Ritesh Fule

Artemether-Soluplus Hot-Melt Extrudate Solid Dispersion Systems for Solubility and Dissolution Rate Enhancement with Amorphous State Characteristics.

This work studied artemether (ARTM) solid dispersion (SD) formulation using mixture of polymer excipient Soluplus, PEG 400, Lutrol F127, and Lutrol F68 melts at temperatures lower than the melting point of ARTM using a laboratory-size, single-screw rotating batch extruder. The effects of three surfactants PEG 400, Lutrol F127, and Lutrol F68 and parameters like mixing temperature, screw rotating speed, and residence time were systematically studied. SEM, XRD, and FT-IR were employed to investigate the evolution of ARTMs dissolution into the molten excipient. Differential scanning calorimetry (DSC) was used to quantitatively study the melting enthalpy evolution of the drug. The results showed that the dissolution rate increased with increasing the ratio of polymer and surfactant to that of drug. It was concluded that the dissolution of the drug in the polymer melt is a convective diffusion process and that laminar distributive mixing can significantly enhance the dissolution rate. The aqueous solubility and dissolution rate of prepared solid dispersion were significantly enhanced. In vitro antimalarial studies revealed marked improvement in IC50 values. Thus hot-melt extrusion (HME) is a promising technology for improving solubility and dissolution profile of ARTM.

Development of hot melt co-formulated antimalarial solid dispersion system in fixed dose form (ARLUMELT): Evaluating amorphous state and in vivo performance.

The aim of this study was to investigate the industrial feasibility of developing a co-formulated solid dispersion (SD) containing two antimalarial drugs artemether (ARTM) and lumefantrine (LUMF). Soluplus(®) (polyethyleneglycol-polyvinyl caprolactam-polyvinyl acetate grafted copolymer) was used as primary carrier matrices via hot-melt extrusion processing to improve solubility profile and the oral bioavailability of the combination. Based on the preliminary screening, the optimized quantities of PEG 400, Lutrol F127 and Lutrol F68 were incorporated as surfactant with soluplus in different ratios to improve extrudability, increase wettability and the melt viscosity of the HME process. Soluplus(®) was proved to successfully stabilize both the drugs inside its polymeric network during extrusion via forming a stable solid dispersion. Physicochemical properties of the APIs and the SDs characterized by thermo-gravimetric analysis (TGA), differential scanning calorimetry (DSC), MDSC, FTIR spectroscopy and X-ray diffractometry (XRD) revealed the amorphous existence of the drug in all SDs developed. Molecular level morphology of solid dispersion characterized by using advanced physicochemical characterization techniques such as Raman spectroscopy, atomic force microscopy (AFM) and 2D NMR showed the transformation of the crystalline drugs to its stable amorphous state. All manufactured SDs retained their amorphicity even after a stability study conducted in accelerated condition over 6 months. The solubility and in vitro dissolution performance of both drugs in SD formulations was improved significantly when compared with pure drugs and marketed product while the in vivo studies revealed the same.The pharmacokinetic studies in rats revealed that the SD (AL1) shows a 44.12-65.24 folds increase in the AUC(0-72) and 42.87-172.61 folds increase in Cmax compared to that of pure drugs and a better bioavailability than that of commercial product.

Solubility modulation of bicalutamide using porous silica

AbstractObjective of the present study was to explore the potential of porous silica (AEROPERL® 300 Pharma) in modulating dissolution kinetics of poorly water soluble drug bicalutamide (BCL). The drug release from the developed formulation was found to be significantly higher as compared to neat BCL. This improved release kinetics of BCL may be attributed to high surface area, improved wettability and decreased crystallinity. Solid state characterization of the developed formulation was carried out with respect to IR, XRPD, SEM, DSC and dissolution. The proposed system showed a significant capability for the solubility enhancement of BCL. The dissolution profile from BCL-AEROPERL® 300 Pharma (AP) system was fitted into various drug release kinetics models, in order to understand the BCL release mechanism.

