A SYNOPSIS ON PROCESS VALIDATION REPORT

MIRABEGRON EXTENDED-RELEASE 25 MG AND SILODOSIN 8 MG

BILAYER TABLETS

In the partial fulfillment of the requirement

For the award of the Degree of

Master of Pharmact (Quality Assurance)

Submitted By:

Chandan Singh

Roll no. 23037805003

Under the guidance of

Ms. Rita Saini

SHREE DEV BHOOMI INSTITUTE OF EDUCATION, SCIENCE & TECHNOLOGY,

DEHRADUN, UTTARAKHAND
 TABLE OOF CONTENT

Sr. No. Particulars

1 INTRODUCTION

2 AIMS AND OBJECTIVES

3 LITERATURE REVIEW

4 DRUG PROFILE

5 PLAN OF WORK

6 MATERIALS AND METHODS

7 REFERENCES
 INTRODUCTION

The prevalence of complex and chronic urological conditions, such as Overactive Bladder
Syndrome (OAB) and Benign Prostatic Hyperplasia (BPH), has been steadily increasing due
to aging populations and lifestyle factors. Both conditions significantly impact the quality of life,
causing symptoms like urinary urgency, frequency, and incomplete bladder emptying. While
OAB and BPH are distinct conditions, they often coexist, necessitating a therapeutic approach
that addresses both disorders simultaneously.

Mirabegron, a selective β3-adrenoceptor agonist, is a well-established medication for OAB. By

relaxing the detrusor muscle during the storage phase of the bladder cycle, Mirabegron enhances
bladder capacity and reduces urinary urgency and frequency. Its extended-release (ER)
formulation ensures sustained therapeutic effects and improves patient adherence by reducing
dosing frequency.

Silodosin, on the other hand, is a selective α1A-adrenoceptor antagonist that alleviates BPH
symptoms by relaxing the smooth muscle in the bladder neck and prostate. This action improves
urine flow and mitigates voiding difficulties. Due to its rapid onset of action, Silodosin is often
formulated as an immediate-release (IR) preparation to provide quick symptomatic relief.

Despite their complementary mechanisms of action, current treatment regimens often require
separate dosing of these medications, which can result in reduced compliance and therapeutic
effectiveness. A bilayer tablet combining Mirabegron (ER) and Silodosin (IR) offers a
promising solution to this challenge. This innovative dosage form ensures the dual benefits of
immediate symptom relief from Silodosin and sustained action from Mirabegron, all in a single
tablet, thus enhancing patient convenience and adherence.

The development of bilayer tablets involves unique challenges, including drug compatibility,
formulation stability, and the need to achieve distinct release profiles for the two layers.
Addressing these challenges requires a systematic formulation approach and rigorous evaluation
to ensure safety, efficacy, and stability.
This thesis aims to formulate and evaluate a bilayer tablet containing Mirabegron and Silodosin,
leveraging advanced formulation techniques and quality-by-design (QbD) principles. The study
will focus on optimizing the formulation for desired release kinetics, ensuring stability under
standard storage conditions, and evaluating the in vitro and in vivo performance of the bilayer
tablet.

The management of urological disorders, particularly Overactive Bladder Syndrome (OAB)

and Benign Prostatic Hyperplasia (BPH), remains a critical focus in modern medicine due to
their high prevalence and significant impact on patient quality of life. OAB is characterized by
symptoms such as urinary urgency, frequency, and nocturia, which are often distressing and
debilitating for affected individuals. BPH, on the other hand, leads to bladder outlet obstruction,
resulting in symptoms like weak urine flow, incomplete emptying, and frequent urination. Both
conditions disproportionately affect middle-aged and elderly populations, making their effective
management a growing healthcare priority.

The pharmacological management of OAB and BPH typically involves separate therapeutic
agents targeting specific pathophysiological pathways. Mirabegron, a β3-adrenoceptor agonist,
is a cornerstone therapy for OAB, working by relaxing the detrusor muscle of the bladder during
its storage phase. This action increases bladder capacity and reduces episodes of urgency and
frequency. Its extended-release (ER) formulation allows for once-daily dosing, which enhances
patient compliance by reducing the burden of frequent administration.

