Pazopanib Hydrochloride Research Articles

Supersaturated Liquid Formulation of Pazopanib Hydrochloride Loaded with Synergistic Precipitation Inhibitors

Supersaturated Liquid Formulation of Pazopanib Hydrochloride Loaded with Synergistic Precipitation Inhibitors

Self-microemulsifying drug delivery system-based gastroretentive in situ raft of pazopanib with enhanced solubility and bioavailability.

Pazopanib hydrochloride (PZH) is a Biopharmaceutics Classification System class II drug that faces challenges at the formulation forefront including low aqueous solubility (0.043 mg/mL) and poor oral bioavailability (14-39%). The present investigation aimed to develop a self-microemulsifying drug delivery system (SMEDDS) of PZH using a blend of Capryol® 90, Labrasol®, and propylene glycol to improve its solubility. Furthermore, a sustained-release SMEDDS-based gastroretentive floating system was developed and optimized using the Central Composite Design approach of DoE. The optimized SMEDDS-based in situ gelling raft, R-SM-PZH, exhibited minimal floating lag time (3.09 ± 0.8 s), optimal viscosity (1229.4 ± 20.9 cP) and density (0.327 ± 0.15 g/mL) as compared to other formulations under study. Additionally, R-SM-PZH was evaluated for its in vitro dissolution in FaSSGF and FeSSGF, pharmacokinetic profile, and MTT assay (against NCI-H460 lung cancer cells) compared to pure PZH. A 12 h sustained release, three-fold augmentation in dissolution rate and bioavailability, and 15-fold enhancement in cytotoxicity were observed in comparison to pure PZH. Thus, the SMEDDS-based in situ gelling raft presents a promising approach to advancing the developability potential of PZH.

QbD-Based Development and Evaluation of Pazopanib Hydrochloride Extrudates Prepared by Hot-Melt Extrusion Technique: In Vitro and In Vivo Evaluation.

Pazopanib hydrochloride (PZB) is a protein kinase inhibitor approved by the United States Food and Drug Administration and European agencies for the treatment of renal cell carcinoma and other renal malignancies. However, it exhibits poor aqueous solubility and inconsistent oral drug absorption. In this regard, the current research work entails the development and evaluation of the extrudates of pazopanib hydrochloride by the hot-melt extrusion (HME) technique for solubility enhancement and augmenting oral bioavailability. Solid dispersion of the drug was prepared using polymers such as Kollidon VA64, hydroxypropylmethylcellulose (HPMC), Eudragit EPO, and Affinisol 15LV in a 1:2 ratio by the HME process through a lab-scale 18 mm extruder. Systematic optimization of the formulation variables was carried out with the help of custom screening design (JMP Software by SAS, Version 14.0) to study the impact of polymer type and plasticizer level on the quality of extrudate processability by measuring the torque value, appearance, and disintegration time as the responses. The polymer blends containing Kollidon VA64 and Affinisol 15LV resulted in respective clear transparent extrudates, while Eudragit EPO and HPMC extrudates were found to be opaque white and brownish, respectively. Furthermore, evaluation of the impact of process parameters such as screw rpm and barrel temperature was measured using a definitive screening design on the extrude appearance, torque, disintegration time, and dissolution profile. Based on the statistical outcomes, it can be concluded that barrel temperature has a significant impact on torque, disintegration time, and dissolution at 30 min, while screw speed has an insignificant impact on the response variables. Affinisol extrudates showed less moisture uptake and faster dissolution in comparison to Kollidon VA64 extrudates. Affinisol extrudates were evaluated for polymorphic stability up to a 3-month accelerated condition and found no recrystallization. PZB-Extrudates using the Affinisol polymer (Test formulation A) revealed significantly higher bioavailability (AUC) in comparison to the free Pazopanib drug and marketed formulation.

Utilization of Lipophilic Salt and Phospholipid Complex in Lipid-Based Formulations to Modulate Drug Loading and Oral Bioavailability of Pazopanib.

