Automation potential of a new, rapid, microscopy based method for screening drug-polymer solubility

For the pharmaceutical industry, the preformulation screening of the compatibility of drug and polymeric excipients can often be time-consuming because of the use of trial-and-error approaches. This is also the case for selecting highly effective polymeric excipients for forming molecular dispersions in order to improve the dissolution and subsequent bio-availability of a poorly soluble drug. Previously, we developed a new thermal imaging-based rapid screening method, thermal analysis by structure characterization (TASC), which can rapidly detect the melting point depression of a crystalline drug in the presence of a polymeric material. In this study, we used melting point depression as an indicator of drug solubility in a polymer and further explored the potential of using the TASC method to rapidly screen and identify polymers in which a drug is likely to have high solubility. Here, we used a data bank of 5 model drugs and 10 different pharmaceutical grade polymers to validate the screening potential of TASC. The data indicated that TASC could provide significant improvement in the screening speed and reduce the materials used without compromising the sensitivity of detection. It should be highlighted that the current method is a screening method rather than a method that provides absolute measurement of the degree of solubility of a drug in a polymer. The results of this study confirmed that the TASC results of each drug-polymer pair could be used in data matrices to indicate the presence of significant interaction and solubility of the drug in the polymer. This forms the foundation for automating the screening process using artificial intelligence

Fabrication of solid dispersion based patches using hot melt injection moulding and fused deposition modelling 3D printing

The poor aqueous solubility of many APIs, such as felodipine, are significant dissolution rate limiting factors that often lead to poor oral systemic bioavailability. Solid dispersions have been used as a formulation approach to improve drugs dissolution properties. Most of the reported solid dispersion formulations in the literature are binary mixtures with limited functionalities (with enhancing dissolution being the primary function). The aim of this study is to design, characterise and evaluate complex solid dispersions with intentionally designed microstructures (in the form of phase separations). The potential functionalities of these microstructures were explored by this project. In our view, the complex formulations are more representative of real pharmaceutical products in their final forms. HME-IM is a single processing technique for fabricating formulations with high geometric precision in a rapid, efficient and environmentally friendly way. It was used as the main processing method to produce the solid dispersion based buccal patches in this project. The patches were thoroughly characterised using conventional techniques including DSC, MTDSC, TGA, DVS, ATR-FTIR, PXRD, SEM, EDS, IR imaging, mucoadhesion and in vitro dissolution testing. In order to address the spatial distribution of the phase separations, two non-conventional characterisation methods, thermal analysis by structural characterisation and X-ray microcomputed tomography, were introduced to provide novel insights into the heterogeneity and phase distribution of these formulations. The results revealed that HME-IM patches with 10% drug loading were unsaturated while those with 20-30% w/w drug concentration were saturated or even supersaturated. HME-IM patches containing TPGS were more solubilising to felodipine and more stable compared to Tween 80 containing systems. Thermal analysis by structural characterisation provided rapid detection of heterogeneity and the thermal dissolution of crystalline drug fraction while XμCT provided microscale spatial distribution of different phases. Having shown the advantages of using polymeric blends to formulate solid dispersions that were demonstrated by the felodipine buccal patches, we further explored the use of polymer blends for improving the FDM 3D printability of pharmaceutical solid dosage forms with the potential applications in personalised medicine. This project demonstrated the potential and formulation principles of using HME-IM and FDM 3D printing as formulation methods for production of polymer blend based complex solid dispersions for the purposes of enhanced bioavailability of poorly soluble drugs and providing personalised medicines

A multi-technique characterization of the stability of surfactant containing solid dispersion based buccal patches prepared by hot melt injection moulding

This study investigates the stability of typically complex multi-component hydrophilic solid dispersions that could be used in a clinical application. Felodipine solid dispersions in two types of blends consisting of PEG, PEO and Tween 80 or Vit E TPGS were prepared by hot melt-injection moulding (HMIM) across a range of drug loadings and subjected to a range of storage conditions. Microscopy, thermal analysis, spectroscopy and powder X-ray diffraction were used to characterize the systems. The semi-solid surfactant TPGS showed a better solubilizing effect on the drug than the liquid surfactant Tween 80 in the fresh state and offered some degree of protection over the chemical degradation of PEG/PEO. Better storage stability was observed for the systems with low drug loading. Crystallization of a new metastable polymorphic form of felodipine in the patches with drug loadings at and above the saturation point was observed. Quantitative comparison of the data sets was achieved by a normalisation process and calculation of statistical variance. TPGS containing patches were more sensitive to the aging process than Tween containing patches. For both surfactants, such instability is more responsive to the storage temperature than humidity. This study established a methodology for probing the complex stabilities of multi-component dispersions