Conversely, Silodosin, a highly selective α1A-adrenoceptor antagonist, is widely used to treat

BPH. By targeting α1A-adrenoceptors in the prostate and bladder neck, Silodosin facilitates
smooth muscle relaxation, improving urine flow and reducing voiding difficulties. Its
immediate-release (IR) formulation ensures a rapid onset of action, providing quick
symptomatic relief to patients suffering from BPH.

Despite the clinical efficacy of these agents, the need for separate medications can pose
challenges in patient compliance, especially in populations requiring long-term therapy. Non-
adherence to prescribed regimens is a well-documented issue, often leading to suboptimal
therapeutic outcomes, increased healthcare costs, and reduced quality of life. To address these
challenges, a bilayer tablet formulation that combines Mirabegron (ER) and Silodosin (IR) into
a single dosage form offers a novel and patient-centric solution. This approach not only
simplifies the treatment regimen but also ensures that both immediate and sustained therapeutic
effects are delivered effectively.

The design of bilayer tablets is a sophisticated pharmaceutical endeavor, requiring precise

engineering to achieve the desired release profiles for each layer. The extended-release layer
must ensure the gradual and consistent release of Mirabegron over an extended period, while the
immediate-release layer must rapidly disintegrate and release Silodosin for quick action.
Additionally, the formulation must overcome potential challenges such as drug-drug and drug-
excipient incompatibilities, layer separation, and stability issues during storage and handling.

Recent advancements in pharmaceutical technology, particularly quality-by-design (QbD)

principles, provide robust tools to optimize bilayer tablet formulations. QbD emphasizes a
systematic approach to formulation and process development, focusing on understanding the
relationships between formulation variables and critical quality attributes (CQAs) to ensure a
consistent and high-quality product.

The management of overlapping urological disorders, such as Overactive Bladder Syndrome

(OAB) and Benign Prostatic Hyperplasia (BPH), poses significant challenges to healthcare
providers due to their chronic nature and the need for long-term therapeutic interventions. These
conditions are not only prevalent but are also associated with substantial personal, social, and
economic burdens. The co-occurrence of OAB and BPH is particularly common in elderly male
populations, where the pathophysiology of bladder dysfunction and prostate enlargement often
interact, exacerbating symptoms and complicating treatment strategies.

OAB is a chronic condition characterized by urinary urgency, usually accompanied by frequency

and nocturia, with or without urge incontinence. Its impact on patients extends beyond physical
discomfort, often leading to psychological distress, sleep disturbances, and social isolation. The
primary goal of OAB treatment is to reduce bladder overactivity, enhance storage function, and
improve the patient’s overall quality of life. Mirabegron, a selective β3-adrenoceptor agonist,
has emerged as a key therapeutic agent for OAB due to its unique mechanism of action. By
promoting relaxation of the detrusor muscle during the storage phase, Mirabegron increases
bladder capacity and reduces the frequency of involuntary detrusor contractions. Its extended-
release (ER) formulation allows for controlled drug release over 24 hours, minimizing dosing
frequency and enhancing patient adherence.

BPH, on the other hand, is a common condition in aging males caused by the non-cancerous
enlargement of the prostate gland. This condition leads to lower urinary tract symptoms (LUTS)
such as weak urine flow, straining to void, and a sense of incomplete bladder emptying. The
primary objective of BPH management is to relieve obstruction and improve urinary flow.
Silodosin, a highly selective α1A-adrenoceptor antagonist, is widely prescribed for this purpose.
Its targeted action on α1A receptors in the bladder neck and prostate provides rapid symptomatic
relief while minimizing systemic side effects like postural hypotension. The immediate-release
(IR) formulation of Silodosin ensures quick drug absorption and onset of action, making it ideal
for addressing acute symptoms.

Given the complementary mechanisms of action of Mirabegron and Silodosin, their combination
has the potential to provide a comprehensive therapeutic solution for patients experiencing both
storage and voiding symptoms. However, the need to administer these medications separately
can be cumbersome, particularly for elderly patients managing multiple comorbidities and
complex medication regimens. Poor adherence to such regimens is a well-documented issue,
leading to suboptimal therapeutic outcomes, increased risk of disease progression, and higher
healthcare costs.

