A Process Development and Validation of Mirabegron Extended Release 25 Mg and Silodosin 8mg Bilayer Tablet

Bilayer tablets continue to represent a new era in which controlled delivery design can be effectively advanced laterally through a variety of methods to provide an approach to an effective drug transport system (Han et al., 2022). Bi-layer tablets appear to be designed for the simultaneous release of two drugs, two discordant constituents, and then similarly for sustained release tablets, where the maintenance dose is the second layer and the immediate release is the first layer.  Bilayer tablets continue to be an improved, advantageous way to overcome the shortcomings of single-layered tablets (Maddiboyina et al., 2020).  The concept of validation has undergone constant development since it was originally            introduced in the US in 1978.The idea of validation has grown over time to include a      variety of tasks, from computerized systems for clinical trials to analytical techniques used for quality control of pharmacological ingredients and items. Because each process is so different, there is one-size-fits all method for validation and regulatory agencies like the FDA and EC have created broad optional standards (Ishitsubo et al., 2024).  Nevertheless, validation is one component of quality assurance related to a specific process. The term validation simply implies "action of proving effectiveness" or "assessment of validity." Validation, as defined by the European Community for pharmaceutical products, is the "action of proving" that any procedure, process, requirement, material, activity, or system genuinely produces the desired results in line with GMP principles. A documented procedure that offers a high level of assurance that a particular process will reliably yield a product that satisfies its predefined specifications and quality attributes is known as process validation (Swetanshu et al., 2020). Mirabegron (Mrb), a β3-adrenoceptor agonist, was a new class of pharmaceutical treatment for OAB. The mechanism of action differences suggest that adding a β3-adrenoceptor agonist to an antimuscarinic agent could enhance efficacy in the treatment of OAB (Lee et al., 2019). The european urology association guideline recommends α-1-blokers for distal ureteric stones. Tamsulosin and silodosin are the most commonly used alpha1-blokers in medical expulsive therapy. Silodosin has a 38-fold higher selectivity for α-1A than tamsulosin. In a study by Gupta et al, tamsulosin and silodosin had expulsion rates of 58% and 82%, respectively. Silodosin was also associated with a shorter expulsion time compared to tamsulosin. In the opposite way of thinking, ureter relaxation may be helpful for easy F-URS procedure, and this can easily be achieved by administering silodosin preoperatively (Diab et al., 2024).

1. MATERIALS AND METHODS
   1. Raw Materials

Mirabegron was purchased from MSN Laboratories Pvt. Ltd. (Telangana, India). Silodosin purchased from PRUDENCE PHARMA CHEM, Microcrystalline cellulose (Ankit pharma), lactose monohydrate (MODERN DAIRIES LIMITED), sodium starch glycolate (SUDEEP PHARMA PVT. LTD.), povidone (SUDEEP PHARMA PVT. LTD.), HPMC K4 M (coloron India), polyethylene glycol 6000 (Vasudha chemicals, Mumbai, India), magnesium stearate (SKANT India), and colloidal silicon dioxide were purchased from (CABOT SANMAR LIMITED). Polyethylene oxide (Dupont India). and Opadry® coating agent (Opadry red 85G55308) were purchased from Coloron India.

1. 2. Preparation of Bilayer Tablet

The formulations are designed for bilayer tablets combining IR (immediate release) and ER (Extended release) components in different ratios. Each drug layer has its separate granulation procedure. For the preparation of Immediate Release (IR) granules, Silodosin, microcrystalline cellulose, lactose monohydrate, and SSG (sodium starch glycolate) were mixed with an inactive binding solution, which is povidone-90 dissolved in purified water, using a high-speed mechanical stirrer. After mixing solutions in dry powder, the wet granules were dried using an FBD. Dried granules were further sized using the 1.0 mm mesh and lubricated with magnesium stearate and Aerosil/colloidal silicon dioxide. For the preparation of SR granules, mirabegron, lactose, starch and HPMC K4 passed through the sieve and further binding done by using PVPK-90. The dry powder was mixed in RMG, and further binding has been done by the binding agent and dried by using FBD 120 kg. Dried granules sized by 1.0 mm mesh and mixed using Double cone Blender 185 ltr capacity. After mixing, the granules were lubricated with magnesium stearate (Jadiya et al., 2024). The both layer granules were further compressed to form the bilayer tablets consisting of Immediate Release and Sustained release layers using an Cadpress IV compression machine using the round shape plain punches. The compaction pressure was set at 10 kN, to achieve the required hardness of tablets during the process of compression. The batch size was 2.0 lac tablets. After forming the bilayer tablets, the tablets were further coated with Opadry coating material using a solace auto coater 37” capacity. The detailed formulations are shown in table 1 and manufacturing scheme is shown as figure 2.

Table 1. Composition of formulations for bilayer tablet Mirabegron ER and Silodosin.

Selection of Manufacturing Equipment:

The equipment for the manufacturing of the products has been selected based on the equipment capacity & design. The equipment’s used for the manufacturing of bilayer products has been selected on the basis of manufacturing process design, product batch size, and available and required utility assessment criteria. The list of equipment has been approved based on the manufacturing process of the product Mirabegron Extended Release 25 Mg and Silodosin 8mg Tablet (Bilayer Tablets).

Table 2: Details of Equipment’s Used for the Manufacturing of Batches

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Figure 1: Flow chart of manufacturing & packaging process

2.4 Process Validation of Mirabegron (ER) and Silodosin Bilayer Tablet:

Various quality and control evaluation parameters were performed for the evaluation of bilayer table formulation. Table 3 described in detail about manufacturing process, process variables and measuring controls.

RESULTS AND DISCUSSION

As per the process validation protocol, sampling of products has been carried out in different stages of manufacturing, i.e. granulation, compression, coating & finished stage. The samples are further analyzed as per the specification of evaluation parameters of formulation process of bilayer tablet. The sampling plan of product was mentioned in the approved validation protocol accordingly sampling has been done. The analytical result of the product gives assurance that manufacturing processes are well-validated. Product sampling and analytical results of all the validation batches discussed in the below sections.

Pre-Formulation and Evaluation of Bilayer Tablet:

The analytical results of the formulation development process of bilayer tablet Mirabegron (ER) 25 mg and Silodosin 08 mg were observed in dry mixing stage. Sample was collected from three stages of the mixer i.e. top, middle and bottom. Detailed analytical reports of the samples were shown in table 4 & 5.

Table 5: Analytical Results of Silodosin in dry Mixing Stage.

Formulation and Evaluation of Coated Tablet:

Evaluation process was done for the final coated bilayer tablet of Mirabegron 25 mg and Silodosin 08 mg through various parameters like description, identification, average weight, uniformity of weight and dissolution. The detailed evaluation values of the all parameters are show in table 6.

Formulation and Evaluation of Final Bilayer Tablet:

Formulation of the bilayer tablet of Mirabegron 25 mg and Silodosin 08 mg was done with the help of standard operating procedure. The evaluation of the formulation process was done for the final compressed bilayer tablet of Mirabegron 25 mg and Silodosin 08 mg compositions. The detailed evaluation values of the all parameters are show in table 7.