Objectives: This article aimed to develop a method for the simultaneous estimation of Azilsartan medoxomil (AZT) and cilnidipine (CIL) by incorporating a quality-by-design approach, which is used to develop the most accurate and precise analytical method in comparison with traditional method development. Methods: At the initial phase, researchers conducted high-performance liquid chromatography (HPLC) trials as per the traditional method development protocol, and factors such as mobile phase, flow rate, and column temperature were taken into consideration for finalizing the most suitable trial. Quality-by-Design approach is then implemented for further study. As per the Box–Behnken design (BBD) system, the method was optimized. The most suitable optimized solution is used for validation. Results: Based on traditional method development, methanol and 0.1% v/v ortho phosphoric acid selected as a mobile phase in an 82:18 ratio, the flow rate was selected as 1 mL/min, and column temperature was selected at 40°C. Based on these factors, 17 HPLC runs were performed as per BBD protocol the p-values for quadratic model for all factors was found <0.0500, which shows the quadratic model is best for proposed study by which method get optimized, and the validation was carried out on the most appropriate optimized solution. The R2 for AZT and CIL was found to be 0.9998 and 0.9999, respectively. The method was linear for both the drugs, and accuracy was found to be 100.45% for AZT and 99.49% for CIL. Other validation parameters were also found within limits. Conclusion: At the end of the study, it was found that the developed method was accurate, precise, linear, specific, and reproducible. Method is cost-effective and can be able to used for routine analysis in laboratories as well as in industries.

Objectives: This article aimed to develop a method for the simultaneous estimation of Azilsartan medoxomil (AZT) and cilnidipine (CIL) by incorporating a quality-by-design approach, which is used to develop the most accurate and precise analytical method in comparison with traditional method development. Methods: At the initial phase, researchers conducted high-performance liquid chromatography (HPLC) trials as per the traditional method development protocol, and factors such as mobile phase, flow rate, and column temperature were taken into consideration for finalizing the most suitable trial. Quality-by-Design approach is then implemented for further study. As per the Box–Behnken design (BBD) system, the method was optimized. The most suitable optimized solution is used for validation. Results: Based on traditional method development, methanol and 0.1% v/v ortho phosphoric acid selected as a mobile phase in an 82:18 ratio, the flow rate was selected as 1 mL/min, and column temperature was selected at 40°C. Based on these factors, 17 HPLC runs were performed as per BBD protocol the p-values for quadratic model for all factors was found <0.0500, which shows the quadratic model is best for proposed study by which method get optimized, and the validation was carried out on the most appropriate optimized solution. The R2 for AZT and CIL was found to be 0.9998 and 0.9999, respectively. The method was linear for both the drugs, and accuracy was found to be 100.45% for AZT and 99.49% for CIL. Other validation parameters were also found within limits. Conclusion: At the end of the study, it was found that the developed method was accurate, precise, linear, specific, and reproducible. Method is cost-effective and can be able to used for routine analysis in laboratories as well as in industries.

Objective To enhance the aqueous solubility and dissolution rate of cilnidipine (CLN), a BCS Class II antihypertensive drug with poor oral bioavailability (13%), by developing oral nanocrystals (NCs) using a scalable antisolvent precipitation and high-speed homogenization technique. Significance CLN’s therapeutic potential is limited by its low solubility. This study addresses this challenge through nanocrystal formulation, offering a cost-effective and industrially viable strategy to improve bioavailability and dissolution performance. Methods CLN-NCs were prepared by antisolvent precipitation coupled with high-speed homogenization. Stabilizers (PVPk30, mannitol), drug concentrations, and flow rates were systematically optimized. The lead formulation (F19) was characterized for particle size, saturation solubility, and dissolution rate. Solid-state properties were evaluated using SEM, XRPD, DSC, and FTIR to confirm crystalline stability. Results The optimized NCs (F19) exhibited a nanosized particle diameter (19.1 ± 3.8 nm), a 3.3-fold increase in saturation solubility, and a 4.1-fold faster dissolution rate compared to raw CLN. XRPD and DSC confirmed retained crystallinity, while FTIR revealed no drug-stabilizer interactions. SEM showed uniform morphology with no aggregation. Conclusions CLN-NCs significantly improved in vitro solubility and dissolution, demonstrating a scalable preparation method suitable for industrial translation. This approach offers a promising pathway to enhance CLN’s therapeutic efficacy in hypertension management.

