Publications

The purpose of this study was to evaluate the performance of Neusilin® (NEU) a synthetic magnesium aluminometasilicate as an inorganic drug carrier co-processed with the hydrophilic surfactants Labrasol and Labrafil to develop Tranilast (TLT)-based solid dispersions using continuous melt extrusion (HME) processing. Twin-screw extrusion was optimized to develop various TLT/excipient/surfactant formulations followed by continuous capsule filling in the absence of any downstream equipment. Physicochemical characterization showed the existence of TLT in partially crystalline state in the porous network of inorganic NEU for all extruded formulations. Furthermore, in-line NIR studies revealed a possible intermolecular H-bonding formation between the drug and the carrier resulting in the increase of TLT dissolution rates. The capsules containing TLT-extruded solid dispersions showed enhanced dissolution rates and compared with the marketed Rizaben® product.

OBJECTIVES: The aim of this study was to develop mucoadhesive oral strips using hot-melt extrusion as a continuous manufacturing process.

METHODS: Powder blends of ketoconazole, a water-insoluble drug - either hydroxypropyl methylcellulose (HPMC) or soluplus (SOL), sorbitol (SRB) and magnesium aluminometasilicate (MAS) were extruded to manufacture thin strips with 0.5-mm thickness. The presence of the inorganic metasilicate facilitated smooth processing of the extruded strips as it worked as an absorbent directly impacting on the extensive mixing of the drug/excipients inside the extruder barrel.

KEY FINDINGS: The use of MAS also favoured the rapid hydration, swelling and eventual disintegration of the strips. Differential scanning calorimetry and transmission X-ray diffraction analysis revealed the existence of the amorphous drug within the extruded strips. Scanning electron microscopy and energy dispersive X-ray undertaken on the formulations showed a homogeneous drug distribution within the extruded strips.

CONCLUSION: The strips produced via continuous hot-melt extrusion processing showed significantly faster release of ketoconazole compared to the bulk drug substance.

The aim of the study was to investigate the effect of novel polymer/lipid formulations on the dissolution rates of the water insoluble indomethacin (INM), co-processed by hot melt extrusion (HME). Formulations consisted of the hydrophilic hydroxypropyl methyl cellulose polymer (HPMCAS) and stearoyl macrogol-32 glycerides-Gelucire 50/13 (GLC) were processed with a twin screw extruder to produce solid dispersions. The extrudates characterized by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and hot stage microscopy (HSM) indicated the presence of amorphous INM within the polymer/lipid matrices. In-line monitoring via near-infrared (NIR) spectroscopy revealed significant peak shifts indicating possible interactions and H-bonding formation between the drug and the polymer/lipid carriers. Furthermore, in vitro dissolution studies showed a synergistic effect of the polymer/lipid carrier with 2-h lag time in acidic media followed by enhanced INM dissolution rates at pH > 5.5.

Polymeric implantable drug delivery systems have remarkable potential for systemic delivery of various therapeutic agents. Generally, drug-loaded implants do not require a vehicle for delivery and can be used to attain prolonged delivery into the systemic circulation of active pharmaceutical ingredients (APIs) with enhanced drug bioavailability. Furthermore, implants can provide drug release ranging from months to years, which improves patient compliance, especially for poorly bioavailable and rapidly metabolized compounds. Continuous manufacturing technology (e.g., hot-melt extrusion, or HME) has been successfully employed to prepare drug-loaded single-unit polymeric implants. Employing heat and mechanical shear, such systems retain the stability of thermolabile therapeutics (e.g., proteins) in implants. HME has emerged as important because of its varied applications that combine economic viability with solvent-free and easy scale-up processing. Moreover, it has been recognized from a quality-by-design (QbD) viewpoint by the FDA.

