Optimization & Evaluation of Coating Uniformity in Sustained and Immediate Release of Proton Pump Inhibitor (PPIS)

Proton Pump Inhibitors (PPIs) are a class of drugs commonly used to treat acid-related disorders like gastroesophageal reflux disease (GERD), peptic ulcers, and gastritis. These drugs work by inhibiting the proton pump in the stomach, thereby reducing gastric acid secretion. Pantoprazole, omeprazole, and esomeprazole are examples of widely used PPIs. To improve the pharmacokinetics of PPIs, drug formulations often include a combination of sustained-release (SR) and immediate-release (IR) components. This approach is designed to achieve both rapid onset for immediate relief of symptoms and extended therapeutic effects over time. Coating technologies are critical in controlling the release profile of such dosage forms, and coating uniformity plays a pivotal role in ensuring predictable and consistent drug release. Proton pump inhibitors (PPIs) are a class of drugs widely used to treat acid-related disorders, such as gastroesophageal reflux disease (GERD), peptic ulcers, and Zollinger-Ellison syndrome. These drugs act by irreversibly inhibiting the H+/K+-ATPase enzyme in gastric parietal cells, thereby reducing stomach acid secretion. Due to their pH-sensitive nature and instability in acidic environments, PPIs require specialized formulations to ensure their efficacy and stability. Among the various formulation approaches, sustained and immediate release systems have gained significant attention for PPIs. Sustained release formulations provide a prolonged therapeutic effect by maintaining steady plasma concentrations, reducing dosing frequency, and improving patient compliance. Conversely, immediate release systems are designed to rapidly increase drug concentration in the bloodstream, offering fast relief from symptoms. The uniformity of the coating applied to pellets or tablets plays a critical role in achieving the desired drug release profile. Coating uniformity ensures consistent drug release, prevents dose dumping, and protects the drug from environmental factors. Variations in coating thickness or quality can lead to suboptimal therapeutic outcomes or adverse effects, especially for drugs like PPIs, where precise release control is essential. Optimizing coating parameters, including polymer selection, spray rate, drying conditions, and coating thickness, is critical to achieving the desired release kinetics. Advanced coating techniques, such as fluidized bed coating and pan coating, enable precise application of functional coatings to meet the dual objectives of sustained and immediate release. Evaluation methods, including dissolution testing, scanning electron microscopy (SEM), and content uniformity analysis, further aid in assessing coating quality and performance. It is critical to increase the availability of more advanced formulations that are simple to prepare and administer, such as minitablets, orodispersible tablets, and films, particularly those incorporating functional micro- or nanoparticles. Standard enteric-coated tablets or capsules are not appropriate for all people, resulting in typical issues such as dosage adjustments, crushing, or grinding of such forms. Additionally, it has a detrimental impact on patients' compliance and drug adherence. The majority of currently produced formulations are aimed at overcoming these challenges and improving the efficacy and safety of PPI treatment. The physicochemical features of PPIs are briefly presented, with a focus on their pharmacokinetic and pharmacodynamic qualities, stability, and qualitative or quantitative analytical methods. We investigated the content and formulation of PPI-containing commercial medicines. The most important section of this review discusses the various approaches to developing different dosage forms with PPIs, including nanoparticles, microparticles, minitablets, pellets, bilayer tablets, gastroprotective tablets, and mucoadhesive tablets, as well as dosage forms administered via non-oral routes such as parenteral, transdermal, and rectal preparations. Proton Pump Inhibitors (PPIs) are antisecretory medicines [1, 2]. Along with histamine H2-receptor antagonists and potassium-competitive acid blockers (PCAB), they are used to treat gastroesophageal reflux disease (GERD) and other conditions characterized by excessive stomach acid production [3,4,5,6]. According to the IQVIA study on Medicine Spending and Affordability in the United States, omeprazole and pantoprazole were among the top 20 most often prescribed medications in 2020 [7].