Cilnidipine (CIL) is a calcium channel blocker that exhibits low oral bioavailability (∼13%) due to poor aqueous solubility and extensive first-pass metabolism. This study aimed to develop rapidly disintegrating sublingual films of CIL solid dispersions (CILSD) to overcome these limitations. Phase solubility studies identified polyethylene glycol 6000 as the most suitable carrier, as it significantly improved (p < 0.001) the drug solubility. D-optimal mixture design was employed to develop sublingual films by the solvent casting technique using Hydroxypropyl Methylcellulose E15 as polymer and PEG 400 as plasticizer. Infrared spectroscopy proved drug excipient compatibility, while Differential Scanning Calorimetry and X-ray Diffractometry confirmed drug amorphization in CILSD. The films exhibited uniform content, consistent thickness, good flexibility, and quick disintegration times (5.3 ± 0.3 to 26.4 ± 0.2 min). The optimized batch (F15) displayed rapid disintegration (6.9 ± 0.12 min) and complete drug release (DR) in 38.12 ± 2.2 min. Ex vivo permeation indicated the films displayed comparable drug flux (p > 0.1) to that of the drug solution. Scanning electron microscopy (SEM) revealed a smooth surface, while atomic force microscopy (AFM) indicated minimal topographical irregularities in the films, suggesting suitability for transmucosal applications. Overall, CILSD-loaded sublingual films would be a promising platform to bypass first-pass metabolism, elicit a rapid onset, and improve bioavailability for prompt management of cardiovascular emergencies.

Methadone (MTD) is a synthetic opioid, N-Methyl-D-Aspartate (NMDA) antagonist, Tolfenamic acid (TA) is a non-steroidal anti-inflammatory drug (NSAID), and Cilnidipine (CLD) is a calcium channel blocker widely used for the management of various neurological disorders and their associated complications. Investigating the mechanism of MTD, TA, and CLD drugs with Traumatic Brain Injury (TBI) protein has become easier with the advent of network pharmacology. The purpose of this study is to use network pharmacology, a contemporary method, to examine the mechanisms of MTD, TA, and CLD in TBI. A protein-protein interaction (PPI) network was used to determine the primary therapeutic targets of MTD, TA, and CLD against TBI. Several extensive databases (Pubchem, Swiss target prediction database, String and DisGeNET database, ADMET lab2.0, and Swiss ADME database) were consulted to collect MTD, TA, and CLD linked targets and genes relevant to TBI. Drug-Drug interactions (DDIs) of MTD, TA, and CLD were also checked using Drug Bank, Lexicomp® Drug Interactions, Dailymed, and Medscape database. MTD, TA, and CLD were found to have important pathways according to the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. MTD inhibits the NOS1, NOS2, NOS3, and MPO, CXCR4 activated gene pathways and stimulates the DRD2, SLC6A3, SLC6A4, SLC18A2, HTR1A, and AKT1 deactivated gene pathways. TA inhibits the GRIN1, MAPK1, and COX-II activated gene pathways. CLD inhibits the MAP2K1, CACNA1C, CACNA1D, PDE4D, CASP3, mTOR, PTGS2, SCN9N, and GSK3B, and stimulates the IGF1R, DRD2, SHH, HTR2A, FASN, CNR1, ABCB1, and PIK3CA deactivated gene pathways. The pharmacokinetic and toxicity profile was checked using ADMET analysis to make sure that it aligned to the optimum values. Drug-drug interactions (DDIs) were assessed to evaluate safety profile, and no interaction were found between MTD, TA and CLD. This study identified a primary target for MTD such as NOS1, NOS2, NOS3, DRD2, DAT (SLC6A3), MPO, SLC6A4, CXCR4-C-X-C, AKT1, SLC/8A2, HTR1A; for TA: MAPK1, GRIN1 and for CLD: IGF1R, DRD2, SHH, MAP2K1, CACNA1D, HTR2A, PDE4D, CASP3, MTOR, FASN, PTGS2, SCN9N, CNR1, CACNA1C, ABCB1, PIK3CA, GSK3B in the mechanistic regulation of TBI by reducing the activation of several pathways linked to development of TBI.