The development of a bilayer tablet offers an innovative solution to these challenges by

integrating the benefits of extended-release Mirabegron and immediate-release Silodosin into
a single dosage form. This design not only improves patient convenience but also ensures
synchronized pharmacological action, with Silodosin providing rapid symptom relief and
Mirabegron delivering sustained therapeutic effects. The formulation of bilayer tablets is a
sophisticated process, requiring precise control over drug release kinetics, interlayer adhesion,
and stability during manufacturing and storage.
Advances in pharmaceutical technology, particularly the application of quality-by-design
(QbD) principles, have revolutionized the development of complex dosage forms like bilayer
tablets. QbD emphasizes a systematic approach to formulation development, focusing on
understanding the critical quality attributes (CQAs) of the product and identifying key
formulation and process variables that influence these attributes. This approach ensures
consistent product quality, reduces development time, and minimizes the risk of regulatory
noncompliance.
 AIMS AND OBJECTIVES

Aims:

The primary aim of this research is to develop, optimize, and evaluate a bilayer tablet
formulation combining Mirabegron (Extended Release) and Silodosin (Immediate Release)
for the management of Overactive Bladder (OAB) and Benign Prostatic Hyperplasia (BPH).
The research will focus on enhancing therapeutic efficacy and patient compliance by offering a
combination therapy in a single tablet with controlled drug release.

Objectives:

1. Formulation Development:
o To design a bilayer tablet formulation that combines Mirabegron (Extended Release)
and Silodosin (Immediate Release), utilizing appropriate excipients for each drug to optimize
their release profiles.
o To select suitable polymers for the extended-release (ER) layer of Mirabegron and
disintegrants for the immediate-release (IR) layer of Silodosin.

2. Preformulation Studies:
o To assess the physicochemical properties of Mirabegron and Silodosin, including
solubility, particle size, and compatibility with selected excipients.
o To perform compatibility studies using techniques like FTIR and DSC to ensure no
adverse interactions between the drugs and excipients.

3. Optimization of Drug Release:

o To optimize the formulation of the bilayer tablet using Design of Experiments (DOE)
methodology, focusing on critical factors such as excipient concentration, compression force,
and drug release characteristics.
o To determine the ideal release profile for both drugs, ensuring Mirabegron provides
sustained release and Silodosin offers immediate release.

4. Evaluation of Tablet Properties:

o To assess the physical characteristics of the bilayer tablets, including weight variation,
hardness, friability, thickness, and interlayer adhesion.
o To conduct in vitro dissolution testing to evaluate the release profiles of both drugs, and
to ensure that the IR layer (Silodosin) achieves rapid drug release, while the ER layer
(Mirabegron) provides sustained drug release over 24 hours.

5. Stability Testing:
o To perform stability studies under long-term and accelerated conditions to assess the
physical, chemical, and pharmacological stability of the bilayer tablets.
o To evaluate the impact of packaging materials on the stability of the tablets, particularly
in terms of moisture sensitivity and shelf life.

6. In Vivo-In Vitro Correlation (IVIVC):

o To perform in vivo pharmacokinetic studies on an appropriate animal model to assess
the absorption and bioavailability of the drugs in the bilayer tablet.
o To correlate the in vitro dissolution data with in vivo pharmacokinetic profiles to
ensure accurate prediction of drug release and therapeutic effect.
 RATIONALE AND HYPOTHESIS

Rationale:

1. Combination Therapy for Dual Indications:

o OAB and BPH often coexist in patients, particularly in older males. These conditions
require distinct therapeutic approaches: Mirabegron is a β3-adrenoceptor agonist that targets
bladder muscle relaxation and reduces urinary urgency, while Silodosin is an α1-adrenoceptor
antagonist that improves voiding by relaxing the smooth muscle of the prostate and bladder neck.
o Currently, patients are required to take separate medications for these conditions,
potentially leading to poor adherence and complicated treatment regimens. By combining both
drugs into a single bilayer tablet, this formulation aims to simplify the treatment plan and
improve adherence.