The aim of the work reported herein was to implement process analytical technology (PAT) tools during hot melt extrusion (HME) in order to obtain a better understanding of the relationship between HME processing parameters and the extruded formulations. For the first time two in-line NIR probes (transmission and reflectance) have been coupled with HME to monitor the extrusion of the water insoluble drug indomethacin (IND) in the presence of Soluplus (SOL) or Kollidon VA64 hydrophilic polymers. In-line extrusion monitoring of sheets, produced via a specially designed die, was conducted at various drug/polymer ratios and processing parameters. Characterisation of the extruded transparent sheets was also undertaken by using DSC, XRPD and Raman mapping. Analysis of the experimental findings revealed the production of molecular solutions where IND is homogeneously blended (ascertained by Raman mapping) in the polymer matrices, as it acts as a plasticizer for both hydrophilic polymers. PCA analysis of the recorded NIR signals showed that the screw speed used in HME affects the recorded spectra but not the homogeneity of the embedded drug in the polymer sheets. The IND/VA64 and IND/SOL extruded sheets displayed rapid dissolution rates with 80% and 30% of the IND being released, respectively within the first 20min.

In this study molecular modeling is introduced as a novel approach for the development of pharmaceutical solid dispersions. A computational model based on quantum mechanical (QM) calculations was used to predict the miscibility of various drugs in various polymers by predicting the binding strength between the drug and dimeric form of the polymer. The drug/polymer miscibility was also estimated by using traditional approaches such as Van Krevelen/Hoftyzer and Bagley solubility parameters or Flory-Huggins interaction parameter in comparison to the molecular modeling approach. The molecular modeling studies predicted successfully the drug-polymer binding energies and the preferable site of interaction between the functional groups. The drug-polymer miscibility and the physical state of bulk materials, physical mixtures, and solid dispersions were determined by thermal analysis (DSC/MTDSC) and X-ray diffraction. The produced solid dispersions were analyzed by X-ray photoelectron spectroscopy (XPS), which confirmed not only the exact type of the intermolecular interactions between the drug-polymer functional groups but also the binding strength by estimating the N coefficient values. The findings demonstrate that QM-based molecular modeling is a powerful tool to predict the strength and type of intermolecular interactions in a range of drug/polymeric systems for the development of solid dispersions.

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.

The purpose of this study was to evaluate the performance of synthetic magnesium aluminometasilicate (MAS) as a novel inorganic carrier in hot melt extrusion (HME) processing of indomethacin (IND) for the development of solid dispersions. A continuous extrusion process at various IND/excipient blend ratios (20%, 30% and 40%) was performed using a twin-screw extruder. Physicochemical characterization carried out by SEM, DSC, and XRPD demonstrated the presence of IND in amorphous nature within the porous network of the inorganic material for all extruded formulations. Further, AFM and FTIR studies revealed a single-phase amorphous system and intermolecular H-bonding formation. The IND/MAS extrudates showed enhanced INM dissolution rates within 100% been released within 1h. Stability studies under accelerated conditions (40°C, RH 75%) showed that MAS retained the physical stability of the amorphous solid dispersions even at high drug loadings for 12 months.

The article describes the application of a twin-screw granulation process to enhance the dissolution rate of the poorly water soluble drug, ibuprofen (IBU). A quality-by-design (QbD) approach was used to manufacture IBU loaded granules via hot-melt extrusion (HME) processing. For the purpose of the study, a design of experiment (DoE) was implemented to assess the effect of the formulation compositions and the processing parameters. This novel approach allowed the use of, polymer/inorganic excipients such as hydroxypropyl methylcellulose (HPMC) and magnesium aluminometasilicate (Neusilin(®)-MAS) with polyethylene glycol 2000 (PEG) as the binder without requiring a further drying step. IBU loaded batches were processed using a twin screw extruder to investigate the effect of MAS/polymer ratio, PEG amount (binder) and liquid to solid (L/S) ratios on the dissolution rates, mean particle size and the loss on drying (LoD) of the extruded granules. The DoE analysis showed that the defined independent variables of the twin screw granulation process have a complex effect on the measured outcomes. The solid state analysis showed the existence of partially amorphous IBU state which had a significant effect on the dissolution enhancement in acidic media. Furthermore, the analysis obtained from the surface mapping by Raman proved the homogenous distribution of the IBU in the extruded granulation formulations.