Drug amorphous solubility can be changed in the presence of other compounds, making it essential to elucidate the underlying mechanisms for designing supersaturated formulations. In this study, we experimentally determined how a second drug affects the amorphous solubility of ritonavir (RTV) and analyzed these effects from a thermodynamic perspective. Lopinavir (LPV), cilnidipine (CND), and probucol (PBC) were used as second drugs. The coexistence of each second drug in an aqueous solution reduced the amorphous solubility of RTV. In the presence of LPV and CND, the experimentally determined RTV amorphous solubility was close to the value predicted under the assumption of ideal mixing of RTV and second drugs. In contrast, in the presence of PBC, the experimentally determined RTV amorphous solubility exceeded the predicted value. Dynamic vapor sorption (DVS) measurements revealed that the RTV/LPV coamorphous absorbed water similarly to amorphous RTV. Conversely, water absorption in the RTV/CND and RTV/PBC coamorphous decreased compared with amorphous RTV. Using the experimentally determined amorphous solubilities and water absorption data, the interaction parameters between RTV and each second drug within the water-saturated drug-rich phase were calculated. The absolute value of the interaction parameter in the RTV/LPV system is relatively small, suggesting that incorporating LPV into the RTV-rich phase had minimal impact on water absorption and drug-drug interaction strength in the RTV-rich phase, resulting in experimentally determined solubility values that align closely with those predicted by ideal mixing of RTV and LPV. Meanwhile, the interaction parameters of the RTV/CND and RTV/PBC systems were negative, indicating relatively strong drug-drug interactions that can further reduce RTV amorphous solubility. However, for these two systems, the mixing of second drugs also decreased the water content in the RTV-rich phase, which would mitigate the extent of the solubility reduction. In the RTV/CND system, the strong drug-drug interaction and reduced water content largely offset each other. This results in an experimentally determined RTV amorphous solubility similar to the value predicted by the ideal mixing of RTV and CND. In contrast, in the RTV/PBC system, the water content of the RTV-rich phase was more substantially decreased, leading to a higher experimentally determined value of RTV amorphous solubility than that predicted by ideal mixing of RTV and PBC. Overall, this study elucidates the impact of a second drug on the amorphous solubility of a primary drug and provides valuable insights for the design of supersaturated formulations containing multiple drugs.

ABSTRACT Analyzing a drug in a completely overlapping spectrum is always a challenging and inevitable step in the analysis of multi-drug combinations. It requires sophisticated equipment that utilizes more hazardous solvents, which harms environmental safety. Adopting a simple, innovative, low-cost technique for determining compounds in a mixture without affecting the environment is necessary. This study aimed to resolve cilnidipine (CLD), chlorthalidone (CTD), and metoprolol (MTP) combination via an innovative spectrophotometric technique called successive ratio subtraction coupled with the constant multiplication (SRS-CM) and double divisor ratio first derivative method (DD-DD1) without any interference using propylene carbonate (PC) as a green biodegradable solvent. The determination of drugs has been performed in linear concentration ranges of 2.00–14.00, 2.50–11.25, and 2.50–32.50 µg/mL at λmax238.5, 228.5, and 223.2 nm for CLD, CTD, and MTP respectively for method I, and for CLD (243.46 nm), CTD (283.7 nm), and MTP (220.04 nm) using method II. Additionally, the method has been validated by the ICH Q2 R1 guidelines, evaluated through green analytical and sustainability indicators, and confirmed to meet rigorous standards for both environmental responsibility and analytical accuracy while aligning with relevant Sustainable Development Goals (SDGs). Highlights Method validated according to ICH Q2 R1 guidelines. Propylene carbonate, an eco-friendly solvent, was used. Assessed with green analytical tools and sustainability indicators, ensuring environmental responsibility.

