Advances in Twin-Screw Granulation Processing

Twin-screw granulation (TSG) is a pharmaceutical process that has gained increased interest from the pharmaceutical industry for its potential for the development of oral dosage forms. The technology has evolved rapidly due to the flexibility of the equipment design, the selection of the process variables and the wide range of processed materials. Most importantly, TSG offers the benefits of both batch and continuous manufacturing for pharmaceutical products, accompanied by excellent process control, high product quality which can be achieved through the implementation of Quality by Design (QbD) approaches and the integration of Process Analytical Tools (PAT). Here, we present basic concepts of the various twin-screw granulation techniques and present in detail their advantages and disadvantages. In addition, we discuss the detail of the instrumentation used for TSG and how the critical processing paraments (CPP) affect the critical quality attributes (CQA) of the produced granules. Finally, we present recent advances in TSG continuous manufacturing including the paradigms of modelling of continuous granulation process, QbD approaches coupled with PAT monitoring for granule optimization and process understanding

Drug–Smectite Clay Amorphous Solid Dispersions Processed by Hot Melt Extrusion

The aim of this study was to investigate suitability of natural and synthetic smectite clay matrices as a drug delivery carrier for the development of amorphous solid dispersions (ASD). Indomethacin (IND) was processed with two different smectite clays, natural-magnesium aluminium and synthetic-lithium magnesium sodium silicates, using Hot Melt Extrusion (HME) to prepare solid dispersions. Scanning electron microscopy (SEM), Powdered X-ray diffraction (PXRD), Differential scanning calorimetry (DSC) were used to examine the physical form of the drug. Energy dispersive X-ray spectroscopy (EDX) was used to investigate the drug distribution and Attenuated Total Reflectance-Fourier transform infrared (ATR-FTIR) spectroscopic analysis was done to detect any chemical interaction between these two kinds. Both, PXRD and DSC analysis showed that drug-clay solid dispersion contained IND in amorphous form. Energy dispersive X-ray (EDX) analysis showed a uniform IND dispersion in the extruded powders. ATR-FTIR data presented possible drug and clay interactions via hydrogen bonding. In-vitro drug dissolution studies revealed a lag time of about two hours in the acidic media and a rapid release of IND at pH 7.4. The work demonstrated that preparation of amorphous solid dispersion using inorganic smectite clay particles can effectively increase the dissolution rate of IND

Dissolution Improvement of Progesterone and Testosterone via Impregnation on Mesoporous Silica Using Supercritical Carbon Dioxide

Progesterone (PRG) and testosterone (TST) were impregnated on mesoporous silica (ExP) particles via supercritical carbon dioxide (scCO2) processing at various pressures (10–18 MPa), temperatures (308.2–328.2 K), and time (30–360 min). The impact of a co-solvent on the impregnation was also studied at the best determined pressure and temperature. The properties of the drug embedded in silica particles were analysed via gas chromatography (GC), attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy, X-ray diffraction (XRD), differential scanning calorimetry (DSC), and nitrogen adsorption. An impregnation of 1 to 82 mg/g for PRG and 0.1 to 16 mg/g for TST was obtained depending on the processing parameters. There was a significant effect of pressure, time, and co-solvent on the impregnation efficiency. Generally, an increase in time and pressure plus the use of co-solvent led to an improvement in drug adsorption. Conversely, a rise in temperature resulted in lower impregnation of both TST and PRG on ExP. There was a substantial increase in the dissolution rate (> 90% drug release within the first 2 min) of both TST and PRG impregnated in silica particles when compared to the unprocessed drugs. This dissolution enhancement was attributed to the amorphisation of both drugs due to their adsorption on mesoporous silica

Bioconjugated solid lipid nanoparticles (SLNs) for targeted prostate cancer therapy

Prostate cancer is one of the prominent causes of cancer mortality in men all over the world and a challenge to treat. In this study, transferrin (Tf) bioconjugated solid lipid nanoparticles (SLNs) were developed and loaded with curcumin (CRC) for active targeting of prostate cancer cells. Curcumin is an anticancer agent, but its clinical applications are impeded due to the poor water solubility and bioavailability. Prepared blank Tf-SLNs showed minimal cytotoxicity while Tf-CRC-SLNs demonstrated significant in-vitro anti-proliferative activity compared to CRC-SLNs alone. Cellular uptake of Tf-CRC-SLNs were found to be significantly higher (p < 0.05/=0.01) compared to unconjugated SLNs or pure drug alone. Bioconjugated Tf-CRC-SLNs also showed improved early apoptotic and late apoptotic or early necrotic populations (6.4% and 88.9% respectively) to CRC-SLNs and CRC solution. Most importantly, in-vivo studies with Tf-CRC-SLNs in mice bearing prostate cancer revealed significant tumour regression (392.64 mm3 after 4 weeks, p < 0.001) compared to the control group. The findings of this work encourage future investigations and further in-vivo clinical studies on the potential of bioconjugated SLNs for cancer cure