Изменение представления о цели брака в современных духовных учебных заведениях

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Impact of processing parameters on the quality of pharmaceutical solid dosage forms produced by fused deposition modelling (FDM)

Fused deposition modeling (FDM) 3D printing is being increasingly explored as a direct manufacturing method to product pharmaceutical solid dosage forms. Despite its many advantages as a pharmaceutical formulation tool, it remains restricted to proof-of-concept formulations. The optimization of the printing process in order to achieve adequate precision and printing quality remains to be investigated. Demonstrating a thorough understanding of the process parameters of FDM and their impact on the quality of printed dosage forms is undoubtedly necessary should FDM advance from a proof-of-concept stage to an adapted pharmaceutical manufacturing tool. This article describes the findings of an investigation into a number of critical process parameters of FDM and their impact on quantifiable, pharmaceutically-relevant measures of quality. Polycaprolactone, one of the few polymers which is both suitable for FDM and is a GRAS (generally regarded as safe) material, was used to print internally-exposed grids, allowing examination of both their macroscopic and microstructural reproducibility of FDM. Of the measured quality parameters, dimensional authenticity of the grids was found to poorly match the target dimensions. Weights of the grids were found to significantly vary upon altering printing speed. Printing temperature showed little effect on weight. Weight uniformity per batch was found to lie within acceptable pharmaceutical quality limits. Furthermore, we report observing a microstructural distortion relating to printing temperature which we dub The First Layer Effect (FLE). Principal Component Analysis (PCA) was used to study factor interactions and revealed, among others, the existence of an interaction between weight/dosing accuracy and dimensional authenticity dictating a compromise between the two quality parameters. The Summed Standard Deviation (SSD) is proposed as a method to extract the optimum printing parameters given all the perceived quality parameters and the necessary compromises among them

An investigation into the use of polymer blends to improve the printability of and regulate drug release from pharmaceutical solid dispersions prepared via fused deposition modeling (FDM) 3D printing

FDM 3D printing has been recently attracted increasing research efforts towards the production of personalized solid oral formulations. However, commercially available FDM printers are extremely limited with regards to the materials that can be processed to few types of thermoplastic polymers, which often may not be pharmaceutically approved materials nor ideal for optimizing dosage form performance of poor soluble compounds. This study explored the use of polymer blends as a formulation strategy to overcome this processability issue and to provide adjustable drug release rates from the printed dispersions. Solid dispersions of felodipine, the model drug, were successfully fabricated using FDM 3D printing with polymer blends of PEG, PEO and Tween 80 with either Eudragit E PO or Soluplus. As PVA is one of most widely used polymers in FDM 3D printing, a PVA based solid dispersion was used as a benchmark to compare the polymer blend systems to in terms processability. The polymer blends exhibited excellent printability and were suitable for processing using a commercially available FDM 3D printer. With 10% drug loading, all characterization data indicated that the model drug was molecularly dispersed in the matrices. During in vitro dissolution testing, it was clear that the disintegration behavior of the formulations significantly influenced the rates of drug release. Eudragit EPO based blend dispersions showed bulk disintegration; whereas the Soluplus based blends showed the ‘peeling’ style disintegration of strip-by-strip. The results indicated that interplay of the miscibility between excipients in the blends, the solubility of the materials in the dissolution media and the degree of fusion between the printed strips during FDM process can be used to manipulate the drug release rate of the dispersions. This brings new insight into the design principles of controlled release formulations using FDM 3D printing

Novel thermal imaging method for rapid screening of drug-polymer miscibility for solid dispersion based formulation development

This study aimed to develop a rapid, simple and inexpensive screening method for selecting the best polymeric candidates possessing high active pharmaceutical ingredient (API) miscibility during the early stages of formulation development of solid dispersion based pharmaceutical products. A new thermal imaging based method, thermal analysis by structural characterization (TASC), was used as a thermoptometeric tool in conjunction with data analysis software to detect the melting point depression and post-melting dissolution of felodipine particles screened over thin spin-coated films of ten polymers commonly used in the pharmaceutical field. On the polymeric substrates the drug showed different degrees of melting point reduction, reflecting their different levels of polymer-drug miscibility. Using TASC to detect melting point depression is significantly (20-40 times) faster than the conventional DSC method without loss of the sensitivity of detection. The quantity of the material required for the screening is less than 1/1000th of the material used in conventional DSC tests which significantly reduce the material wastage. Isothermal TASC tests and IR imaging confirmed the occurrence of thermal dissolution of the drug in the polymer for more miscible pairs. The real-time stability tests validate the accuracy of the polymer-drug miscibility screening results. These results demonstrate TASC as a promising screening tool for rapidly selecting the polymeric excipients for pharmaceutical formulations development