Background/Objectives: Cilnidipine (CIL) is a calcium channel blocker that exhibits low bioavailability (~13%) due to poor aqueous solubility and extensive pre-systemic gut wall metabolism. The current study aimed to enhance the oral bioavailability of CIL by formulation of polymeric spherical agglomerates (CILSAs)-based orodispersible tablets (ODTs). Methods: Eight different batches of CILSAs were prepared by a crystallo-co-agglomeration technique using different proportions of hydrophilic polymers like hydroxy propyl methyl cellulose E50, polyvinyl pyrrolidone K30, or polyethylene glycol (PEG) 6000 as carriers. Fourier transform infrared spectroscopy (FTIR) of CILSAs proved the chemical integrity of CIL in SAs, while scanning electron microscopy revealed the spherical shape of CILSAs. Results: Differential scanning calorimetry and powder X-ray diffraction studies confirmed that CIL was rendered more amorphous in CILSAs. CILSAs displayed good flow behavior, high percentage yield, and high drug loads. The batch F4 composed of PEG 6000 emerged as the optimized batch as it displayed high percentage dissolution efficiency (57.01 ± 0.01%), which was significantly greater (p < 0.001) compared to CIL (26.27 ± 0.06%). The optimized formulation of CILSAs was directly compressed into ODTs that were rendered porous by vacuum drying. The optimized formulation of porous ODTs (T3) displayed low friability (0.28 ± 0.03%), short disintegration time (6.26 ± 0.29 s), and quicker dissolution (94.16 ± 1.41% in 60 min) as compared to marketed tablet Cildipin® 10 mg (85 ± 2.3%). Conclusions: Thus, porous ODTs of CILSAs can rapidly release the drug, bypass gut metabolism, enhance oral bioavailability, and improve CIL's therapeutic effectiveness for angina and hypertension.

The current investigation aimed to develop nanostructured lipid carriers (NLCs) as a potential transdermal drug delivery system for the improvement of cilnidipine (CIL) bioavailability. The high-pressure homogenization (HPH) method was utilized for the formulation of NLCs. Box-Behnken Design (BBD) was utilized to optimize CIL NLCs for entrapment efficiency, particle size and zeta potential. The resultant NLCs had a mean particle size of 98.2 ± 05.08 nm, a zeta potential of −16.1 ± 2.05 mV and an entrapment efficiency of 92.51 ± 4.18%. Transmission electron microscopy (TEM) revealed spherical or elongated particles for CIL-NLCs. The optimized NLCs were embedded in the transdermal patch and were formulated utilizing the solvent casting method and investigated for CIL content, physical characteristics, skin permeation and in vivo pharmacokinetics study. In vivo pharmacokinetics experiments with an NLCs-embedded transdermal patch show, an increase in C max and T max , 1305.66 ± 7.96 ng/mL and 4 h, respectively, when compared to the oral CIL dose. The flux values for ex vivo permeation studies for the CIL NLCs patch were determined to be 82.54 ± 4.80 µg/cm2/h. The bioavailability of CIL-loaded NLCs transdermal patch was found to be 2.9-fold greater than that of oral drug suspension, thus confirming the improvement of bioavailability of CIL by NLCs loaded transdermal patch.

