g
Sieves
Mortar Pestle
Mortar pestle, sieve
Speed alone
12
Speed
10 RPM
Upto 60 RPM
50 kg/ 150 kg
Vibratory sifter
Blender
Blender/ Fluidized bed granulator
Speed and time
27-60

Chapter 8
Coating
86
Pan brim volume

250ml-1L
4.6- 900 L
Pan speed
40-70 RPM
8-20 RPM
Achievable Process
55%
More than 90 %
efficiency
Table no. 8.28 Parameters to be considered for scale up
Following PAT tools can be applied to manufacturing processes for controlling without
destruction of formulation due to sampling and testing. [39, 40]
Process
Dispensing
Blending
Granulation
Compression
Coating
Dissolution
Parameter
Raw material characterization
Blend uniformity
Particle size distribution
Tablet identification
Thickness
Content uniformity
Water content and hardness
Thickness
Composition of coating polymers
Time
PAT
NIR and Raman Spectroscopy
NIR
Laser light diffraction
Acoustic resonance spectrscopy
At line checkmaster
NIR and Raman Spectroscopy
Diffuse reflectance-NIR
Terahertz pulsed imaging
NIR
Predicted from measured variables
like content uniformity and hardness
Table no. 8.29 PAT tools
Stability Studies:
Samples kept under Accelerated stability conditions were evaluated for hardness, friability,
weight variation, drug content and dissolution study. No significant reduction in the content
of the active drug was observed over a period of one month.
Sr. No.
1.
2.
3.
4.
Parameter
Before Stability
After Stability
Weight Variation
Complies
Complies
Friability
Complies
Complies
Hardness
Complies
Complies
Assay
99.95%
99.55%
Table no. 8.30 Stability studies

Chapter 8
87

SUMMARY AND CONCLUSION
88
SUMMARY
Quality by design (QbD) was defined as 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.
Current process is quality by testing, suffering from process variability by a small
change in processing parameters. Hence it was understood that if we want to reduce
the variability, we have to increase the process understanding, by applying QbD.

Venlafaxine is an antidepressant drug mostly used for treatment of major anxiety
disorder, and social anxiety disorder. For treatment of patients, it is desirable to have
single daily dose preparations. Sustained release tablets are available in market, but
prepared by matrix tablet approach.

Objective of the study was to study in brief and apply QbD approach to formulation
development of a sustained release film coated tablet having similar release profile as
that of marketed product.

Quality target product profile was defined for tablets, and parameters including
parameters like Dosage form and type, route of administration, potency, appearance,
identification, assay, impurities, content uniformity, dissolution, hardness, friability,
pharmacokinetics, coating defects and coating colour uniformity.

Critical quality attributes were defined using initial risk assessment. Risk assessment
was applied also using failure modes effects analysis (FMEA).

Analysis of drug for organoleptic properties, melting point and solubility was done.
Identification was done and interaction with excipients was checked using infrared
spectroscopy.
Selection of tabletting process was done based on flow properties. Granulation was
finalized as tabletting method. Hardness, dimensions, friability and assay were found
to be within limit for core tablet.

For coating, both formula and processing parameters were studied in depth to
understand process better. It included selection of solvents based on viscosity and
drying time, selection of plasticizer based on stickiness and folding endurance, effect
of fillers on film roughness, selection of ratio of sustained release polymer, selection
of % weight gain, effect of temperature on quality of coating, effect of pan load on
coating process efficiency and effect of solid content, pan speed and atomization
pressure on process efficiency, defects, and tablet roughness by application of DOE.

Risk was updated and risk priority number was calculated for every process step and
design space was defined. Control strategy was given to maintain process robustness.

SUMMARY AND CONCLUSION
89
Accelerated stability studies confirmed that product was stable over given time
period.
CONCLUSION
Film coated tablets gave complete and sustained release over 24 hours. Application of initial
risk assessment and FMEA tool helped easy identification of critical quality attributes.
Design of experiments was also useful in designing of proper experiments. Temperature and
pan load had large influence on quality and efficiency of coating process. Further ANOVA
and statistical test showed that concentration of polymer, pan speed; pan load also had an
effect on coating process efficiency, no. of defective tablets and tablet surface roughness.
Taking the results into consideration, a design space and control strategy was defined. In this
way, quality by design approach was successfully applied to sustained release film coated
tablet formulation.
Further study can be extended at pilot and production scale, also using PAT tools like NIR
spectroscopy, Raman spectroscopy, prediction using chemometrics etc.