Characterization of heterogeneity and spatial distribution of phases in complex solid dispersions by thermal analysis by structural characterization and X-ray micro computed tomography

Purpose: This study investigated the effect of drug-excipient miscibility on the heterogeneity and spatial distribution of phase separation in pharmaceutical solid dispersions at a micron-scale using two novel and complementary characterization techniques, thermal analysis by structural characterization (TASC) and X-ray micro-computed tomography (XCT) in conjunction with conventional characterization methods. Method: Complex dispersions containing felodipine, TPGS, PEG and PEO were prepared using hot melt extrusion-injection moulding. The phase separation behavior of the samples was characterized using TASC and XCT in conjunction with conventional thermal, microscopic and spectroscopic techniques. The in vitro drug release study was performed to demonstrate the impact of phase separation on dissolution of the dispersions. Results: The conventional characterization results indicated the phase separating nature of the carrier materials in the patches and the presence of crystalline drug in the patches with the highest drug loading (30% w/w). TASC and XCT where used to provide insight into the spatial configuration of the separate phases. TASC enabled assessment of the increased heterogeneity of the dispersions with increasing the drug loading. XCT allowed the visualization of the accumulation of phase separated (crystalline) drug clusters at the interface of air pockets in the patches with highest drug loading which led to poor dissolution performance. Semi-quantitative assessment of the phase separated drug clusters in the patches were attempted using XCT. Conclusion: TASC and XμCT can provide unique information regarding the phase separation behavior of solid dispersions which can be closely associated with important product quality indicators such as heterogeneity and microstructure

A multi-technique characterization of the stability of surfactant containing solid dispersion based buccal patches prepared by hot melt injection moulding

This study investigates the stability of typically complex multi-component hydrophilic solid dispersions that could be used in a clinical application. Felodipine solid dispersions in two types of blends consisting of PEG, PEO and Tween 80 or Vit E TPGS were prepared by hot melt-injection moulding (HMIM) across a range of drug loadings and subjected to a range of storage conditions. Microscopy, thermal analysis, spectroscopy and powder X-ray diffraction were used to characterize the systems. The semi-solid surfactant TPGS showed a better solubilizing effect on the drug than the liquid surfactant Tween 80 in the fresh state and offered some degree of protection over the chemical degradation of PEG/PEO. Better storage stability was observed for the systems with low drug loading. Crystallization of a new metastable polymorphic form of felodipine in the patches with drug loadings at and above the saturation point was observed. Quantitative comparison of the data sets was achieved by a normalisation process and calculation of statistical variance. TPGS containing patches were more sensitive to the aging process than Tween containing patches. For both surfactants, such instability is more responsive to the storage temperature than humidity. This study established a methodology for probing the complex stabilities of multi-component dispersions

Development of a Simple Mechanical Screening Method for Predicting the Feedability of a Pharmaceutical FDM 3D Printing Filament

Purpose: The filament-based feeding mechanism employed by the majority of fused deposition modelling (FDM) 3D printers dictates that the materials must have very specific mechanical characteristics. Without a suitable mechanical profile, the filament can cause blockages in the printer. The purpose of this study was to develop a method to screen the mechanical properties of pharmaceutically-relevant, hot-melt extruded filaments to predetermine their suitability for FDM. Methods: A texture analyzer was used to simulate the forces a filament is subjected to inside the printer. The texture analyzer produced a force-distance curve referred to as the flexibility profile. Principal Component Analysis and Correlation Analysis statistical methods were then used to compare the flexibility profiles of commercial filaments to in-house made filaments. Results: Principal component analysis showed clearly separated clustering of filaments that suffer from mechanical defects versus filaments which are suitable for printing. Correlation scores likewise showed significantly greater values with feedable filaments than their mechanically deficient counterparts. Conclusion: The screening method developed in this study showed, with statistical significance and reproducibility, the ability to predetermine the feedability of extruded filaments into an FDM printer