Aim And Objectives

The purpose of this study is to summarize the historical context of proton pump inhibitor discovery and development, address formulation concerns linked to this medication class, show modern solutions, and evaluate future potential and challenges in formulation development. This study aims to optimize and evaluate the coating uniformity in sustained and immediate release formulations of proton pump inhibitors, ensuring robust drug performance and therapeutic efficacy. By addressing the challenges of coating application and uniformity, this research seeks to enhance the reliability and clinical utility of PPI formulations. The physicochemical characteristics of PPIs are briefly explained, especially in relation to their pharmacokinetic and pharmacodynamic properties, stability, and methods of qualitative or quantitative analysis. We analyzed the composition and kind of formulation in commercially available preparations with PPIs. The most important part of this review describes the numerous approaches to formulate different dosage forms with PPIs: nanoparticles, microparticles. Rabepeazole sodium treats acid-related gastroduodenal diseases by lowering stomach acid output. Proton pump inhibitors are substituted benzimidazoles with identical core structures and modes of action, but differ in substituent groups. Delayed release dose forms are ideal for medications that are degraded in stomach juices, cause gastric discomfort, or are absorbed more efficiently in the intestine. These preparations include an alkaline core material with the active ingredient, a separating layer, and an enteric coating layer.

Objectives-

• Improve the stability of Proton inhibitor
• Low-cost manufacturing
• Make the process is easy

Drug Profile

Rabeprazole Sodium-

Rabeprazole sodium is an antiulcer drug in the class of proton pump inhibitors. It is a prodrug - in the acid environment of the parietal cells it turns into active sulphenamide form. Rabeprazole inhibits the H+, K+ATPase of the coating gastric cells and dosedependent oppresses basal and stimulated gastric acid secretion.

Chemical structure

IUPAC Name:  2-({[4-(3-Methoxypropoxy)-3-methyl-2 pyridyl] methyl} sulfinyl) -1H-benzimidazole sodium.

Molecular formula: C18H20N3NaO3S.

Molecular weight: 381.42.

Description: A White or almost white powder. Melting point: 170-173 °C

Solubility: Soluble in water.

Half-life: 1-2 hours (in plasma).

Absorption: Absolute bioavailability is approximately 52%.

Volume of distribution: 160 litre.

Protein binding: 96.3% (bound to human plasma proteins).

Pharmacodynamics-  Rabeprazole inhibits the formation of stomach acid. It alleviates symptoms and avoids damage to the esophagus or stomach in people with GERD or ulcers. Rabeprazole can help treat Zollinger-Ellison syndrome, which causes excessive stomach acid production. Rabeprazole can be taken alongside medicines to eliminate germs linked to some ulcers. Rabeprazole, an irreversible proton pump inhibitor, reduces stomach acid production by inhibiting the H+, K+-ATPase at the secretory surface of parietal cells. This restricts the passage of hydrogen ions into the stomach lumen by exchanging them with potassium.

Mechanism of action- Rabeprazole is a type of antisecretory compound (substituted benzimidazole proton-pump inhibitor) that suppresses gastric acid secretion by inhibiting the gastric H+/K+ATPase (hydrogen-potassium adenosine triphosphatase) at the secretory surface of the gastric parietal cell. It does not have anticholinergic or histamine H2-receptor antagonist properties. Because this enzyme is recognized as the Rabeprazole acts as a stomach acid (proton) pump in the parietal cell. Proton pump inhibitor. Rabeprazole inhibits the last stage of stomach acid output. Rabeprazole is converted to active sulfenamide in gastric parietal cells by protonation and accumulation. In vitro studies show that rabeprazole activates at pH 1.2 and has a half-life of 78 seconds.

Metabolism- Rabeprazole is extensively metabolized. Throatier and sulphone are the main metabolites detected in human plasma. These metabolites did not show considerable antisecretory action. Rabeprazole is principally metabolized in the liver by cytochromes P450 3A (sulphone metabolite) and 2C19. Rabeprazole reduction produces the throatier metabolite.

MATERIALS AND METHODS

METHODOLOGY

The research methodology for the optimization and evaluation of coating uniformity in sustained and immediate release formulations of PPIs involves a systematic approach combining formulation development, coating optimization, uniformity evaluation, and drug release analysis. The methodology can be divided into the following key steps:

1. Formulation of PPI Pellets/Tablets:

1. Selection of Drug: Choose a PPI (such as pantoprazole, omeprazole, or rabeprazole) based on its suitability for sustained and immediate release formulations.
2. Core Material Preparation:
   • Prepare pellets or tablets as the core material. Pellets are preferred due to their uniform surface area, which allows better control of the coating process.
   • Use excipients like binders (e.g., PVP), diluents (e.g., lactose), and disintegrates (e.g., croscarmellose) for proper pellet formation and uniformity.
   • Granulation may be performed if necessary to improve the uniformity of the core material.
3. Drug Loading: Ensure the required dose of the PPI is uniformly distributed within the pellet or tablet matrix.