Hot Melt Extruded Amorphous Solid Dispersion of Posaconazole with Improved Bioavailability: Investigating Drug-Polymer Miscibility with Advanced Characterisation

Invasive antifungal infections are reasons for morbidity and mortality in immunogenic patients worldwide. Posaconazole is a most promising antifungal agent against all types of invasive infections with high % of cure rate. The marketed suspension formulation has low bioavailability and is needed to be taken with food. In this paper, PCZ hot melt extruded amorphous solid dispersion (SD) with immediate release and improved bioavailability was prepared using Soluplus (Sol) as primary carrier for solubilization. Surfactants such as PEG 400, Lutrol F27, Lutrol F68, and TPGS are also used in combination with Soluplus to improve the physicochemical performance of the formulation when it comes in contact with GI (gastrointestinal) fluid. Drug-polymer miscibility of SD was investigated using advanced techniques. In the in vivo study, the AUC(0–72) and Cmax of PCZ/Soluplus were 11.5 and 11.74 time higher than those of pure PCZ. The formulation of the extrudate SD had an AUC(0–72) and Cmax higher than those with the commercial capsule (Noxafil). Molecular dynamic (MD) simulation studies were carried out using in silico molecular modelling to understand the drug-polymer intermolecular behaviour. The results of this research ensure enhanced dissolution and bioavailability of the solid dispersion of PCZ prepared by HME compared with the PCZ suspension.

Hot melt extrusion based solid solution approach: Exploring polymer comparison, physicochemical characterization and in-vivo evaluation

The objective of this study was to develop solid solution (SSL) using hot-melt extrusion as a continuous manufacturing method. Powder blends of artesunate (ARS) a water insoluble drug with either Soluplus (SOL) or Kollidon VA64 (VA64) and additives in the form of surfactants or plasticizers were extruded to manufacture extrudes. The incorporation of surfactant or plasticizers facilitates smooth extrusion processing of the drug-excipient blend which directly reduced the residence time to form extrudes and works as parameter to control flow of the drug-excipients melt inside the extruder barrel. Differential scanning calorimetry (DSC) and X-ray diffraction (TXRD) analysis revealed the existence of the drug within the extrudes in amorphous state. Scanning electron microscopy (SEM), Raman spectroscopy (RS), Raman imaging (RI) and Atomic force microscopy (AFM) analytical characterization were carry out on the SSL formulations showed a homogeneous drug distribution within the extrudes. (2)D NMR and (1)H NMR studies were undertaken to reveal the possible drug-excipient interactions. The SSL produced via continuous HME processing showed significantly faster release of ARS compared to the pure drug substance. It is observed that F1 SSL (soluplus based) have 66.44 times higher AUC(0-72) and 16.60 times higher Cmax than pure ARS. Also K1 SSL (Kollidon VA64 based) have 62.20 times higher AUC(0-72) and 13.40 times higher Cmax than pure ARS.

Porous Starch: a Novel Carrier for Solubility Enhancement of Carbamazepine

To circumvent the solubility-related issues associated with Biopharmaceutics Classification System class II drugs, a novel porous carrier has been developed. In the present study, a process for preparation of porous starch (PS) is demonstrated. The process briefly comprises of translucent gel preparation followed by solvent replacement, drying, and sizing. Carbamazepine (CBZ) was used as a drug candidate to exhibit solubility enhancement potential of PS. PS and CBZ-loaded PS (CBZ-PS) systems were characterized with respect to IR, DSC, XRD, SEM, and dissolution kinetic studies. PS-CBZ was found to follow a Fickian behavior during dissolution. In vivo studies conducted in mice displayed a superior performance of CBZ-PS as compared to neat CBZ.

Investigational Studies on Highly Purified Fenugreek Gum as Emulsifying Agent

In this study, highly purified galactomannan containing fenugreek gum was isolated by newly reported method and investigated for its surface and emulsification property. Comparative studies were carried out with other galactomannan containing natural emulsifiers like locust bean gum, guar gum, and non-galactomannan anionic xanthan gum. The results revealed that highly purified fenugreek gum has better surface and interfacial tension reducing property among all gums used in this study. Emulsion prepared with 0.6% highly purified fenugreek gum showed greater reduction in droplets size with greater surface area compared to guar gum, locust bean gum, and xanthan gum emulsion. Zeta potential values indicated that highly purified fenugreek gum emulsion showed greater repulsive forces and was able to form more stable emulsion compared to other gums. No coalescence or phase separation was observed during storage.