Objective The objective of current research is to design, develop, and optimize a cilnidipine (CLN) nanostructured lipid carrier (NLC)-based drug delivery system for the effective treatment of hypertension (HT). Significance Oral administration of CLN-loaded NLC (CLN NLC) containing glyceryl monostearate (GMS) as a solid and isopropyl myristate (IPM) as a liquid lipid may show remarkable lymphatic uptake through payer patches. Methods The emulsification probe sonication technique was used followed by optimization using 32 factorial designs. Results The optimized batch showed a mean particle size of 115.4 ± 0.22 nm with encapsulation efficiency of 98.32 ± 0.23%, polydispersity index (PDI) of 0.342 ± 0.03, and zeta potential (ZP, ζ) was −60.5 ± 0.24 which indicate excellent physical stability. In vitro studies showed a controlled release of CLN NLCs. Pharmacokinetics studies determined the C max of NLCs (373.47 ± 15.1) indicates 2.3-fold enhancement compared with plain drug (160.64 ± 7.63). Pharmacodynamic studies indicated that CLN NLCs were maintaining systolic blood pressure in a controlled manner without any signs of side effects. Conclusion CLN NLCs significantly improved lymphatic delivery and proved to be effective in the treatment and management of HT. It has been proved that CLN NLCs are found to be better than any traditional CLN dosage form due to enhancement in solubility, absorption, bioavailability, intestinal permeability, avoidance of first-pass metabolism, P-glycoprotein efflux and reduction in dose-related side effects, achievement of controlled and sustained release action.

Impact of Colloidal Drug-Rich Droplet Size and Amorphous Solubility on Drug Membrane Permeability: A Comprehensive Analysis

The analytical community prioritizes adopting green techniques due to concerns over the environmental impact of chemical research. This study employs an integrated experimental strategy, combining the concept of design of experiment (DOE) and green analytical chemistry (GAC), to establish a robust, green RP-HPLC approach for the simultaneous estimation Cilnidipine (CIL) and Metoprolol succinate (MET). For method optimization, a central composite design (CCD) was implemented. Separation utilized Inertsil ODS 3 column (250 mm x 4.6 mm, 5 μm), with gradient mobile phase (ethanol: 17.65% at 0 min, 75.5% at 3 min) and phosphate buffer, flowing at 1 ml/ min. Detection wavelength at 230 nm. Column temperature (35±1°C), and injection volume 5 μL. Retention times: MET (4.672 min), CIL (7.457 min). The linearity was established over the range of 7-13 μg/ml for CIL and 35-65 μg/ml for MET. The values obtained for LOD and LOQ are 0.819 and 2.482 μg/ml (CIL) respectively, 3.875 and 11.743 μg/ml (MET). As per ICH Q14, the technique has been validated. Finally the green nature was examined by GAPI, AES and AGREE. Method found to be ecofriendly, simple and robust for simultaneous CIL and MET estimation in pharmaceutical formulations, easily adaptable for routine analysis.

The greenness assessment of analytical methods is an important aspect of green analytical chemistry, which focuses on making analytical procedures eco-friendly and safer. This study conducts a thorough comparative analysis of chromatographic methods utilized in the analysis of Cilnidipine (CLN), a commonly employed antihypertensive medication. The research aims to not only evaluate the analytical performance of different chromatographic techniques but also assess their environmental impact, with a focus on promoting sustainable and eco-friendly practices in pharmaceutical analysis.The greenness profiles of twelve chromatographic methods for CLN and its derivatives were evaluated utilizing multiple assessment metrics including the Green Analytical Procedure Index (GAPI), Analytical GREEness (AGREE), Analytical eco-scale (ESA), Chloroform-oriented Toxicity Estimation (ChlorTox scale), Blue Applicability Grade Index (BAGI), and Red-Green-Blue 12 (RBG 12). By quantifying the environmental implications, the study aims to highlight the importance of adopting greener practices in pharmaceutical analysis. This assessment encompasses considerations such as solvent used, energy consumed, and waste generated by the method. The outcomes of this research contribute valuable insights into the selection of environmentally friendly chromatographic methods for CLN, promoting a balance between analytical efficiency and ecological responsibility in the pharmaceutical field.