REFERENCES
90
References
1. Patel H., Parmar S., Patel B. A Comprehensive Review on Quality by Design (QbD)
in Pharmaceuticals. Int. J. Pharm. Sci. Rev. Res., 2013;21: 232-235
http://globalresearchonline.net/journalcontents/v21-1/37.pdf
(Accessed
on
15/12/2013)
2. ICH Q8 (R2) Guideline for industry, Pharmaceutical development, www.ich.org ,
2009
3. Guidance for quality by design as an alternative approach to process validation
4. Strategy and approach to Quality by Design, from viewpoints of simultaneous global
development, 9th Drug evaluation Forum, Tokyo, Japan, 11 April 2012
5. Trivedi B. Quality By Design (Qbd) In Pharmaceuticals. International Journal of
Pharmacy and Pharmaceutical Sciences 2012;4(1):17-29
6. Nadpara N.,Thumar R., Kalola V., Patel P.. Quality By Design (QBD) : A Complete
Review. Int. J. Pharm. Sci. Rev. Res., 2012;17(2): 22-25.
7. Gawade A, Chemate S., Kuchekar A. Pharmaceutical Quality by Design: A New
Approach in Product Development by Research and Reviews. Journal of Pharmacy
and Pharmaceutical Sciences, 2013; 2(3): 5-11
8. Quality by Design for ANDAs: An Example For Immediate-Release Dosage Forms
Http://Www.Fda.Gov/Downloads/Drugs/Developmentapprovalprocess/Howdrugsared
evelopedandapproved/Approvalapplications/Abbreviatednewdrugapplicationandagene
rics/UCM304305.Pdf. (Accessed on 2/10/2014)
9. ICH Q9 (R2) Guideline for industry, Quality Risk Management, www.ich.org, 2009
10. Quality by design A project submitted for the partial fulfilment of Degree of
Bachelor of Pharmacy 2012 , University of Pune, by Miss Dipshikha Bhuyan
11. Gupta P, Shende M.A., Shaikh D. M., Ordinal Logistic Regression Model of Failure
Mode and Effect Analysis (FMEA) in Direct Compressible Buccal Tablet,
International Journal of Pharma Research & Review, 2013; 2(6):9-17
12. WHO guidelines on quality risk management, WHO technical report series no.981,
2013, P.No.62-92 http://www.who.int/ medicines/areas /quality_safety /quality_
assurance /Annex2TRS-981.pdf (Accessed on 2-09-2014)
13. Process Understanding For Scale-Up and Manufacture of Active Ingredients, edited
by Ian Housen - Google Books.html, http://as.wiley.com/ WileyCDA /WileyTitle/
product Cd-3527325840.html# (Accessed on 2-09-2014)

REFERENCES
91
14. Practical considerations for DOE implementation in Quality by Design, Shivhare M ,

McCreath G, Bioprocess International, 2010;22-30
15. Guidance for industry PAT- A framework for Innovative pharmaceutical development,
manufacturing, and quality assurance, US department of Health vand human services,
Food and drug administration, CDER, CVM, ORA, Pharmaceutical cGMPs
September 2004;1-16
16. Gibaldi M, Perrier D. Pharmacokinetics, New York, Marcel Dekker, 1982: 88-203
17. Lachmann, L, Lieberman H, Kanig J. The Theory & Practice of Industrial Pharmacy,
Varghese Publishing House, Bombay,3rd edition, 1991: 430.
18. Robinson J, Lee H. Controlled Drug Delivery: Fundamentals & Applications, Marcel
Dekker Inc., New York, 2nd edition, 1987: 373.
19. Gennaro AR (Ed.) Remington. The Science & Practice of Pharmacy. 19 th Edition,
Vol. II, 1995: 1662.
20. Shargel L, Andrew BC. Applied Biopharmaceutics and Pharmacokinetics, 4th Edition,
174.
21. Innovations in tablet coating technology: A review, Kamble N, Choudhary P, Oswal
R, Kshirsagar S, Antre R, International Journal of applied biology and pharmaceutical
technology, 2011;21: 214-218
22. Gaikwad D, Jadhav RT, Limkar A, Sangeeta S, Bobe K, Patil M. ,Formulation and
evaluation of sustained release tablet of Acceclofenac by film coating, International
Journal of research in pharmaceutical and biomedical Sciences,2011; 2(1):310-318
23. Rao HP, Iswariya V.T., Lokeswara V Rao A S, A review on controlled drug delivery
system, Interanational Journal of Pharmacy, 2014;4(3): 275-282
24. Chowdary K, Surya K, Recent research on matrix tablets for controlled release a
review, International research journal of pharmaceutical and applied sciences, 2013;
3(1):142-148
25. Roy S.,Quality by design: A holistic concept of building quality in pharmaceuticals,
International Jourrnal of Pharmaceutical and biomedical research, 2012,;3(2):100-108
26. Pharmaceutical development case study: Ace tablets, Prepared by CMC- IM working
group, 2008, Ver 2:1-92
27. Boddeda B., Kumari K, Chowdary K.P.R.,Formulation and evaluation of glipizide
sustained release tablets, International Jounal of Pharmaceutical and biomedical
research, 2012; 3(2): 44-48