Pazopanib hydrochloride (PAZ) displays strong intermolecular interaction in its crystal lattice structure, limiting its solubility and dissolution. The development of lipid-based formulations (LbFs) resulted in reduced PAZ loading due to solid-state mediated low liposolubility. This study aims to enhance our understanding of PAZ crystallinity by synthesizing a lipophilic salt and phospholipid complex and investigating its impact on the drug loading in LbFs. The synthesized pazopanib lipophilic salt and phospholipid complex were extensively characterized. The solid form of pazopanib docusate (PAZ-DOC) and pazopanib phospholipid complex (PAZ-PLC) indicates a reduction in characteristic diffraction peaks of crystalline PAZ. The lipid formulations were prepared using synthesized PAZ-DOC and PAZ-PLC, where PAZ-DOC demonstrated sixfold higher drug solubility than the commercial salt form and twice that of the PAZ-PLC due to differences in the crystallinity. Further, the impact of salt and complex formation was assessed on the aqueous drug solubilization using lipolysis and multimedia dissolution experiments. Moreover, the LbFs showed notably faster dissolution compared to the crystalline PAZ and marketed tablet. In terms of in vivo pharmacokinetics, the PAZ-DOC LbF exhibited a remarkable 11-fold increase in AUC value compared to the crystalline PAZ and a 2.5-fold increase compared to Votrient®. Similarly, PAZ-PLC LbF showed an approximately ninefold increase in drug exposure compared to the crystalline PAZ, and a 2.2-fold increase compared to Votrient®. These findings suggest that disrupting the crystallinity of drugs and incorporating them into LbF could be advantageous for enhancing drug loading and overcoming limitations related to drug absorption.

Cases of Cervical Extramedullary Recurrent Malignant Solitary Fibrous Tumors Treated Multimodally with Pazopanib Hydrochloride

Cases of Cervical Extramedullary Recurrent Malignant Solitary Fibrous Tumors Treated Multimodally with Pazopanib Hydrochloride

Analytical Method Development and Validation of RP-HPLC Method for Estimation of Pazopanib Drug Sample and It’s Dosage Form

The study focuses on developing and verifying a cost-effective Reverse Phase High-Performance Liquid Chromatography (RP-HPLC) technique for quantifying Pazopanib HCl in both bulk and tablet forms. The study aims to develop a cost-effective approach for routine quality control analysis by utilizing the simplicity and wide accessibility of HPLC. A Shimadzu C18 column (5 µm, 250 mm × 4.6 mm) was successfully used to separate Pazopanib HCl via chromatography. The mobile phase consisted of a mixture of Potassium dihydrogen phosphate in water (pH 2.9, corrected with Phosphoric Acid) and Acetonitrile in a ratio of 25:75 v/v. The isocratic elution mode was utilized with a flow rate of 1.0 mL/min, a column temperature of 25°C, and an injection volume of 20 µL. Pazopanib hydrochloride had a retention period of 2.8 minutes when measured at an isobestic wavelength of 215 nm. The described RP- HPLC technique showed exceptional specificity, accuracy, precision, linearity, and durability, rendering it a viable instrument for Pazopanib HCl tablets' regular quality control analysis. This method is both efficient in terms of analytical performance and economically profitable, making it very suitable for frequent pharmaceutical analysis.

Process of Preparing 3-methyl-6-nitro-1H-indazole by Scale of 180 g/batch as an Important Intermediate for the Preparation of Pazopanib

Pazopanib hydrochloride, marketed worldwide under the brand name Votrient, is an anti-cancer medication manufactured by Novartis. It is the first and only tyrosine kinase inhibitor currently approved for the treatment of multiple histological subtypes of soft tissue sarcoma (STS). In previous studies, we presented initial results regarding the synthesis of 3-methyl-5-nitro-2H-indazole (3) as an important indazole component on a laboratory scale (approximately 10 g/batch). In this study, we have successfully synthesized this compound (3) at a scale of 200 g/batch, achieving an overall process yield of 79.6 % from the starting material ethylaniline. This yield is higher than that reported in previous publications. Some of the technical conditions that have been improved include optimizing the amount of sulfuric acid in the nitration reaction, the amount of acetic acid, sodium hydroxide in the diazotization reaction for ring closure, reaction temperature, and the feed method to control the reaction safely and achieve high efficiency at a scale of 200 g/batch.

