Formulation Development and Analytical Method Development of Dapsone and Ethoxzolamide Bilayer Tablet Used in Treatment of Severe Burn Dissertation

Bi-layered tablets:

Bi-layer tablets require fewer materials than compression-coated tablets and may be thinner. For unique tablet identity, colouring the separate layers provides many possibilities. Currently, several pharmaceutical companies are preparing bilayer tablets for a variety of reasons, viz. patent extension, therapeutic, and marketing, to name a few. There are various problems associated with the formulation of bilayer tablets, such as layer separation, insufficient hardness, inaccurate individual layer weight control, cross contamination between the layers, reduced yield, etc.

Types of Bilayer tablets:

A. Homogeneous type

Bilayer tablets are preferred when the release profiles of the drugs are different from one another. These are prepared with one layer being immediate release and the other layer being designed to give a second dose or controlled release.

Fig.1.Bilayer tablets (some drug with different-different release pattern-Homogeneous

B. Heterogeneous type

The bilayer tablet is suitable for the sequential release of two drugs in combination, separating two incompatible substances

Fig. 2. Bilayer tablet (with two drug-Heterogeneous)

Need of developing bilayer tablets

For the supervision of fixed dose combinations of drugs, prolonging the drug product life cycle, buccal/mucoadhesive drug delivery systems, develop novel drug delivery systems such as chewing devices and floating tablets for gastro-retentive drug delivery systems.

1. To control the delivery rate of either a single or two different APIs.
2. To adapt the total surface area available for the API layer, either by sandwiching with one or two inactive layers in order to achieve swellable/erodible barriers for controlled release.
3. To isolate incompatible APIs and control the release of one layer by using the functional properties of the other layer.

Advantages

1. It has the greatest chemical and microbial stability as compared to other oral dosage forms.
2. Provide the most precision with the least amount of content uniformity.
3. Suitable for mass production.

Disadvantages

1. It adds complexity, and also, bi-layer rotary presses are expensive.
2. It has insufficient hardness, layer separation, and reduced yield.
3. There may be cross contamination between the layers.

Applications

1. They are suitable for the sequential release of two drugs in combination.
2. It is improved technology that overcomes the single-layered tablet's shortcoming.
3. They are used to deliver the loading dose and a sustained dose of the same or different drugs.

Quality and GMP requirements

For the manufacturing of a good quality bi-layer tablet according to GMP guidelines, it is important that the selected press be capable of the following:

1. Capping and de-lamination should be avoided.
2. Sufficient tablet hardness should be maintained.
3. Keep the two layers from becoming contaminated with each other.

Compression Cycle for Bilayer Tablet

The bi-layer tablet is made by compressing two different granulations fed into a die in succession. One on top of another in layers. Individual layers come from a separate feed frame with individual weight control. The rotary tablet press is set up for two or three layers.

Fig. 3. Compaction process of Bi-layered tablet

Literature Review:

• Patel et al. (2010) studied challenges in the formulation of bi-layered tablets. This article explains why the development and production of quality bi-layer tablets needs to be carried out on purpose-built tablet presses to overcome common bi-layer problems, such as layer-separation, insufficient hardness, inaccurate individual layer weight control, cross-contamination between the layers, reduced yield, etc. Using a modified tablet press may therefore not be your best approach in producing a quality bi-layer tablet under GMP-conditions
• Anupam Sarma et al. (April 2013) this article explains why the development and production of quality bi-layer tablets needs to be carried out on purpose-built tablet presses to overcome common bi-layer problems, such as layer-separation, insufficient hardness, inaccurate individual layer weight control, cross-contamination between the layers, reduced yield, etc. Using a modified tablet press may therefore not be your best approach to producing a quality bi-layer tablet under GMP-conditions. Especially when in addition high production output is required
• Sowmya et. Al (2012) This article explains about the novel approach of oral drug delivery system. Bi-layer tablet is a new era for the successful development of controlled release formulation along with various features to provide a way of successful drug delivery system. Bi-layer tablet is suitable for sequential release of two drugs in combination, separate two incompatible substances and also for sustained release tablet in which one layer is immediate release as initial dose and second layer is maintenance dose. Bi-layer tablets has been developed to achieve controlled delivery of different drugs with predefined release profiles.
• Gill P et al. reported "Differential Scanning Calorimetry Techniques: Applications in Biology and Nanoscience" Thermoanalytical parameters of biomolecules and nanomaterials may be obtained using DSC, which is a strong method. Furthermore, recent advancements have enabled the evaluation of the purification yield of various pharmaceutical medicines, such as antibodies.
• Prasanna Kumar Desu et al. reviewed different techniques for bilayer tablet. Bi-layer tablet quality and GMP-requirements can vary widely. This explains why many different types of presses are being used to produce bi-layer tablets, ranging from simple single-sided presses to highly sophisticated machines. Whenever high quality bi-layer tablets need to be produced at high speed, the use of an 'air compensator' in combination with displacement control appears to be the best solution. The present study shows that quality and GMP requirements can vary widely for bilayer tablets. This explains why many different types of presses are being used to produce bi-layer tablets, ranging from simple single-sided presses to highly sophisticated machines such as the Courtoy-R-292F.

