A Review on Analytical Techniques for the Determination of Anti-diabetic Drugs in Pharmaceutical Dosage Forms

Diabetes mellitus (DM) is becoming an important global health problem. Current estimates suggest that the prevalence of the disease is 8.5% of the world’s adult population, and this is expected to rise to 10.9% by 2030. The number of people affected is expected to increase significantly, putting pressure on healthcare systems across the world.[1]

The development of Diabetes Mellitus is complex and may occur in many ways, so any system of classification is to some extent flexible. However, classification is important because it helps the healthcare professional to understand the disease and to choose the most appropriate treatment. The current classification system includes the etiology of diabetes and the pathogenesis and is useful in diagnosis and clinical management. In this system, diabetes is generally classified into four broad categories: Type 1 Diabetes, Type 2 Diabetes, Gestational Diabetes, and other types of diabetes caused by specific medical conditions, disorders, or underlying pathologies.[2]

Fig No. 1 Types of Diabetes Mellitus

Diabetes is a long-term condition where the body can’t manage blood sugar (glucose) properly. This may be because the pancreas does not make enough insulin, or because the body cannot use insulin well. Insulin is a hormone that is produced by special cells in the pancreas (called beta cells). Its main function is to help control the level of sugar in the blood by letting it into the cells, where it can be used as fuel. In many people with diabetes especially type 2 diabetes the body develops a condition called insulin resistance. That means the cells in the body no longer respond well to insulin. This makes it hard for glucose to get into the cells and it starts to build up in the blood.[3]

Type 2 diabetes is a common metabolic condition that occurs when two major problems happen at the same time: the pancreas doesn’t make enough insulin, and the body’s tissues don’t respond to insulin as they should. This means that the body has more difficulty regulating blood sugar levels effectively. There are several factors that can increase the risk of developing this condition such as high blood sugar levels over time, being overweight, high triglyceride levels, poor eating habits, lack of physical activity, aging, and a family history of diabetes. Factors can also include feelings like stress, anxiety, and depression. Type 2 diabetes usually requires a mix of treatments to manage. This can include insulin therapy and medications such as metformin and other drugs that help lower blood sugar levels, along with lifestyle changes to support overall health.[4]

Analytical chemistry is the branch of chemistry that deals with figuring out what matter is and how much of it there is. Analytical chemistry is not an independent discipline within chemistry; rather, it is the practical application of chemical principles. Pharmaceutical Analysis is the process of using analysis to find out how pure, safe, and high-quality a drug or chemical is. "Quantitative pharmaceutical chemistry" is another name for "pharmaceutical analysis." Pharmaceutical analysis encompasses both qualitative and quantitative evaluations of drugs and pharmaceutical substances, ranging from bulk drugs to final dosage forms. In quantitative analysis, the method used is based on the quantitative performance of appropriate chemical processes. This involves either measuring the amount of reagent needed to complete the reaction or finding out how much reaction product was made.[5]

1. Quality by design: [6]

Quality is the most important thing when it comes to drugs. The effectiveness, safety, and quality of pharmaceutical products have a direct effect on the health and safety of patients. QbD is a cutting-edge method that focuses on building quality into processes and products from the start, rather than just testing finished products. It is an important part of making sure that pharmaceutical goods always meet these high standards. QbD was first used in the pharmaceutical industry, but now it is being used in many other fields, such as biotechnology, chemical manufacturing, and food production, because it is a systematic and scientific way to make sure quality.

2.1 Benefits of QbD

Fig No.2 Benefits of QbD

2.2 Key Principles of QbD

QbD is based on several key principles that guide its implementation:

2.2.1 Gaining an understanding of the product and process:

To do Qbd, you need to know a lot about the product and how it is made. This means figuring out what quality traits you want and what can change them.

2.2.2 Building quality into product:

The goal is to create a process that naturally guarantees quality, so there is less need for a lot of testing and quality checks after production. The focus is on creating processes that naturally guarantee quality, which reduces the need for extensive testing and quality checks after production.