Application of Simplex Lattice Mixture design and desirability function in the development and Optimization of SEDDS for protein kinase inhibitor-Pazopanib Hydrochloride

Pazopanib Hydrochloride is a tyrosine protein kinase inhibitor molecule approved by USFDA and European agencies for the treatment of renal cell carcinoma (RCC) patients and other renal malignancies, but it has very poor aqueous solubility. Therefore, it is essential need to improve the solubility and in vitro dispersion or release characteristics. The purpose of this study was to investigate the Pazopanib hydrochloride drug solubility in various vehicles and screening of suitable solubilizers for the preparation of self-emulsifying lipid-based drug delivery systems (SE-LBDDS) of a poorly water-soluble drug (BCS class II), Pazopanib HCl by using simplex lattice mixture design. Ternaryplots wereconstructed by using oil (Labrafac WL 1349l), surfactant (Labrasol), and co-surfactant (Transcutol-P), and the concentration ranges were determined by using a simplex lattice design. The composition of pazopanib HCl SEEDS was optimized through various dependent variables (responses)such as solubility (Y1), precipitation after 15 min (Y2), and, particle size (Y3).Solubility study of pazopanib HCl in different oils, surfactants, and co-surfactants was carried out by shake flask method at 37°C. Three formulation components were chosen based on the maximum solubility results inthe oil, surfactant, and co-surfactant category and included in the experimental design. The results were analyzed by model fitting using the standard least-squares method. Pazopanib HCl were shown maximum solubility i.e. 25.64±0.24mg/g, 57.84 ±2.91mg/g and, 44.61±1.51mg/g in Labrafac WL 1349 (oil), Labrasol (surfactant) and Transcutol-P (co-surfactant) respectively. Hence these chosen formulation component's concentrations were further optimized by using a simplex lattice design (SLD). Derived mathematical polynomial equations and models were exercised to evaluate the impact of formulation input variables on the output variables (responses) using JMP software. The model p-value for both the responses i.e. solubility and particle size were found less than 0.05 hence models were significant. The results of the mathematical analysis demonstrated that the formulation components have a significant impact on the studied responses. Hence simplex lattice mixture design can be used as a powerful quality design to predict the optimized SEDDS formulation.The applicability of simplex lattice design with desirability function helped optimize a SEEDS formulation of pazopanib HCl and the selected model has made it possible to identify the impact of the critical factors to optimize the required responses.

Solubility of pazopanib hydrochloride (PZH, anticancer drug) in supercritical CO2: Experimental and thermodynamic modeling

It is essential to understand drug compounds' solubility and other properties to formulate and create a supercritical fluid-based technology that can produce micro or nanosized particles of the pharmaceutical substance. Accordingly, at temperatures (308–338 K) and pressures (120–270 bar), the solubility of anticancer drug, pazopanib hydrochloride (PZH), in supercritical carbon dioxide (Sc-CO2) was experimentally investigated, for the first time. PZH dissolved (in the Sc-CO2 mole fractions) ranged from 1.87 × 10−6 to 14.25 × 10−6, resulting in solubilities between 0.015 and 0.120 g/L. Correlations between the experimental results were made using three different models: (1) six models of density-based (Chrastil, Méndez–Santiago & Teja (MST), Bartle et al., Kumar–Johnston, Alwi-Garlapati, and Sodeifian et al.), (2) solid-liquid equilibrium models (expanded liquid model proposed by Sodeifian et al., and Flory-Huggins theory with modified solubility parameters), and (3) equation of state (EoS) (PR with vdW2 mixing rule). All examined models were able to produce acceptable fits with the data at a satisfactory level of precision; however, the empirical density-based model proposed by Sodeifian et al., was found superior in terms of the AARD% criterion. In addition, the vaporization (∆Hvap), total (∆Htot), and solvation (∆Hsol) enthalpies were computed.