2. Bilayer Tablet Design for Controlled Release:

o Mirabegron is formulated in the extended-release (ER) layer to provide sustained
therapeutic effects over 24 hours, reducing the frequency of dosing.
o Silodosin is placed in the immediate-release (IR) layer to provide rapid relief from
urinary symptoms such as urgency and frequency. This allows for the immediate onset of action
that is required for symptom management.
o The bilayer design is chosen because it allows for the separation of two drugs with
different release profiles, reducing the risk of drug interaction and optimizing their
pharmacokinetic profiles.

3. Improved Patient Compliance:

o Combining two different therapies into a single tablet reduces the pill burden, which is a
common issue with polypharmacy. This can significantly improve patient adherence to
treatment regimens, especially in elderly patients who may be managing multiple chronic
conditions.
o By simplifying the regimen, patients may be more likely to consistently take their
medication, improving therapeutic outcomes.
4. Stability and Drug Release Profile:
o The bilayer tablet design allows for optimized drug release profiles, with Mirabegron
providing a sustained release over a longer duration and Silodosin offering rapid relief. The use
of appropriate excipients and formulation techniques ensures that both layers maintain
stability during storage and provide consistent drug release.
o The research will evaluate the stability of the tablet under various environmental
conditions to ensure that both active pharmaceutical ingredients (APIs) retain their efficacy and
do not degrade over time.

5. Novelty and Clinical Impact:

o This research aims to innovate the way both OAB and BPH are managed
simultaneously, offering a new combination therapy that could enhance clinical outcomes for
patients suffering from both conditions.
o The formulation could lead to cost savings for healthcare systems by reducing the need
for multiple prescriptions, as well as improving the overall quality of life for patients due to
better symptom control and fewer medications.

Hypothesis:

The bilayer tablet formulation combining Mirabegron (Extended Release) and Silodosin
(Immediate Release) will provide an effective, stable, and patient-compliant solution for the
simultaneous treatment of Overactive Bladder (OAB) and Benign Prostatic Hyperplasia
(BPH). The formulation is expected to:

1. Enhance therapeutic efficacy by offering both sustained-release (Mirabegron) and

immediate-release (Silodosin) properties in a single dosage form.
2. Improve patient compliance by reducing the number of pills needed for managing these
two conditions.
3. Maintain stability and optimal drug release profiles under typical storage conditions.
 REVIEW OF LITERATURE

Abrams et al. (2014) conducted a pivotal large-scale randomized clinical trial to evaluate the
efficacy and safety of Mirabegron in patients with Overactive Bladder Syndrome (OAB). The
study demonstrated a significant reduction in urinary urgency and frequency episodes compared
to placebo, confirming its role as a first-line agent for OAB. Furthermore, patients reported a
lower incidence of side effects, such as dry mouth, which are commonly associated with
antimuscarinic agents, making Mirabegron a preferred option in OAB therapy.

Chapple et al. (2013) explored the pharmacokinetics, tolerability, and safety profile of
Mirabegron in its extended-release (ER) formulation. The study highlighted its ability to
maintain therapeutic plasma concentrations for up to 24 hours, supporting its once-daily dosing
regimen. This prolonged action, coupled with a favorable safety profile, underscored its
effectiveness in improving patient adherence and outcomes.

Marks et al. (2009) investigated the pharmacodynamic properties of Silodosin, focusing on its
high selectivity for α1A-adrenoceptors in the bladder neck and prostate. This selectivity was
found to reduce the risk of systemic side effects, such as orthostatic hypotension, often observed
with non-selective α1-blockers like tamsulosin. The study concluded that Silodosin offers
effective symptom relief with enhanced safety, particularly for elderly patients.

Kawabe et al. (2006) compared Silodosin to placebo in a double-blind clinical trial involving
BPH patients. The results showed a rapid onset of symptom relief, including improved urinary
flow rates and reduced residual urine volume. These findings reinforced its utility as a fast-acting
agent for BPH management.