REFERENCES
92
28. Butani S, Development and Optimization of Venlafaxine Hydrochloride Sustained

Release Triple Layer Tablets Adopting Quality by Design Approach, ,journal of
Scientific Reaseach, Pharmacology and Pharmacy, 2013; 4: 9-16
29. Thorat R, Patil P, Aage R., Puranik P., Salve V, Formulation development and
evaluation of Venlafaxine sustained release matrix tablet, International Jounal of
Pharmacy and Pharmaceutical Sciences, 2013; 5(3): 757-765
30. Sundarganapathy R, Jambulingam M., Ananda Thangadurai S, Subasini U,
Development and validation of UV spectrophotometric method for determination of
Venlafaxine hydrochloride in bulk and solid dosage forms, International journal of
pharmaceutical and industrial research, 2011;1 (1): 28-31
31. Tobiska S, Kleinbudde P, Coating uniformity and coating effeiciency in a Bohle Lab
Coater using oval tablets, Europian Journal of Pharmaceutics and Biopharmaceutics, ,
2003;56: 3-9
32. Patel S, Patel P, Vora C, Patel N, Patel J, Formulation, process parameters
optimization,and evaluation of delayed release tablets of rabeprazole sodium,
International journal of pharmacy and pharmaceutical sciences,2010; 2 (3):144-156
33. Cunningham C, Neely C,
Opadry II, high productivity film coating system,
application data, reprint of poster presented at American association of

pharmaceutical scientists meeting, 1-12
34. Vesey C, Rizzo M, and Ali R. Rajabi, Identification and Influence of Critical Coating
Process Parameters on Drug Release from a Fully Formulated Aqueous Ethylcellulose
Dispersion, Poster Reprint, AAPS annual meeting, 2007;1-6
35. Ratnaparakhi P, Chaudhari S, Dhage K, Dhiwar S , Bhore S, Optimization of coating
formula and critical process parameter for aqueous film coating of tablet, International
journal of research in pharmaceutical and biomedical sciences, 2012; 3 (4):1488-1496
36. Chen W, Early W, Chan S, Varia S.A, An evaluation of process parameters to improve
coating efficiency of aqn active tablet film coating process, International journal of
pharmaceutics,2012;21:163-169
37. Ranga S, Jaimini M, Sharma S, Chauhan B, Kumar A, A review on design of
experiments (DOE), International journal of research and reviews in pharmacy and
applied science.2013; 867-882
38. Lundstedt T, Seifert E, Abramo L, Thelin B, Experimental design and optimization,
Chemometrics and Intelligent Laboratory Systems 1998;48: 340