Preparation and Characterization of Pazopanib Hydrochloride-Loaded Four-Component Self-Nanoemulsifying Drug Delivery Systems Preconcentrate for Enhanced Solubility and Dissolution.

The aim of this study was to develop a four-component self-nanoemulsifying drug delivery system (FCS) to enhance the solubility and dissolution of pazopanib hydrochloride (PZH). In the solubility test, PZH showed a highly pH-dependent solubility (pH 1.2 > water >> pH 4.0 and pH 6.8) and was solubilized at 70 °C in the order Kollisolv PG (5.38%, w/w) > Kolliphor RH40 (0.49%) > Capmul MCM C10 (0.21%) and Capmul MCM C8 (0.19%), selected as the solubilizer, the surfactant, and the oils, respectively. In the characterization of the three-component SNEDDS (TCS) containing Kolliphor RH40/Capmul MCM C10, the particle size of dispersion was very small (<50 nm) and the PZH loading was 0.5% at the weight ratio of 9/1. In the characterization of FCS containing additional Kollisolv PG to TCS, PZH loading was increased to 5.30% without any PZH precipitation, which was 10-fold higher compared to the TCS. The optimized FCS prepared with the selected formulation (Kolliphor RH40/Capmul MCM C10/Kollisolv PG) showed a consistently complete and high dissolution rate (>95% at 120 min) at four different pHs with 1% polysorbate 80, whereas the raw PZH and Kollisolv PG solution showed a pH-dependent poor dissolution rate (about 40% at 120 min), specifically at pH 6.8 with 1% polysorbate 80. In conclusion, PZH-loaded FCS in this work demonstrated enhanced solubility and a consistent dissolution rate regardless of medium pH.

Development and Validation of a Stability-Indicating Method for the Determination of Pazopanib Hydrochloride by RP-HPLC

A precise, accurate, highly sensitive, rapid, and reproducible stability HPLC method was developed and validated for the estimation of Pazopanib Hydrochloride (PAZO) in bulk and tablet dosage form. Decent quality chromatographic separation of Pazopanib Hydrochloride was done by using Eclipse plus C18 column (4.5 mm i.e. X 150 mm, 3.5µm particle size) (based on 99.99 % ultra-high purity silica) using mobile phase that containing 0.1 % Orthophosphoric acid: Acetonitrile (55:45 % v\v) at a flow rate of 1.0 mL/minute. The wavelength ?max of PAZO used for the detection was found to be 271.4 nm. The retention time for Pazopanib was found to 1.43 minutes. The PAZO was linear in the concentration range of 2-10 µg/mL (r2 = 0.9999) for HPLC method. The regression equation for PAZO was found to be Y = 700955 x + 28022 for HPLC. The LOD and LOQ were found to be 0.1675 ?g/mL, 0.0552 µg/mL for the HPLC method, respectively. The developed methods are validated in pursuance of ICH Q2 (R1) guidelines. The method was linear, precise, accurate with recoveries in the range of 98 – 102 %, and minimum values of % RSD indicate the accuracy of the method. The % assay of the PAZO was found to be 99.85 ± 1.2, which was in good agreement with the labeled claim. Pazopanib was subjected to stressed conditions like acidic, basic, oxidative, photolytic, and thermal conditions. The degradation results were found satisfactory. The developed gradient RP-HPLC method can be successfully practiced for the routine quality control analysis of PAZO in pharmaceutical tablets and routine quality control analysis.