2.2.3 Risk management:

QbD means finding and controlling risks at every stage of a product's life. This proactive approach helps to find and fix problems before they affect the quality of the products.

2.2.4 Design of experiment:

Structured experiments that look into the links between process factors, product factors, and product qualities make process optimization possible.

2.2.5 Continuous improvement:

To make the products better and more efficient. QbD is an ongoing process that includes watching, evaluating, and improving processes.

2.3 ICH Guidelines:

Guidelines: The ICH has developed several guidelines that incorporate QbD, including:

ICH Q8: Pharmaceutical development

ICH Q9: Quality risk management

ICH Q10: Pharmaceutical quality system

Objectives: ICH guidelines aim to harmonize regulatory expectation across regions, promoting a unified approach to pharmaceutical quality.

2.4 Role of QbD in Analytical Method Development:

Analytical method development is the process of coming up with ways to accurately measure compounds or properties. When developing analytical methods with QbD, you make sure that they are reliable, reproducible, and fit for their intended use.

2.5 Benefits of Using QbD in Analytical Method Development:                          

• Improved understanding of methods
• Enhanced method robustness
• Reduction of variability
• Efficiency in development
  6. Key aspects of QbD includes: [7]

Fig No. 3 Key aspects of QbD

2.7 Tools and Techniques in QbD for Analytical Method Development:

2.7.1 Statistical software:

• JMP: Offers powerful visualization and analysis tools.
• Minitab: Widely used for statistical analysis in various industries.
• Design-Expert: Specializes in the DoE and optimization.

2.7.2 Risk assessment tools:

Fishbone Diagram: Identifies potential causes of variability.

Failure mode and effect analysis: Risks are systematically assessed together with their effects using FMEM.

Risk ranking and filtering: Prioritizes risk based on severity and probability.

2.7.3 Process analytical technology:

PAT involves using real-time data to monitor and control processes, ensuring compliance with quality standards.

2. RP-HPLC Method development and validation of Anti-diabetic drugs.

      This review focus on HPLC method development and validation of Anti-diabetic drugs in BCS Class II : [8]

Table No.1 Anti-diabetic Drugs in BCS Class II

There are many methods developed for anti-diabetic drugs RP-HPLC methods in API and combination drugs. This method seems to be economic than other methods.

Table No.2 RP-HPLC Method development and validation of anti-diabetic drugs

This review emphasis on different method development and validation of glimepiride as follows:

3. Drug Profile:

Table No. 3 Drug Profile of Glimepiride

4. Method Development and Validation

I) Method Development

There are many methods developed for glimepiride by UV Visible Spectroscopy, HPLC, HPTLC, LCMS methods in API and combination drugs. This method seems to be economic than other methods.[25]

5.1 By using UV-Visible Spectroscopy:

Table No. 4 UV-Visible Spectroscopy Method for Glimepiride

5.2 By using HPLC:

Table No. 5 HPLC Method for Glimepiride

5.3 By using LC-MS/MS

Table No. 6 LC-MS/MS Method for Glimepiride

5.4 By using UPLC-MS/MS

Table No. 7 UPLC-MS/MS Method for Glimepiride

II) Validation

The methodical process of evaluating and presenting unbiased proof that particular requirements for a given intended use are satisfied is known as validation. It entails assessing a method's effectiveness and proving that it can satisfy particular requirements. Validation basically gives you a thorough understanding of what your method can consistently produce, especially when working with low doses or difficult conditions in analytical methods.[5]

Method Validation

Method validation is the process to confirm that analytical procedure employed for a specific test is suitable for its intended use. Method needs to be validated or revalidated;

• Before their introduction into routine use
• Whenever the conditions change for which, the method has been validated, e.g., instrument with different characteristics
• Whenever the method is changed, and the change is outside the original scope of the method.