Background: The research on poorly aqueous-soluble drugs of BCS class II such as Cilnidipine (CLD) demands significant improvement in their aqueous solubility and dissolution rate. Such requirements may be fulfilled by adapting the nanocrystal approach with considering the various challenges. Objective: The prime purpose of this research work was to develop, optimize and characterize the nanocrystal of the poorly aqueous soluble drug (CLD) using the antisolvent-precipitation ultrasonication method. Such a method was followed for rapid re-dispersion of drugs in water with improving their dissolution rate. Methods: In this study, the different nanosuspension formulations were prepared using varying concentrations of three stabilizers - Pluronic F-68, Pluronic F-127, and HPMC-15cps, as selected stabilizer candidates. The selected and optimized formulation was followed by a lyophilization process with the incorporation of two selected distinct cryoprotectants - Mannitol and Lactose. The obtained nanocrystals were evaluated for their physical appearance, aqueous re-dispersibility, and particle size. Additionally, the optimized nanoformulation was also evaluated for morphology, dissolution rate, assay, drug entrapment efficiency, and drug loading content. The in vitro dissolution of optimized drug nanocrystal was done in the phosphate buffer solution of pH 6.8 and compared with bulk CLD and a physical mixture of CLD and pluronic F-68. Results: For optimizing drug nanosuspension, the effect of pluronic F-68 and cilnidipine concentration was investigated, and the optimal values were 0.3% w/v and 5 mg/ml, respectively. Mannitol-containing nanocrystals exhibited a white crystalline powder having a particle size of 154 nm and a good polydispersity index (0.217). Nanocrystals also demonstrated an excellent re-dispersibility in deionized water after manual shaking and no particles were observed at the bottom of the container till 15 days. Such optimized formulation also indicated an increase in dissolution rate in comparison to bulk CLD and their physical mixture with pluronic F-68. It released approximately 72.25% of the drug within 90 minutes while bulk CLD and physical mixture released only 31.24% and 30.37% of the drug, respectively at the same time. The drug assay method indicated that only 92% of the drug was present in optimized nanocrystals after the transformation of nanosuspension into nanocrystals which was less than the initial amount. In this research, the experimental work also analyzed that optimized nanocrystal has only 28.6% of drug loading content. Conclusion: The selected method and cryoprotectant have ability to develop the aqueous re-dispersible nanocrystal for enhancing the dissolution rate and water solubility of CLD-like poorly soluble drugs.

Abstract According to the concept of green analytical chemistry, the analytical method development should be carried out by avoiding or minimizing the usage of toxic organic solvents for the safety of human and aquatic animal life and the protection of the environment. Hence, the green analytical chemistry (GAC)‐assisted robust liquid chromatographic method has been developed for chromatographic analysis of azilsartan medoxomil and cilnidipine (CIL) using safe organic solvents. The chromatographic method was developed by the implementation of analytical quality by design using chemometrics and response surface modeling. The chromatographic separation was carried out using Shim‐Pack C18 (250 × 4.6 mm, 5.0 μm) column as stationary phase and ethanol: 0.1% V/V ammonia solution (45:55, %V/V) as mobile phase. The chromatographic peak of AZL and CIL was found to be at the retention time of 3.5 and 4.5 min, respectively. The flow rate was kept at 1.0 mL/min and the column oven temperature was set to 40˚C. The developed method was found to be validated as per the International Council for Harmonization Q2 (R1) guideline. The method was applied for the assay of fixed‐dose combination and results were found in compliance with the labeled claim. The greenness of the method was evaluated using GAC tools.

Application of advanced environmentally benign assessment tools in determining ternary cardiovascular drug combination by RP-HPLC with analytical quality by design: Application to stability indicating method evaluation