Drug Profile

Table 1. Drug Profile of Dapsone

Particulars	Description
Name	Dapsone
Category	Anti-biotic
CAS registry number	80-08-0
Chemical Structure
Chemical Formula	C12H12N2O2S
IUPAC name	4-[(4-aminobenzene)sulfonyl]aniline
Molecular weight	248.30 g/mol
Appearance, Colour	White Crystalline powder, Odourless, Slightly bitter taste.
Melting Point	175-176 °C
Solubility	Practically insoluble in water
BCS Class	Class II
Storage	Store at room temperature between 20°C-25°C away from light and moisture.
PKa	2.41
Dose	50 to 100 milligrams (mg) once a day; or 1.4 mg per kilogram (kg) (0.6 mg per pound) of body weight once a day.
Half Life	The elimination half-life of dapsone is about 30 hours.
Protien Binding	About 70 to 90% protein bound
Log P	0.97
l max	290 nm
Ph	5.5-7.0
Cmax	0.63-4.82 mg/L
Adverse effect	Hemolysis, Toxic hepatitis and cholestatic jaundice, Other adverse effects include nausea, headache, and rash (which are common), and insomnia, psychosis, and peripheral neuropathy.

Table 2. Drug Profile of Ethoxzolamide

Particulars	Description
Name	Ethoxzolamide
Category	Diuretic agent
CAS registry number	452-35-7
Chemical Structure
Chemical Formula	CH10N2O3S2
IUPAC name	6-ethoxy-1,3-benzothiazole-2-sulfonamide
Molecular weight	222.24 g/mol
Appearance, Colour	White to faintly yellowish-white, odorless crystalline powder
Melting Point	188-190.5 °C
Solubility	Slightly soluble in alcohol, acetone, chloroform & ether, practically insoluble in water

MATERIALS AND METHODOLOGY

Formulation of Bilayer tablet containing Dapsone and Ethoxzolamide

Following formulations of Dapsone and Ethoxzolamide Bilayer tablets were used for developmental work.

Table 3 Composition of Immediate release tablet containing Dapsone (D1-D4)

Table 4 Composition of Sustained release tablet containing Ethoxzolamide (A1-A4)

The bilayer tablets were prepared using the direct compression method. The sustained release layer was poured first into the die cavity, followed by the immediate release layer, which was poured and compressed into the tablets using a 12 station tablet compression machine (Rimek, Mini Press-II MT. Karnavati Engineering Ltd., 12 station) with an average hardness of 4.0-6.0 kg/cm². (Monsanto hardness tester)

RESULTS AND DISCUSSION

Drug Authentication:

Organoleptic properties:

Table.5. Comparison of Organoleptic Properties of Dapsone with the Reported Standards

Table. 6 Comparison of Organoleptic Properties of Ethoxzolamide with the Reported standards

FTIR Study

Figure 4 IR Spectra of Dapsone

Figure. 5.IR Spectra of Ethoxzolamide

DSC Study

Figure.6. DSC graph of pure Dapsone

Figure.7 DSC graph of pure Ethoxzolamide

UV-Visible spectroscopy

Fig.8 Calibration curve of Dapsone

Fig. 8.Calibration curve of Ethoxzolamide

Drug-excipient compatibility study

DSC Study

The DSC thermogram for Dapsone in combination with various excipients shows the peak onset temperature (Tonset) [176.86°C]. The thermogram of Dapsone showed a sharp endothermic peak at 180°C. In this thermogram, the melting endotherm of Dapsone (T onset and T peak) was well preserved, with light broadening shifting towards the lower temperature range.

Fig.9.: DSC graph for Dapsone with excipients

Fig.10: DSC graph for Ethoxzolamide with excipients

Evaluation of prepared tablet blends for pre compression study:

The characterization of mixed blend was done for determination of mass-volume relationship parameters. The evaluated parameters are angle of repose, bulk density, tapper density; Hauser's ratio and compressibility index were reported in Table for Dapsone as the immediate release layer and for Ethoxzolamide as the sustained release layer.

Table. 7.Evaluation of Powder Blend Dapsone (DP1-DP4)

±S.D. (n=3)

Table 8. Evaluation of Powder Blend Ethoxzolamide (A1-A4)

Tables indicates the results obtained for angle of repose of all the formulations. All formulations showed the angle of repose within 30°. It indicates that all formulations showed excellent flow properties. From the results of pre- compression studies of the batches DP1-DP4 and E1-E4, it is concluded that a powder mixture has good flow properties and compressibility properties.

Evaluation of Tablets:

All batches (DE1-DE4) were subjected for weight variation, thickness, hardness, friability, drug content, in vitro disintegration time, and kinetic studies were carried out. All the formulations were passed the parameter which was reported in Table.

Table.9. Evaluation of bilayer tablets

The formulated tablets, batches DP1-DP4, were tested for assay by UV spectroscopy. Dapsone absorbance in methanol is measured at 296nm (max). The assay was found to be in the range of 98.12% to 99.78%, which is within the standard record limit. The formulated tablets, batches E1-E4, were tested for assay by UV spectroscopy. Ethoxzolamide absorbance in methanol is measured at 299nm (2max). The assay was found to be in the range of 98.63% to 101.04%, which is within the standard record limit.

Figure. 11. Cumulative percentage of drug released of formulations (DPI-DP4)

Figure. 12. Cumulative percentage of drug released of formulations (E1-E4)

Kinetic analysis of In-vitro Drug Release Study

Table.10. Kinetics of drug release profile for Dapsone (DP1-DP4)

Table.11. Kinetics of drug release profile for Ethoxzolamide (E1-E4)