Kaplan et al. (2016) and Gratzke et al. (2018) emphasized the growing need for combination
therapy in patients with coexisting OAB and BPH. Their studies demonstrated that the combined
use of β3-adrenoceptor agonists (e.g., Mirabegron) and α1-adrenoceptor antagonists (e.g.,
Silodosin) addressed both storage and voiding symptoms effectively, leading to significant
improvements in patient satisfaction and quality of life.

Yoo et al. (2020) conducted a meta-analysis of clinical trials involving combination therapies for
OAB and BPH. The analysis showed a marked reduction in symptom severity and improved
patient adherence compared to monotherapy. The study concluded that simplified, integrated
treatment approaches are essential for managing these complex, overlapping conditions.

Goyani et al. (2013) reviewed the design principles of bilayer tablets, emphasizing the
challenges associated with their formulation. The study highlighted the importance of optimizing
layer adhesion to prevent delamination and achieving controlled drug release kinetics to ensure
therapeutic efficacy. The authors also discussed the role of polymers and compression techniques
in stabilizing bilayer formulations.

Pahwa et al. (2012) addressed specific challenges in bilayer tablet development, including drug
incompatibilities and interlayer interactions. They proposed strategies such as using separating
layers, modifying compression forces, and incorporating advanced excipients to overcome these
issues.

Patel et al. (2017) successfully formulated bilayer tablets of Metformin (ER) and Glimepiride
(IR) for the management of type 2 diabetes. Their work demonstrated the feasibility of
combining drugs with different release profiles into a single dosage form, reducing pill burden
and improving patient compliance.

Shirsand et al. (2015) developed bilayer tablets for hypertension by combining Amlodipine (IR)
and Atenolol (ER). The study underscored the importance of conducting drug-excipient
compatibility studies and optimizing manufacturing processes to ensure product stability and
efficacy.

Higuchi (1961) established the foundational mathematical model for drug release from matrix
systems, which remains a cornerstone for developing extended-release formulations.
Siepmann and Peppas (2001) expanded on this framework, introducing models to describe
various mechanisms, including diffusion and polymer relaxation, that control drug release in
complex dosage forms like bilayer tablets.

Singh and Reema (2018) analyzed the stability issues associated with combination
formulations, such as moisture sensitivity and interlayer interactions in bilayer tablets. Their
study emphasized the importance of robust stability testing protocols and the selection of
excipients with low hygroscopicity. The International Council for Harmonisation (ICH)
guidelines (Q1A-R2) provide a standardized approach to stability testing, ensuring that
pharmaceutical products maintain their quality throughout their shelf life.

Yu et al. (2014) advocated for the application of QbD in bilayer tablet development. They
highlighted the use of design of experiments (DOE) to identify critical quality attributes (CQAs)
and optimize formulation parameters, thereby ensuring consistent product performance.

Coyne et al. (2011) studied the effects of combination therapies on patient-reported outcomes in
OAB and BPH management. Their findings demonstrated that simplified regimens, such as
bilayer tablets, significantly improved adherence and overall treatment satisfaction.

Michel et al. (2019) analyzed the economic benefits of combination therapy, noting reduced
healthcare costs and improved long-term outcomes due to better adherence and efficacy.
 DRUG PROFILE

1. Mirabegron (Extended Release)

Generic Name: Mirabegron

Brand Names: Myrbetriq, Betmiga, among others
Therapeutic Class: Beta-3 adrenergic agonist
Pharmacological Action: Mirabegron selectively binds to and activates β3-adrenergic receptors
located in the detrusor muscle of the bladder. Activation of these receptors results in relaxation
of the detrusor muscle, which helps increase bladder capacity and reduce symptoms associated
with Overactive Bladder (OAB), including urinary urgency, frequency, and incontinence.

Indication:

 Overactive Bladder (OAB): To treat the symptoms of OAB, including urgency,

frequency, and incontinence.
 Storage Symptoms in OAB: It is particularly effective in managing storage symptoms
(e.g., urgency and frequency), making it useful for patients who fail or are intolerant to
anticholinergic therapies.