93
REFERENCES
39. Kamble R, Sharma S, Process Analytical Technology (PAT) in Pharmaceutical

Development and its Application, International Journal of Pharmaceutical Sciences
Review and Research, 2013;23 (2): 212-223
40. Valrsson H, PAT implementation in pharmaceutical manufacturing and its
economical impact. Thesis submitted to university of Basel, P. No. 1-310
41. Kan S, Lu J, Liu J, Wang J Zhao Y, A quality by design case study on enteric coated
pallets: screening critical variables and establishment of design space at laboratory
scale. Asian journal of pharmaceutics,2014; 268-278
42. Wang J, Hemenway J, Chen W, Desai D, Early W, Paruchuri S, Chang SY, Stamato
H, Varia S. Int J Pharm. 2012; 427(2):163-169.
43. http://www.drugs.com/venlafaxine.html (Accessed on 28-8-2014)
44. http://en.wikipedia.org/wiki/Venlafaxine (Accessed on 28-8-2014)
45. http://www.drugbank.ca/drugs/DB00285 (Accessed on 28-8-2014)
46. http://eudragit.evonik.com/product/eudragit/en/products-services/eudragitproducts/sustained-release-formulations/rl-po/pages/default.aspx (Accessed on 28-82014)
47. http://www.higuchi-inc.co.jp/pharma/excipient/eudragit/pdf/detail_eudragitRLRS.pdf
(Accessed on 28-8-2014)
48. http://www.chemicalbook.com/ChemicalProductProperty_EN_CB8685418.htm
49. James Swarbrick, James C. Boylan. Encyclopedia of Pharmaceutical Technology.
Second edition, Vol.2, Marcel Dekker, Inc., New York. Basel, 2669-2689 (Accessed
on 28-8-2014)
50. (http://en.wikipedia.org/wiki/Talc#Uses) (Accessed on 28-8-2014)
51. (http://www.brenntagspecialties.com/en/downloads/Products/Personal_care/T
alcs/PDS_WCD_2755_Talc.pdf (Accessed on 28-8-2014)
52. http://www.worldofchemicals.com/chemicals/chemical-properties/microcrystallinecellulose.html(Accessed on 28-8-2014)
53. http://www.drugs.com/inactive/lactose-monohydrate-368.html(Accessed
on
28-8-
2014)
54. http://apps.who.int/prequal/trainingresources/pq_pres/workshop_China2010/english/2
2/002-Excipients.pdf(Accessed on 28-8-2014)
55. http://www.drugs.com/inactive/magnesium-stearate-147.html(Accessed
on
28-8-
2014)
56. https://en.wikipedia.org/wiki/Magnesium_stearate(Accessed on 28-8-2014)
57. Korakianiti E, New quality paradigm: Quality by design ICH Q8-9-10, Presentation
at QWP- Quality assessors training, 2009, 1-41
58. Roy A, Ghosh A, Datta S, Das S, Mohanraj P., Effects of plasticizers and surfactants
on the film forming properties of hydroxypropyl methylcellulose for the coating of
diclofenac sodium tablets, Saudi pharmaceutical journal, 2009; 17: 233-241
REFERENCES
94
59. Dias V, Ambudkar V, Fegely K A, Ali R., The Influence of Solvent Type on Extended
Release Coating with Ethylcellulose Barrier Membranes, poster reprint, controlled
release society, annual meeting, 2008, 1-4
60. A presentation at Workshop by ICH Q-CWG members on Design Space, International
conference on harmonization of technical requirements for registration of
pharmaceuticals for human use, 2010, 1-26
61. Brock D, Zeitler A, Funke A, Knop K, Kleinebudde P, Evaluation of critical process
parameters for inter-tablet coating uniformity of active-coated GITS using Terahertz
Pulsed Imaging, Europoian journal of pharmaceutics and biopharmaceutics, an article
in press, 2014, 1-9
62. Bodkhe A, Zurao P, Chandewar A.V., Jaiswal S. B., Designing and evaluation of
extended release tablet of Venlafaxine hydrochloride using hydrophobic matrix, Der
Pharmacia Lettre, 2010;2 (1):329-335
63. Radhika P.R., Karanam D, Sivkumar T., Fabrication of sustained release matrix tablets
of Venlafaxine hydrochloride using eudragits, Indian journal of research in ayurveda
and pharmacy, 2011; 2: 1386-1389
64. Product
information
leaflet,
Effexor
XR,
Wyeth
pharmaceuticals,
http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/020699s081lbl.pdf,
65. Cobb J, Brett R. J, Ruff M, Berry A, Epps R, Using Quality by Design (QbD) for
Process Optimization of a Novel Oral Solid Dosage Form, metrics inc,
http://www.pharmoutsourcing.com/1613-WhitePapers-ApplicationNotes/130571Using-Quality-by-Design-QbD-for-Process-Optimization-of-a-Novel-Oral-SolidDosage-Form (Accessed on 25-8-2014)
66. Andre Raw, Quality by Design Example for Generic Modified Release Drug
Products, a presentation at FDA, 2012, 1-43 https://www.aaps.org /uploaded Files/
Content/Sections_nd_GroupsRegional_Discussion_Groups/Sept%20presentation.pdf
67. Understanding challenges to quality by design, final deliverable for FDA, 2009, 129http://www.pharmaqbd.com/wp-content/uploads/2011/05/UnderstandingChallenges-to-Quality-by-Design.pdf (Accessed on 25-8-2014)
68. Indian Pharmacopoiea, Controller of Publication, Govt. of India, Ministry of Health
and Family Welfare, New Delhi, 1985, Vol. 1, 178-184
69. British Pharmacopoiea, HMSO Publication: London; 2007, Vol. 1, 546-547
70. http://www.accessdata.fda.gov/scripts/cder/dissolution/dsp_SearchResults_Dissolutio
ns.cfm (Accessed on 28-7-2014)
71. Kumar G., Pallavi C, Direct compression, an overview, international journal of
research in pharmaceutical and biomedical sciences, 2013;21:155-158
REFERENCES
95
72. Aditya Sakhare, Effect of glycerin as plasticizer in orodissolving films of losartan