Solid crystal suspension of Efavirenz using hot melt extrusion: Exploring the role of crystalline polyols in improving solubility and dissolution rate

Poor aqueous solubility of drugs has emerged as a major issue for pharmaceutical scientists from many decades. The current study explores the manufacture and development of a thermodynamically stabilized solid crystal suspension (SCS) of poorly water soluble drug efavirenz via hot melt extrusion. Efavirenz is a non-nucleoside reverse transcriptase inhibitor and belongs to BCS class II. The SCS was prepared using pearlitol and xylitol as a crystalline carrier. The drug-excipient blend was processed by hot melt extrusion with up to 50% (w/w) drug loading. Physico-chemical characterization of the SCS conducted via a scanning electron microscopy, differential scanning calorimetry and hot stage microscopy confirmed that SCS are in crystalline state. Similarly, X-ray powder diffraction analysis revealed highly crystalline existence of pure drug, crystalline carriers and developed SCS. The FTIR chemical imaging analysis of SCS formulations showed a homogeneous drug distribution within respective crystalline carriers while an advanced chemical analysis via atomic force microscopy and Raman analysis complemented the foregoing findings. The developed SCS1 formulation showed up to 81 fold increase in the solubility and 4.1 fold increase in the dissolution rate of the drug compared to that of the bulk substance. Surprisingly, the developed SCS formulation remained stable for a period of more than one year at accelerated conditions inferred from dissolution studies. It can be concluded that the SCS approach can be used as an alternative contemporary technique to enhance the dissolution rates of many other poorly water-soluble drugs by means of thermal HME processing.

Advanced surface chemical analysis of continuously manufactured drug loaded composite pellets

The aim of the present study was to develop and characterise polymeric composite pellets by means of continuous melt extrusion techniques. Powder blends of a steroid hormone (SH) as a model drug and either ethyl cellulose (EC N10 and EC P7 grades) or hydroxypropyl methylcellulose (HPMC AS grade) as polymeric carrier were extruded using a Pharma 11mm twin screw extruder in a continuous mode of operation to manufacture extruded composite pellets of 1mm length. Molecular modelling study using commercial Gaussian 09 software outlined a possible drug-polymer interaction in the molecular level to develop solid dispersions of the drug in the pellets. Solid-state analysis conducted via a differential scanning calorimetry (DSC), hot stage microscopy (HSM) and X-ray powder diffraction (XRPD) analyses revealed the amorphous state of the drug in the polymer matrices. Surface analysis using SEM/energy dispersive X-ray (EDX) of the produced pellets arguably showed a homogenous distribution of the C and O atoms in the pellet matrices. Moreover, advanced chemical surface analysis conducted via atomic force microscopy (AFM) showed a homogenous phase system having the drug molecule dispersed onto the amorphous matrices while Raman mapping confirmed the homogenous single-phase drug distribution in the manufactured composite pellets. Such composite pellets are expected to deliver multidisciplinary applications in drug delivery and medical sciences by e.g. modifying drug solubility/dissolutions or stabilizing the unstable drug (e.g. hormone, protein) in the composite network.

Development and validation of a stability indicating HPTLC-densitometric method for lafutidine

Background: A simple, selective, precise, and stability indicating high-performance thin layer chromatographic method has been established and validated for analysis of lafutidine in bulk drug and formulations. Materials and Methods: The compounds were analyzed on aluminum backed silica gel 60 F 254 plates with chloroform:ethanol:acetic Acid (8:1:1) as mobile phase. Densitometric analysis of lafutidine was performed at 230 nm. Result : Regression analysis data for the calibration plots were indicative of good linear relationship between response and concentration over the range 100-500 ng per spot. The correlation coefficient (r 2 ) was 0.998±0.002. Conclusion: Lafutidine was subjected to acid, base, peroxide, and sunlight degradation. In stability tests, the drug was susceptible to acid and basic hydrolysis, oxidation, and photodegradation.