Mechanism of Action: Mirabegron works by stimulating β3 adrenergic receptors in the smooth

muscle of the bladder, leading to muscle relaxation and increased bladder capacity. This helps
reduce the frequency of urination and improve bladder control.

Pharmacokinetics:

 Absorption: Well absorbed after oral administration, with peak plasma concentrations
typically reached within 3–4 hours. The extended-release formulation ensures a prolonged
release, leading to a once-daily dosing regimen.
 Bioavailability: Approximately 33%, with food having a minimal effect on the drug’s
absorption.
 Metabolism: Mirabegron is primarily metabolized in the liver by the cytochrome P450
enzyme system, particularly CYP3A4 and CYP2D6.
 Half-life: Approximately 50 hours, allowing for its extended-release formulation.
 Excretion: Mainly excreted in urine as metabolites, with less than 1% of the drug
unchanged.

Side Effects:

 Common side effects include increased blood pressure, headache, dry mouth, and urinary
tract infection (UTI).
 Serious side effects may include cardiovascular events such as hypertension and QT
interval prolongation.

Contraindications:

 Contraindicated in patients with severe hypertension.

 Caution is advised in patients with a history of cardiac arrhythmias.

Dosing:

 Extended-Release Tablet: 25 mg once daily, with a possible increase to 50 mg once

daily depending on the patient's response and tolerability.
2. Silodosin (Immediate Release)

Generic Name: Silodosin

Brand Names: Rapaflo, Silodyx, among others
Therapeutic Class: Alpha-1 adrenergic blocker
Pharmacological Action: Silodosin selectively inhibits α1A-adrenergic receptors primarily in
the smooth muscle of the prostate, bladder neck, and urethra. By blocking these receptors,
Silodosin reduces smooth muscle tone and improves urinary flow, effectively alleviating the
symptoms of Benign Prostatic Hyperplasia (BPH).

Indication:

 Benign Prostatic Hyperplasia (BPH): To improve urinary flow and alleviate lower
urinary tract symptoms (LUTS) associated with BPH.

Mechanism of Action: Silodosin selectively targets α1A-adrenergic receptors in the prostate and
bladder neck, leading to the relaxation of smooth muscle, which improves urine flow and reduces
symptoms such as urinary retention, straining, and incomplete voiding.

Pharmacokinetics:

 Absorption: Rapidly absorbed after oral administration, with peak plasma concentrations
occurring within 2–4 hours of dosing.
 Bioavailability: Approximately 32%, due to significant first-pass metabolism.
 Metabolism: Silodosin is extensively metabolized by the liver, primarily via CYP3A4,
producing active metabolites with similar pharmacological activity.
 Half-life: Approximately 13 hours, supporting its once-daily dosing.
 Excretion: Excreted in the urine, with most of the drug eliminated as metabolites.

Side Effects:

 Common side effects include dizziness, retrograde ejaculation, nasal congestion, and
headache.
 Serious side effects include hypotension, syncope, and priapism (rare).

Contraindications:

 Contraindicated in patients with severe liver impairment.

 Caution is advised in patients with a history of hypotension or orthostatic hypotension.

Dosing:

 Immediate Release Capsule: Typically administered as 8 mg once daily, with a possible

reduction to 4 mg in patients with renal impairment.
 PLAN OF WORK

1. Pre-Formulation Studies

1. Physicochemical Characterization of Drugs:

o Analyze the physical and chemical properties of Mirabegron and Silodosin to determine
their compatibility with potential excipients.
o Conduct particle size analysis, solubility studies, and polymorphism investigations using
techniques like FTIR, DSC, and PXRD.

2. Excipient Selection and Compatibility:

o Select excipients suitable for the bilayer tablet, including binders, fillers, disintegrants,
and release modifiers.
o Perform compatibility testing between drugs and excipients (e.g., FTIR, DSC) to ensure
no adverse interactions.

2. Formulation Development

1. Design of Bilayer Tablet:

o Design a bilayer tablet structure where Mirabegron is in the extended-release (ER) layer,
and Silodosin is in the immediate-release (IR) layer.
o Consider factors such as drug release profiles, layer adhesion, and stability during
formulation.