All the variables of the method should be considered, including sampling procedure, sample preparation, chromatographic separation, detection and data evaluation chromatographic methods used in analytical applications there is more consistency in validation practice with key analytical parameters.[5]

The process of evaluating an analytical method's performance uniqueness and compliance with the requirements for its intended use is known as validation, and it is established through laboratory studies. The first step in the validation process for analytical procedures is the applicant's deliberate and methodical collection of validation data to support the analytical procedure.[39]

 Parameters

The following are typical analytical performance characteristics which may be tested during methods validation:

• Accuracy
• Precision
• Linearity and Range
• Detection limit
• Quantitation limit
• Specificity
• Robustness
• Ruggedness
• System suitability determination
• Stability studies

1. Accuracy

It is the degree to which the method's test results closely resemble the actual value. Using a known quantity of standard drug solution added to the sample solution, recovery studies were conducted using the standard addition method.[4]

2. Precision

The degree of agreement or scattering between a series of measurements made under particular conditions from multiple samplings of the same homogeneous material is known as precision in the context of analytical methods. Precision is a crucial parameter for evaluating the reproducibility of the entire analytical process. Repeatability and intermediate precision are the two parts of precision.

The variation that a single analyst experiences on a single instrument is known as repeatability. It does not differentiate between variance resulting from the instrument or system and variance brought about by the sample preparation process. The fluctuation that takes place in a laboratory on different days, with different instruments, and involving different analyses is referred to as intermediate precision.[17]

3. Linearity

The ability of an analytical procedure to yield test results that are exactly proportionate to the analyte concentration in the sample, within a given range, is known as linearity. It is essential to assess this linear relationship throughout the analytical technique's range. To directly demonstrate linearity on the drug substance, the suggested method entails diluting a standard stock solution containing the components of the medical product. [17]

4. Detection limit

The most fundamental indicator of an analyte in a sample that can be identified but not precisely quantified is the detection limit of a single analytical technique. This limit, which serves as a key indicator of the method's sensitivity, is the lowest concentration at which the analyte's presence can be consistently detected.[17]

5. Quantification limit

The lowest amount of analyte in a sample that can be precisely and accurately measured quantitatively is known as the quantitation limit of a particular analytical system. The quantitation limit serves as a threshold for accurate quantitative measurements in analytical techniques and is essential for detecting contaminants and/or impurities in samples.[17]

6. Specificity

The ability of an analytical method to precisely measure an analyte in the presence of interference, such as synthetic precursors, excipients, enantiomers, and known (or likely) degradation products that might be expected to be present in the sample matrix, is known as selectivity.[40]

7. Robustness

It is described as a measure of an analytical method's capacity to show its dependability under typical use while remaining unaffected by slight but intentional changes in method parameters (e.g., pH, mobile phase composition, temperature, and instrumental settings). The methodical process of changing a parameter and assessing the impact on the procedure by keeping an eye on system suitability and/or sample analysis is known as robustness determination.[40]

8. Ruggedness

The sample solutions were prepared and examined under various analytical conditions, such as different laboratory settings, and the findings are presented.[4]

9. System suitability determination

Testing for system suitability is a common procedure in liquid chromatography. They act as a guarantee that the resolution, detection sensitivity, and repeatability of the chromatographic system are adequate for the planned analysis. These tests are predicated on the idea that the instruments, electronics, analysis procedures, and samples to be tested are all parts of a bigger system that can be evaluated collectively.

Key parameters such as peak resolution, the number of theoretical plates, peak tailing and capacity are examined during system suitability tests to assess the adequacy and performance of the employed analytical method.[17]

10. Stability studies

In order to determine whether special storage conditions, such as refrigeration or light protection, are required, the stability of standards and samples is established during validation under normal conditions, normal storage conditions, and occasionally in the instrument.

6. Difference between UV Visible and HPLC

Table No. 8 Difference between UV-Visible spectroscopy and HPLC