Powder X-ray diffraction of pazopanib hydrochloride Form 1, C21H24N7O2SCl

The crystal structure of pazopanib hydrochloride Form 1 has been refined using synchrotron X-ray powder diffraction data and optimized using density functional theory techniques. Pazopanib hydrochloride crystallizes in space group P-1 (#2) with a = 8.45008(6), b = 8.71310(12), c = 16.05489(35) Å, α = 79.5996(9), β = 86.4784(5), γ = 87.3764(3)°, V = 1159.724(9) Å3, and Z = 2. The crystal structure is essentially identical to that of CSD Refcode CEVYEK. There are four strong N–H⋯Cl hydrogen bonds to the chloride anion. Several additional weaker N–H⋯Cl and C–H⋯Cl hydrogen bonds are also present. A variety of C–H⋯O, C–H⋯N, and N–H⋯S hydrogen bonds also contribute to the lattice energy. The powder pattern has been submitted to ICDD® for inclusion in the Powder Diffraction File™.

Development and validation of RP-HPLC method for the determination of Pazopanib Hydrochloride (A tyrosine kinase inhibitor) in pharmaceutical dosage form

Development and validation of RP-HPLC method for the determination of Pazopanib Hydrochloride (A tyrosine kinase inhibitor) in pharmaceutical dosage form

Stability Indicating HPTLC Method Development and Validation for the Estimation of Pazopanib Hydrochloride in Bulk and its Dosage Form

Stability Indicating HPTLC Method Development and Validation for the Estimation of Pazopanib Hydrochloride in Bulk and its Dosage Form

Solubility and bioavailability improvement of pazopanib hydrochloride

The anti-cancer drug pazopanib hydrochloride (PZH) has a very low aqueous solubility and a variable oral bioavailability. A new pharmaceutical formulation with an improved solubility may enhance the bioavailability and reduce the variability. A broad selection of polymer excipients was tested for their compatibility and solubilizing properties by conventional microscopic, thermal and spectrometric techniques. A wet milling and mixing technique was used to produce homogenous powder mixtures. The dissolution properties of the formulation were tested by a pH-switch dissolution model. The final formulation was tested in vivo in cancer patient following a dose escalation design. Of the tested mixture formulations, the one containing the co-block polymer Soluplus® in a 8:1 ratio with PZH performed best in terms of in vitro dissolution properties. The in vivo results indicated that 300 mg of the developed formulation yields similar exposure and a lower variability (379 μg/mL∗h (36.7% CV)) than previously reported values for the standard PZH formulation (Votrient®) at the approved dose of 800 mg. Furthermore, the expected plasma-Cthrough levels (27.2 μg/mL) exceeds the defined therapeutic efficacy threshold of 20 μg/mL.

Evaluation of Pazopanib Phase Behavior Following pH-Induced Supersaturation.

Salts of weakly basic active pharmaceutical ingredients are widely used to improve aqueous solubility and/or dissolution rate. However, these compounds are prone to precipitation due to the lower solubility of the un-ionized species at the higher pH in the intestinal region, and this can result in poor and/or variable absorption. The goal of this study was to investigate the degree of supersaturation achieved following dissolution of different amounts of pazopanib hydrochloride at low pH, followed by rapid pH increase. Using pH solubility profiles, phase boundaries were defined for crystalline and amorphous free base forms. The resultant phase diagram was used to rationalize the observed supersaturation and phase behavior of pazopanib following pH adjustment. In the presence of a crystallization inhibitor, hydroxypropylmethyl cellulose (HPMC), the degree of supersaturation was found to be very high, approximately 600-fold, at pH 6.5. At a dose equivalent to the clinical dose, the maximum free drug concentration observed at pH 6.5 was dictated by the amorphous solubility. Solutions that exceeded the amorphous solubility upon pH increase were found to undergo glass-liquid phase separations (GLPS) with the formation of amorphous colloidal drug-rich particles. Microscopic observations confirmed that HPMC delayed the appearance of pazopanib free base crystals. The phase behavior upon pH change is thus well predicted by the phase diagram, after taking into consideration the initial dose, the extent of supersaturation generated upon pH change, and the presence or absence of a crystallization inhibitor.