2. Formulation Optimization Using DOE:

o Apply Design of Experiments (DOE) methodology to optimize formulation variables
like:
 Polymer types (e.g., HPMC, ethylcellulose) for the ER layer.
 Disintegrants (e.g., sodium starch glycolate) for the IR layer.
 Compression force, excipient concentration, and granulation techniques.

3. Preliminary Formulation Trials:

o Formulate different batches of bilayer tablets based on the selected excipients and
optimized formulation.
o Assess the physical properties of the tablets (weight, thickness, hardness, and friability).

3. Evaluation of Tablets

1. Physical Testing:
o Evaluate the physical characteristics of the tablets, including:
 Thickness, Hardness, Friability, and Weight Variation: Following USP guidelines.
 Interlayer Adhesion: Test the strength of adhesion between the layers to prevent
delamination during storage and handling.

2. Dissolution Testing:
o Perform in vitro dissolution tests using USP apparatus for both layers:
 IR Layer (Silodosin): Test in simulated gastric fluid (pH 1.2) to ensure rapid release
within 30 minutes.
 ER Layer (Mirabegron): Test in simulated intestinal fluid (pH 6.8) to ensure controlled,
sustained release over 24 hours.
o Apply the Higuchi and Korsmeyer-Peppas models to evaluate the drug release kinetics.

3. Content Uniformity and Assay:

o Assess the uniformity of drug content in each tablet using HPLC to ensure consistent
drug delivery in both layers.
o Ensure the tablets meet the USP content uniformity requirements.

4. Stability Studies

1. Short-Term and Long-Term Stability Testing:

o Conduct stability testing under ICH-recommended conditions:
 Long-Term Stability (25°C ± 2°C / 60% RH ± 5% RH): Evaluate changes in physical
appearance, dissolution profiles, and drug content over a period of 6 months.
 Accelerated Stability (40°C ± 2°C / 75% RH ± 5% RH): Assess changes over a shorter
period (3 months) to predict long-term stability.
o Monitor the bilayer tablet for physical, chemical, and pharmacological stability.

2. Impact of Packaging on Stability:

o Study the effect of packaging materials (e.g., blister packs, HDPE bottles) on the stability
of the bilayer tablets, particularly with regard to moisture sensitivity.

5. In Vivo and In Vitro Correlation

1. Establishing In Vitro-In Vivo Correlation (IVIVC):

o In Vivo Studies: Conduct pharmacokinetic studies in an appropriate animal model to
determine the pharmacokinetic parameters of both drugs.
o In Vitro-In Vivo Comparison: Correlate the in vitro dissolution profiles with in vivo
drug release data, assessing parameters like Tmax, Cmax, and AUC.
 FLOW CHART

├──> Preformulation Studies

│ ├──> Physicochemical Characterization of Drugs
│ │ ├──> Particle Size, Solubility, Polymorphism
│ │ └──> FTIR, DSC, PXRD
│ └──> Excipient Compatibility Studies
│ ├──> Excipient Selection
│ └──> Compatibility Testing (FTIR, DSC)
│
├──> Formulation Development
│ ├──> Bilayer Tablet Design
│ │ ├──> ER Layer: Mirabegron (Extended Release)
│ │ └──> IR Layer: Silodosin (Immediate Release)
│ ├──> Formulation Optimization Using DOE
│ │ ├──> Select Polymer/Disintegrant
│ │ └──> Optimize Compression and Granulation
│ └──> Preliminary Formulation Trials
│ └──> Assess Physical Properties (Weight, Hardness, Friability)
│
├──> Evaluation of Tablets
│ ├──> Physical Testing
│ │ ├──> Thickness, Hardness, Friability, Weight Variation
│ │ └──> Interlayer Adhesion Test
│ ├──> Dissolution Testing
│ │ ├──> IR Layer (Silodosin): Simulated Gastric Fluid (pH 1.2)
│ │ └──> ER Layer (Mirabegron): Simulated Intestinal Fluid (pH 6.8)
│ └──> Assay and Content Uniformity
│ └──> HPLC Analysis
│
├──> Stability Studies
 │ ├──> Short-Term Stability (25°C/60% RH)
│ └──> Accelerated Stability (40°C/75% RH)
│
├──> In Vivo and In Vitro Correlation (IVIVC)
│ ├──> Pharmacokinetic Studies in Animal Model
│ └──> Compare In Vitro and In Vivo Data (Tmax, Cmax, AUC)
 MATERIALS METHODOLOGY