2. Optimization of Coating Process:

1. Coating Material Selection: Choose appropriate materials for the sustained release coating, such as:
   • Hydroxypropyl Methylcellulose (HPMC)
   • Ethyl cellulose
   • Eudragit (e.g., Eudragit RL, RS) for pH-sensitive release, which can control drug release in specific regions of the GIT.
2. For the immediate release (IR) layer, materials like microcrystalline cellulose (MCC) and gelatines can be used to ensure rapid dissolution.
3. Coating Solution Preparation: Prepare coating solutions with appropriate polymer concentration, plasticizers (e.g., glycerin), and solvents. The concentration of the coating polymer will affect the release rate and the uniformity of the coating.
4. Coating Process (Pan Coating or Fluidized Bed Coating):
   • Pan Coating: Coat the pellets/tablets using a pan coater. Monitor and optimize the spray rate, atomization pressure, and drying temperature during the coating process to ensure uniformity.
   • Fluidized Bed Coating: Coat pellets in a fluidized bed, which is ideal for achieving a consistent layer and improving drug release predictability.

The coating parameters to be optimized include:

• • Viscosity of the coating solution
  • Spray rate and atomization conditions
  • Drying air temperature and relative humidity

3. Evaluation of Coating Uniformity:

1. Visual Inspection: Perform an initial visual inspection of the coated pellets or tablets to detect any obvious defects like cracks, agglomeration, or uneven coating.
2. Microscopic Evaluation:
   • Scanning Electron Microscopy (SEM): Use SEM to inspect the morphology of the coating. SEM allows for detailed observation of the coating's uniformity, thickness, and surface characteristics.
   • Optical Microscopy: A simple technique to visually inspect coating defects and surface irregularities.
3. Coating Thickness: Use microtome sectioning or optical methods to measure the coating thickness. Uniformity in thickness is crucial for achieving consistent release profiles.
4. X-ray Microtomography: Non-destructive imaging to examine the internal structure of the coated pellets/tablets and confirm coating uniformity.

4. In Vitro Dissolution Testing:

1. Dissolution Studies:
   • Conduct dissolution testing to assess the release profile of the drug from the coated pellets or tablets. The testing should simulate gastric and intestinal conditions (using dissolution media with different pH values).
   • The test should include both immediate release and sustained release phases. The dissolution conditions should be optimized to mimic the GI tract.
2. Release Kinetics Analysis:
   • Zero-Order Kinetics: Evaluate if the drug release follows zero-order kinetics, where the release rate is constant over time.
   • Other Kinetics Models: If zero-order kinetics is not achieved, explore first-order, Higuchi, or Korsmeyer-Peppas models to describe the release mechanism.

The release rate for both immediate and sustained phases should be carefully monitored to ensure they meet therapeutic requirements.

5. Stability Studies:

1. Accelerated Stability Testing: Conduct stability studies at 40°C ± 2°C and 75% RH ± 5% (or other suitable conditions) to assess the chemical and physical stability of the formulations.
2. Long-Term Stability: Store the formulations at recommended conditions (usually 25°C ± 2°C and 60% RH ± 5%) and analyze the formulations periodically to evaluate the drug content, release profile, and coating integrity over time.

6. Bioavailability Evaluation (Optional):

1. If applicable, perform bioavailability studies to assess the absorptionandtherapeutic effect of the formulation. This step helps in confirming the clinical relevance of the developed formulation in improving the pharmacokinetics of the PPI.

7. Data Analysis:

1. Statistical Analysis: Analyze the data obtained from dissolution tests, coating uniformity evaluation, and stability studies using appropriate statistical methods to ensure the reliability and significance of the results.
2. Comparative Analysis: Compare the release profiles of the newly developed formulation with commercially available PPIs to assess the improvements in release kinetics and uniformity.

RESULTS AND DISCUSSION

Preformulation Studies-

Description-

Table No. 1: Description of Rabeprazole Sodium

Discussion: The colour, odour, nature and taste of the API were evaluated. It was found to be as per the monograph.

Solubility-

Table No. 2 Solubility of drug

Discussion: Thus the results revealed that the drug was soluble in water, methanol and ethanol

Compatibility Studies By FT-IR-

Figure 1: FTIR Spectra of Rabeprazole Sodium