A Review on Analytical Methods for Determination of Lobeglitazone Sulfate in Pharmaceutical and Biological Matrices

Chronic metabolic disease known as diabetes mellitus (DM) is typified by ongoing hyperglycaemia. It could be brought on by decreased insulin secretion, resistance to insulin's peripheral effects, or both. The International Diabetes Federation (IDF) estimates that in 2015, 415 million adults in the 20–79 age range had diabetes mellitus.[1] As this number is predicted to increase to an additional 200 million by 2040, diabetes is proving to be a global public health burden.[1] In individuals with diabetes mellitus, chronic hyperglycaemia can exacerbate other metabolic abnormalities and harm multiple organ systems. This can result in life-threatening and incapacitating health complications, the most common being microvascular (retinopathy, nephropathy, and neuropathy) and macrovascular (a 2- to 4-fold increased risk of cardiovascular diseases). Based on its origin and clinical manifestation, diabetes mellitus is categorized into three main types: type 1 diabetes, type 2 diabetes, and gestational diabetes (GDM). Secondary diabetes and monogenic diabetes are two other, less prevalent forms of the disease.[2][3][4][5]

Diabetes Mellitus Type 1 (T1DM)

5% to 10% of people with diabetes have type 1 diabetes mellitus (T1DM), which is defined by the autoimmune destruction of the beta cells in the pancreatic islets that produce insulin. Consequently, there is a complete lack of insulin. Autoimmunity has been linked to a mix of genetic predisposition and environmental influences, including viruses, poisons, and certain food items. T1DM can occur at any age, however it is more frequently observed in children and adolescents.

Diabetes Mellitus Type 2 (T2DM)

Roughly 90% of all instances of diabetes are type 2 diabetic mellitus (T2DM). Insulin resistance is the term used to describe the reduced response to insulin in type 2 diabetes. In order to maintain glucose homeostasis during this condition, insulin is ineffective and is initially countered by an increase in insulin production. However, over time, insulin production diminishes, leading to type 2 diabetes. Adults over 45 are most typically diagnosed with type 2 diabetes. However, because obesity, physical inactivity, and energy-dense diets are on the rise, it is becoming more common among kids, teens, and young adults.

Gestational diabetes mellitus

Gestational diabetes mellitus, or hyperglycemia in pregnancy, is the term used to describe hyperglycemia that is initially discovered during pregnancy. Though it can happen at any point during pregnancy, pregnant women are most likely to experience GDM in the second and third trimesters. The American Diabetes Association (ADA) states that 7% of pregnancies end in complications due to GDM. Future type 2 diabetes mellitus is more likely to occur in children born to women with GDM. Hypertension, preeclampsia, hydramnios, and GDM can all exacerbate the condition and increase the need for surgical treatments. The fetus may be larger and heavier than usual (macrosomia) or it may have congenital abnormalities. These newborns may experience respiratory distress syndrome even after delivery, which increases the risk of childhood and teenage obesity. Risk factors for gestational diabetes mellitus include advanced age, obesity, high gestational weight gain, a family history of diabetes, and a history of congenital abnormalities in prior children.

Diabetes monogenic

This kind of diabetes is brought on by a single genetic mutation in an autosomal dominant gene. Neonatal diabetes mellitus and maturity-onset diabetes of the young (MODY) are two instances of monogenic diabetes. Monogenic diabetes accounts for 1% to 5% of all instances of diabetes. A hereditary condition, MODY typically manifests in people under the age of 25.

Diabetes Secondary

Complications from other pancreatic disorders (like pancreatitis), hormone imbalances (like Cushing disease), or medication side effects (like corticosteroids) might result in secondary diabetes. Lobeglitazone Sulphate (C24H24N4O5S) is a new drug candidate for Type2 diabetes mellitus treatment. LBG is a medication belonging to the thiazolidinedione class, serves as an antidiabetic agent (Figure 1). It is chemically known as 5-(4-(2-((6-(4-Methoxyphenoxy) pyrimidin-4-yl) (methyl)amino) ethoxy) benzyl) thiazol2,4-dione. Molecular weight of lobeglitazone sulphate is 578.6 g\mol.Physical properties and taxonomy are mentioned in table 1 and 2, respectively Its main mechanism involves enhancing insulin sensitivity by engaging Peroxisome Proliferator-Activated Receptors (PPAR) gamma found in adipose tissue. Through this activation, lobeglitazone facilitates insulin's binding to adipose cells, leading to decreased blood glucose levels, improved HbA1C levels, and better lipid and liver profiles. [7,8]

Figure 1: Chemical structure of Lobeglitazone sulphate

Table 1: Physical property of Lobeglitazone sulphate ^[7]

Table 2: Summary of Lobeglitazone pharmacokinetic parameters after a single oral dose of 0.5 mg in health male subjects ^[8]

Values are presented as mean±standard deviation unless indicated otherwise. Tmax, time to Cmax; Cmax, maximum plasma concentration; AUCinf, area under concentration–time curve from 0 to infinity; CL/F, oral clearance; t1/2, elimination half-life; fe, fraction excreted unchanged in urine; CYP, cytochrome P450. A Median and range are presented for Tmax, bFraction of Lobeglitazone excreted unchanged in urine was below the lower limit of quantification (0.2 ng/mL).