potassium, International journal of science and research, 2014;18: 772-778
73. Modified release, Effect of Dissolution Media pH on the Release of Aspirin from
Sureteric Coated Tablets, technical data sheet, https:// www.colorcon.com
/literature /marketing/ mr/Delayed
%20Release/Sureteric/English/effect_ph_release.pdf (Accessed on 25-7-2014)
74. http://www.colorcon.com/technical-services/trouble-shooting-chart (Accessed on 248-2014)

PUBLICATIONS
1
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Title: Formulation and evaluation of sustained release film coated tablets using quality
by design (QbD) approach
Journal: Indian Journal of pharmaceutical sciences
Status: Communicated
Title: Design & Development of Transdermal Drug Delivery System For Arthritis
Journal: Inventi Journals Pvt. Ltd.
Status: Communicated

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Chapter 1

Fig No 1.1 Overview of Quality by design [1]

FORMULATION AND EVALUATION OF SUSTAINED RELEASE FILM COATED

1.1. Regulatory aspects:

Fig. 1.2 Regulatory Aspects: ICH Q8,Q9, Q10 guidelines [4]

FORMULATION AND EVALUATION OF SUSTAINED RELEASE FILM COATED

1.4. Steps in Quality by Design[5]

FORMULATION AND EVALUATION OF SUSTAINED RELEASE FILM COATED

Fig. 1.3 Steps in Quality by Design

is currently primarily expressed in clinical terms such as clinical pharmacology, indications

1.6. Critical Quality Attributes:[2, 5]

CQAs are generally associated with the drug substance, excipients,

intermediates (in-process materials) and drug product.

Fig. 1.4 Quality risk management

Figure 1.5 - Ishikawa fishbone diagram

Selection of the process

Review of the process

FORMULATION AND EVALUATION OF SUSTAINED RELEASE FILM COATED

Brainstorm potential failure modes

List of potential effects of each failure mode

Assign a severity rating for each effect

Assign an occurrence rating for each failure mode

Assign a detection rating for each failure mode and effect

Prioritize the failure modes for action

Taken action to eliminate or reduce the high risk failure modes

Improvement index (II): II = (RPN before improvement) / (RPN after improvement)

1.9.1. C. Fault tree analysis

Fig. No.1.6 Schematic representation of Design Space

Identify the unclassified parameters.

unclassified parameters fixed.

1.10.2. Implications of Design Space: [13]

Increased process and product understanding.

Increased assurance to regulators i.e. regulatory flexibility.

FORMULATION AND EVALUATION OF SUSTAINED RELEASE FILM COATED

Frequency of monitoring and control. (ICH Q10)

1.11.1 Developing the control strategy: [1]

FORMULATION AND EVALUATION OF SUSTAINED RELEASE FILM COATED

A full factorial or fractional factorial design.

1.13. Introduction to sustained release:

FORMULATION AND EVALUATION OF SUSTAINED RELEASE FILM COATED

The frequency of drug administration is reduced.

dosage forms can be reduced.

and systemic adverse side effects can be reduced in sensitive patients.

Disadvantages of controlled release formulations:

Administration of controlled release medication does not permit the prompt

average drug biologic half-lives.

Physico-chemical factors influencing oral controlled release dosage form [15]:

FORMULATION AND EVALUATION OF SUSTAINED RELEASE FILM COATED

anticholinergic drugs from controlled /sustained release formulations.

minimize fluctuations in blood levels accompanying

Modified drug release

Coating Process Design & Control [21]

Batch identification and Recipe selection (film or sugar coating)

Advantages of tablet coating [21]

Disadvantages of tablet coating [21]

In these systems the dug is dispersed in an insoluble matrix of rigid non-swellable

Sandipan Roy [25]

Case study explaining each step of

Sustained Release Formulation