Thermal study of pazopanib hydrochloride

The currently marketed formulation of pazopanib hydrochloride has a poor bioavailability and pharmacokinetic profile. An alternative formulation of the drug might have an improved performance. Knowledge about the thermal behavior of the drug may be instrumental in the development process of such a formulation. The aim of this study was to thermally characterize raw bulk drug material of the multiple kinase inhibitor pazopanib hydrochloride using different analytical techniques. Solid-state characterization was carried out with Fourier transform infrared spectroscopy and X-ray diffraction. Thermal characterization was performed with thermogravimetric analysis and differential scanning calorimetry. Thermal and thermodynamic parameters were assessed using the Ozawa–Flynn–Wall, Friedman and Kissinger–Akahira–Sunose isoconversional methods.

New RP-HPLC Method Development and Validation for the Determination of Pazopanib Hydrochloride in Tablet Dosage Form

The aim of this paper was to develop and validate the stability indicating RP-HPLC method for the determination of Pazopanib hydrochloride in bulk and pharmaceutical dosage forms. A simple, accurate, precise, sensitive and stability indicating RP-HPLC method has been developed for the determination of Pazopanib hydrochloride in bulk drug and pharmaceutical dosage form, in which separations are done using develosil C18, 5μm, 150 × 4.6mm i.d. column at a flow rate of 1.0mL/min with an injection volume of 20μL. The beer’s law was obeyed over the concentration range of 5 - 35μg/mL. The correlation coefficient was found to be 0.996 and it showed good linearity, reproducibility, precision in this concentration range. The % recovery values were found to be within the limits, which showed that the method was accurate. The LOD and LOQ were calculated using statistical methods. The % RSD values were less than 2. The developed method was successfully applied for determination of Pazopanib hydrochloride in pharmaceutical dosage form. The results obtained are in good agreement with those obtained by using the standard method.

Characterization of forced degradation products of pazopanib hydrochloride by UHPLC-Q-TOF/MS and in silico toxicity prediction.

Pazopanib (PZ), an anti-cancer drug, was subjected to forced degradation under hydrolytic (acid, base and neutral), oxidative, photolytic and thermal stress conditions as per International Conference on Harmonization guidelines. A selective stability indicating validated method was developed using a Waters Acquity UPLC HSS T3 (100 × 2.1 mm, 1.7 µm) column in gradient mode with ammonium acetate buffer (10 mM, pH 5.0) and acetonitrile. PZ was found to degrade only in photolytic conditions to produce six transformation products (TPs). All the TPs were identified and characterized by liquid chromatography/atmospheric pressure chemical ionization-quadrupole-time of flight mass spectrometry experiments in combination with accurate mass measurements. Plausible mechanisms have been proposed for the formation of TPs. In silico toxicity was predicted using TOPKAT and DEREK softwares for all the TPs. The TP, N4-(2,3-dimethyl-2H-indazol-6-yl)-N4-methylpyrimidine-2,4-diamine, was found to be genotoxic, whereas all other TPs with sulfonamide moiety were hepatotoxic. The data reported here are expected to be of significance as this study foresees the formation of one potential genotoxic and five hepatotoxic degradation/transformation products.

Rare Case of Metastasis to Maxillary Sinus Accidently Diagnosed after Operation of Metastatic Renal Cell Carcinoma

The classic presentation of renal cell carcinoma (pain, hematuria, and flank mass) occurs in a minority of patients and often is indicative of advanced disease. Common sites of metastatic renal cell carcinoma are lung, soft tissues, bone, and liver. Paranasal sinus is an unusual site for metastasis of renal cell carcinoma. One 73-year-old male presented to Soonchunhyang University Seoul Hospital with melena. Renal cell carcinoma with metastasis to duodenum was diagnosed by computed tomography (CT). He underwent right radical nephrectomy and Whipple’s operation. Positron emission tomography/CT was performed postoperatively, and then metastasis to maxillary sinus was found by accident. He was treated with molecular targeted therapy (pazopanib hydrochloride 800 mg).