3D printed bilayer tablet with dual controlled drug release for tuberculosis treatment

In this study Fusion Deposition Modelling (FDM) was employed to design and fabricate a bilayer tablet consisting of isoniazid (INZ) and rifampicin (RFC) for the treatment of tuberculosis. INZ was formulated in hydroxypropyl cellulose (HPC) matrix to allow drug release in the stomach (acidic conditions) and RFC was formulated in hypromellose acetate succinate (HPMC – AS) matrix to allow drug release in the upper intestine (alkaline conditions). This design may offer a better clinical efficacy by minimizing the degradation of RFC in the acidic condition and potentially avoid drug-drug interaction. The bilayer tablet was prepared by fabricating drug containing filaments using hot melt extrusion (HME) coupled with the 3D printing. The HME and 3D printing processes were optimized to avoid drug degradation and assure consistent deposition of drug-containing layers in the tablet. The invitro drug release rate was optimized by varying drug loading, infilling density, and covering layers. Greater than 80% of INZ was released in 45 mins at pH 1.2 and approximately 76% of RFC was releases in 45 mins after the dissolution medium was changed to pH 7.4. The work illustrated the potential application of FDM technology in the development of oral fixed dose combination for personalized clinical treatment

Layered Silicate-Alginate Composite Particles for the pH-Mediated Release of Theophylline

Numerous natural and synthetic clay minerals have proven to be excellent drug carriers for high drug-loaded and sustained release formulations due to their considerable ion exchange, adsorption, and swelling capacities. Moreover, the synthetic smectite clays have added advantages in terms of compositional purity and controlled cation exchange capacity in comparison to natural clays. This study involves the intercalation of theophylline (TP) in a synthetic clay, Laponite® (LP), followed by the inclusion of the resulting intercalates into sodium alginate (SA) beads to achieve pH-controlled drug release. Maximum intercalated drug incorporation of 68 mg/g was obtained by ion exchange at pH 1.2 and confirmed by an increase in basal spacing of the clay from 12.9 to 15.5 Å. TP release from the binary LP-TP intercalates in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) was found to be 40% and 70%, respectively. LP-TP particles were also incorporated in an SA matrix via polymer crosslinking using CaCl2(aq) to improve the pH selective release. The ternary polymer-clay-drug composite particles effectively prevented the release of TP at low pH in SGF and resulted in sustained release in SIF, with 40% dissolution within 120 min

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 11 mm twin screw extruder in a continuous mode of operation to manufacture extruded composite pellets of 1 mm 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

Preparation of Solid Dispersions of Simvastatin and Soluplus Using a Single-Step Organic Solvent-Free Supercritical Fluid Process for the Drug Solubility and Dissolution Rate Enhancement

The study was designed to investigate the feasibility of supercritical carbon dioxide (scCO2) processing for the preparation of simvastatin (SIM) solid dispersions (SDs) in Soluplus® (SOL) at temperatures below polymer’s glass transition. The SIM content in the SDs experimental design was kept at 10, 20 and 30% to study the effect of the drug–polymer ratio on the successful preparation of SDs. The SIM–SOL formulations, physical mixtures (PMs) and SDs were evaluated using X-ray diffraction (XRD), differential scanning calorimetry (DSC), attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR), scanning electron microscopy (SEM), and dissolution studies. The scCO2 processing conditions and drug–polymer ratio were found to influence the physicochemical properties of the drug in formulated SDs. SIM is a highly crystalline drug; however, physicochemical characterisation carried out by SEM, DSC, and XRD demonstrated the presence of SIM in amorphous nature within the SDs. The SIM–SOL SDs showed enhanced drug dissolution rates, with 100% being released within 45 min. Moreover, the drug dissolution from SDs was faster and higher in comparison to PMs. In conclusion, this study shows that SIM–SOL dispersions can be successfully prepared using a solvent-free supercritical fluid process to enhance dissolution rate of the drug

Development of 3D printed drug-eluting contact lenses

Objectives The aim of the work was to introduce 3D printing technology for the design and fabrication of drug-eluting contact lenses (DECL) for the treatment of glaucoma. The development of 3D printed lenses can effectively overcome drawbacks of existing approaches by using biocompatible medical grade polymers that provide sustained drug release of timolol maleate for extended periods. Methods Hot melt extrusion was coupled with fusion deposition modelling (FDM) to produce printable filaments of ethylene-vinyl acetate copolymer–polylactic acid blends at various ratios loaded with timolol maleate. Physicochemical and mechanical characterisation of the printed filaments was used to optimise the printing of the contact lenses. Key findings 3D printed lenses with an aperture (opening) and specified dimensions could be printed using FDM technology. The lenses presented a smooth surface with good printing resolution while providing sustained release of timolol maleate over 3 days. The findings of this study can be used for the development of personalised DECL in the future

Continuous twin-screw granulation for enhancing the dissolution of poorly water soluble drug

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