Table 4: Marketed formulations of Lobeglitazone sulfate

Many different analytical methods have been reported for the estimation of Lobeglitazone Sulfate in bulk and dosage form as well as in biological fluids.

High Performance Liquid Chromatography (HPLC) methods

A simple, precise, and accurate reverse-phase high-performance liquid chromatography approach is described by Kalepu Eswar Krishna Sai et al. to determine the amount of Lobeglitazone in both bulk and pharmaceutical dose forms. A 250 cm×4.6 mm×5 μm Phenomenex Luna column was used for the chromatographic separation. The mobile phase consisted of acetonitrile and potassium dihydrogen orthophosphate in a 70:30 V/V ratio and a pH of 4.0 that was adjusted using orthophosphoric acid. The effluents were detected at a wavelength of 250 nm, with a flow rate of 1.0 mL/min. Lobeglitazone was shown to have a retention period of 2.157 minutes. In accordance with ICH criteria, the HPLC technique was designed and verified satisfactorily. (Table 5).

 Piyusha D. Gulhane et al developed a simple, rapid, reliable, precise, accurate, sensitive and selective analytical method for the estimation of Lobeglitazone in human plasma using as an internal standard (IS). The method was developed using acetonitrile-methanol-water (6:3:1, v/v) 10 μL of supernatant was injected into the HPLC system. The method showed good linearity Subsequently, serial dilutions of five different concentrations ranging between 3.12–50 ppm were made, ultrasonicated and then analysed as per the chromatographic condition for Plasma (r 2 ≥ 0.9996). The mean percent extraction recovery of Lobeglitazone was 90.8 % for plasma. The intra-day precision of plasma ranged from 0.233, 0.290, 1% (RSD), respectively, and the inter-day precision of plasma ranged from 1.5 to 0.115 and 0.99, 1%, respectively. The method was validated with respect to accuracy,precision, linearity and robustness.

Table 6: Validation parameters reported by Piyusha D. Gulhane et al ^[10]

High Performance Thin Layer Liquid Chromatography (HPTLC) methods

The HPTLC technique was developed by Asim Kumar Sen et al. to accurately quantify glimepiride and lobeglitazone sulfate in tablet formulations. Aluminum plates coated with silica gel 60F254 were used for the HPTLC examination. The solvent solution comprised ethyl acetate, benzene, and hexane (4:3:1 v/v/v), which was followed by densitometric scanning at 238 nm. It was determined that the Rf value for GLM was 0.48 ± 0.002 and for LBZ it was 0.68 ± 0.001. With correlation values of 0.9988 and 0.9981 for LBZ and 200–4000 ng/band for GLM, respectively, the approach demonstrated linearity in these ranges. With quantification limits of 72.32 ng/band for LBZ and 176.55 ng/band for GLM, and detection limits of 23.86 ng/band for LBZ and 58.26 ng/band for GLM, exceptional sensitivity was noted (Table 7).

Jeel Dobariya et al., developed two UV spectrophotometric methods for accurately analyzing Lobeglitazone Sulfate and Glimepiride in combined dosage form, used in the treatment of type 2 Diabetes Mellitus. Method I, known as the simultaneous equation method (Vierodt’s Method), relies on measuring the absorption at 250 nm for Lobeglitazone Sulfate and 227 nm for Glimepiride, their respective λmaxvalues. Method II involves the second order derivative method, where the absorbance of Lobeglitazone Sulfate is measured at 297 nm (zero-crossing point of Glimepiride), and that of Glimepiride is measured at 259 nm  (zero-crossing  point  of  Lobeglitazone  Sulfate).  Both  methods  exhibit  linearity within  specified  concentration ranges:  3-13 μg.mL-1 for  Lobeglitazone  Sulfate  and  6-26 μg.mL-1for  Glimepiride,  using  methanol  as  the  solvent.  The accuracy of these methods was confirmed through recovery studies, yielding results within the range of 98-102% for both drugs.  Precision  was  evaluated  through  repeatability  and  intermediate  precision  studies,  demonstrating  %  RSD  values below  2%,  indicating  high  precision (Table 8) .