The development and evaluation of a bilayer tablet combining Mirabegron (ER) and Silodosin
(IR) involves systematic formulation design, preformulation studies, optimization of tablet
manufacturing, and comprehensive evaluation of its physical, chemical, and pharmacological
properties. The following methodology will be employed:

1. Preformulation Studies

1. Physicochemical Characterization of APIs:

o Mirabegron (ER): Evaluate particle size, solubility, melting point, pKa, and
polymorphic form.
o Silodosin (IR): Assess solubility, hygroscopicity, and thermal behavior.
o Characterize both drugs using techniques such as Fourier Transform Infrared (FTIR)
Spectroscopy, Differential Scanning Calorimetry (DSC), and Powder X-Ray Diffraction
(PXRD).

2. Drug-Excipient Compatibility Studies:

o Perform compatibility studies to identify suitable excipients for both layers.
o Use accelerated conditions (e.g., 40°C/75% RH) to assess physical and chemical stability
of drug-excipient mixtures.

2. Formulation Development

1. Selection of Excipients:
o For the ER layer (Mirabegron):
 Use hydrophilic and hydrophobic polymers (e.g., HPMC, ethylcellulose) to achieve
sustained release.
o For the IR layer (Silodosin):
 Select disintegrants (e.g., sodium starch glycolate) and binders for rapid drug release.
o Include appropriate lubricants, glidants, and fillers for both layers.

2. Bilayer Tablet Design:

o Optimize the bilayer structure to prevent interlayer mixing and delamination.
o Design a separating layer if needed to avoid interactions between the two drug layers.

3. Optimization of Tablet Compression:

o Use a rotary tablet press with a bilayer attachment to compress the two layers
sequentially.
o Optimize compression force and dwell time to ensure interlayer adhesion.

4. Formulation Trials:
o Apply Design of Experiments (DOE) to evaluate critical formulation variables:
 Polymer type and concentration for the ER layer.
 Disintegrant type and concentration for the IR layer.
o Optimize the formulation to meet desired release profiles and mechanical strength.

3. Evaluation of Bilayer Tablet

1. Physical Characterization:
o Measure thickness, hardness, friability, and weight variation using standard protocols
(USP guidelines).
o Evaluate interlayer adhesion strength to ensure mechanical stability.

2. Dissolution Studies:
o Conduct in vitro dissolution testing for both layers using a USP dissolution apparatus.
 Simulated gastric fluid (pH 1.2) for the IR layer.
 Simulated intestinal fluid (pH 6.8) for the ER layer.
o Compare drug release profiles to ensure:
 Immediate release of Silodosin within 30 minutes.
 Sustained release of Mirabegron over 24 hours.
o Analyze data using release kinetics models (Higuchi, Korsmeyer-Peppas) to understand
the mechanism of drug release.

3. Assay and Content Uniformity:

o Use High-Performance Liquid Chromatography (HPLC) to determine drug content in
each layer.
o Ensure compliance with USP acceptance criteria for content uniformity.

4. Stability Studies:
o Perform stability testing under ICH-recommended conditions:
 Long-term (25°C ± 2°C / 60% RH ± 5% RH).
 Accelerated (40°C ± 2°C / 75% RH ± 5% RH).
o Monitor physical appearance, hardness, dissolution profiles, and drug content over time.

4. In Vitro-In Vivo Correlation (IVIVC)

1. Establishment of IVIVC:
o Correlate in vitro dissolution data with in vivo pharmacokinetic data using Level A
correlation.
o Conduct pharmacokinetic studies in appropriate animal models to evaluate:
 Tmax, Cmax, and AUC for both drugs.
 Verify the synchronized release of Silodosin (IR) and Mirabegron (ER).
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