Two novel UV spectrophotometric methods have been developed for the simultaneous estimation of cilnidipine (CIL) and nebivolol hydrochloride (NBV) in combined dosage form. Method I was based on absorbance correction principle while method II was Q absorption ratio method. For absorbance correction method, λmax of CIL 242.6nm was chosen as λ1, as NBV shows nil absorbance at this wavelength and 280.6nm, the λmaxof NBV was chosen as λ2 , as both the drugs showed satisfactory absorbance at this wavelength. Beer’s law was obeyed in the concentration range of 4-48μg/mL and 4-100μg/mL for cilnidipine and nebivolol hydrochloride respectively with correlation coefficients (r2) greater than 0.990. For Q absorption ratio method, 275nm (Isosbestic point) and 280.6nm (λmax of NBV) were chosen as the two wavelengths for analysis. Beer’s law was obeyed in the concentration range of 4-48μg/mL and 4-100μg/mL for cilnidipine and nebivolol hydrochloride, respectively with correlation coefficients (r2) greater than 0.990. The developed methods were validated as per ICH guidelines. The % assays of cilnidipine and nebivolol hydrochloride in tablet dosage form were found to be 97% and 102%, respectively by absorbance correction method and 95% and 105% by Q absorption ratio method, which were within acceptance limits. The developed methods can thus serve as powerful quality control tools for simultaneous determination of cilnidipine and nebivolol hydrochloride in bulk and in combined dosage form.

Analytical ‘Quality-by-Design’ paradigm in development of a RP-HPLC method for the estimation of cilnidipine in nanoformulations: Forced degradation studies and mathematical modelling of in-vitro release studies

The fixed-dose combination (FDC) of metoprolol succinate (MTS), cilnidipine (CDN), and telmisartan (TST) is used for the management of hypertension. Numerous reversed phase (RP)-HPLC methods have been reported in the literature for chromatographic analysis of MTS, CDN, and TST. According to the concept of green analytical chemistry (GAC), toxic organic solvents should be avoided or minimized during chromatographic method development for the safety of analysts and the protection of the environment. The reported RP-HPLC methods have been developed using acetonitrile (ACN) or methanol as an organic component of the mobile phase and diluent for sample preparation. These organic solvents are considered toxic solvents as per the International Council for Harmonization (ICH) Q3C (R6) guideline and Pfizer medicinal chemistry solvent selection (PMCSS) guide. We aimed to develop an environment-friendly and economical RP-HPLC-photo-diode array (PDA) method for the analysis of MTS, CDN, and TST using less toxic organic solvents to support the concept of GAC. The method development was carried out by the implementation of chemometrics and design of experiments (DoE) to avoid wastage of organic solvent. Principal component analysis (PCA) was applied as a chemometric tool for the identification of critical method risk variables (MRVs) and method performance attributes (MPAs). The identified critical MRVs and MPAs were further studied by DoE-based response surface modelling for optimization of the method. The chromatographic analysis of MTS, CDN, and TST was carried out using a Shim-pack ODS column as a stationary phase and ethanol as an organic modifier in the mobile phase. The developed method was applied to the assay of FDCs and results were found to be in compliance with the label claim. The greenness profiles of reported and present RP-HPLC methods were evaluated by national environmental method index (NEMI) and analytical greenness (AGREE) methods. The developed method was found to be green, robust, and economical as compared to published methods for the analysis. Development and validation of an RP-HPLC method for simultaneous estimation of MTS, CDN, and TST using safe organic solvents. Implementation of a analytical quality by design (AQbD) approach in method development using PCA and DoE. Application of the method for assay of FDCs of MTS, CDN, and TST.

A combination of Azilsartan Medoxomil and Cilnidipine is prescribed in the treatment of Hypertension. The present work represents an accurate and precise high-performance thin layer chromatographic method for the estimation of Azilsartan Medoxomil (AZL) and Cilnidipine (CLN) in combined tablet dosage form. Pre-coated silica gel- G60 F254 aluminum sheet (100 × 100 mm, 0.2 mm layer thickness) were used as stationary phase and Ethyl Acetate: Toluene: Glacial Acetic Acid (5: 4.9: 0.1 %v/v/v) in the mixture was used as mobile phase. The method was linear in the concentration range of 200 - 2000 ng/band for AZL and 50 -500 ng/band for CLN with a correlation coefficient (r2) of 0.996 for AZL and 0.999 for CLN. The proposed method was validated with respect to linearity, accuracy, precision, and robustness as per ICH Q2 (R1) guideline. A forced degradation study was performed to assess the stability indicating the nature of the method. All the degradant peaks were well resolved from the peak of the drug without any interference. The method was successfully applied for the analysis of AZL and CLN in combined tablet formulation.