Material Sparing Research Articles

The Use of a Closed Feed Frame for the Development of Near-Infrared Spectroscopic Calibration Model to Determine Drug Concentration.

This study evaluates the use of the closed feed frame as a material sparing approach to develop near-infrared (NIR) spectroscopic calibration models for monitoring blend uniformity. The effect of shear induced by recirculation on NIR spectra was also studied. Calibration models were developed using NIR spectra obtained in the closed feed frame for two cases. For case 2, blends that flowed through the open feed frame were predicted with the model. The shear effect of the feed frame on the blends was assessed through the characterization of powder properties before and after recirculation. The physical characterization of the blends confirmed that the powder properties were not altered after recirculation within the closed feed frame. Both calibration models provided highly accurate predictions of the test sets with low bias (0.03% w/w and -0.06% w/w) and relative standard error of prediction (1.9% and 3.7%), respectively. The predictive performance of the calibration models was not affected by the shear effect. Recirculation within the closed feed frame did not change the physical properties of the blends studied. The prediction of blends flowing through the open feed frame was possible with a calibration model developed in the closed feed frame. The closed feed frame could reduce the materials needed to develop calibration models by more than 90%.

Simulation of roller compaction by combination of a compaction simulator and oscillating mill – A material sparing approach

This study investigates the feasibility of a compaction simulator and oscillating mill to mimic a roller compactor as a material sparing approach for process development. Microcrystalline cellulose and dicalcium phosphate dihydrate were selected to represent soft and hard materials, respectively. The relative density of ribbons and riblets was determined using a pycnometer and granules size distribution was determined by laser diffraction. Tablet tensile strength and relative density were determined using a hardness tester and pycnometer, respectively. This study showed that the relative density of riblets and ribbons were similar between 1 and 12 kN/cm, which indicates that the compaction simulator adequately mimics the compaction of the roller compactor using a Kp of 1. The size distribution of granules produced by the oscillating mill and roller compactor were similar, which indicates that the oscillating mill adequately mimics the roller compactor when using a similar gap and sieve design. Finally, the tablet tensile strength and relative density were similar independent of the applied granulation method and deformation behaviour of the material. In conclusion, the use of a compaction simulator and an oscillating mill in combination adequality mimics the roller compactor, which ultimately can save large amounts of material and time during process development.

Tabletability and compactibility of α-lactose monohydrate powders of different particle size. II: predicted relationships

This study aimed to evaluate a material sparing method to predict tabletability and compactibility relationships. Seven α-lactose monohydrate powders with varying particle size were used as test materials. The compressibility of the powders was determined experimentally, whereas tabletability and compactibility profiles were derived both experimentally and predicted. In the prediction method, two experimental compression parameters (Kawakita and Heckel plastic stiffness) and a single tensile strength reference value were used, all necessary data obtained from a single compression experiment. For both predicted and experimental relationships, compaction and tableting parameters (performance indicators) were calculated. The correction for viscoelastic recovery was successful in generating compressibility profiles that corresponded to the series of experimental out-of-die tablet porosities. For both the tabletability and compactibility, the experimental and predicted profiles showed a high degree of similarity. Good correlations were obtained between the predicted and experimental compaction and tableting parameters. It is concluded that the hybrid prediction method is a material sparing method, which can give good approximations of tabletability and compactibility relationships. The prediction method has the potential to be included as a part of a protocol for the characterisation of the tableting performance of particulate solids.

Case Studies in the Application of a Workflow-Based Crystallization Design for Optimized Impurity Rejection in Pharmaceutical Development

Crystallization is an important unit operation in pharmaceutical drug substance manufacturing for the isolation of organic products. Impurity control is a recurring critical quality attribute in most commercial pharmaceutical crystallization processes. A systematic workflow that can reveal the incorporation mechanism of various impurities during crystallization and guide us to understand impurity rejection is useful for crystallization process design. Such a workflow was recently published by Urwin et al. Herein, we present three case studies implementing this workflow, covering surface deposition, conglomerate formation, and agglomeration as principal routes for impurity incorporation during crystallization of a drug substance’s active pharmaceutical ingredient and its intermediates. We demonstrate the experimental steps to identify various impurity incorporation mechanisms and discuss the strategy for impurity rejection in each case. We built upon the previous approach to demonstrate a material sparing approach through our case studies. We highlight the value of stepwise dissolution and show the importance of doing it early in the impurity incorporation identification stage. At this stage, we introduce a missing incorporation mechanism in prior work, namely, conglomerate systems. We show how to identify and resolve this mode of incorporation mechanism through stepwise dissolution and solubility-limited rejection maps.

Considerations in Raman Spectroscopy for Real-Time API Concentration Measurement at Tablet Press Feed Frame

Raman spectroscopy is one of the important process analytical technology tools available for implementation in the continuous manufacturing of oral solid dosages. The aim of this study was to investigate several practical considerations in generating real-time measurements using Raman spectrometer at a tablet press feed frame, including the effects of fluorescence interference, photobleaching, feed-frame rpm, and material particle size. Fluorescence, in particular, is a significant drawback of Raman spectroscopy, compared to the use of near-infrared spectroscopy. Potential material sparing strategies were also investigated, including using stationary powders for calibration and isolation of feed-frame materials. Acetaminophen was used as the main active pharmaceutical ingredient (API), and microcrystalline cellulose (MCC) and lactose were used as excipients. The fluorescent behavior of MCC at 785 nm laser wavelength was reported and discussed. Raman spectra of a blend of MCC and acetaminophen and lactose and acetaminophen were collected at the feed frame of the tablet press. A series of preprocessing steps applied to remove the fluorescence interference was found to be effective, including the use of standard normal variate, subtraction of spectra of fluorescent material, baseline correction, and smoothing. Three different PLS models were prepared for different scenarios and their performances were compared. The models were able to predict the concentration of acetaminophen with root mean squared error prediction (RMSEP) of 0.29% w/w when there was no fluorescence interference and 0.57% w/w when there was fluorescence interference in background spectra. The study demonstrated the feasibility of using Raman spectroscopy for API concentration prediction even in the case of fluorescent interference and showed that Raman measurements were robust; that is, they were not much affected by feed-frame rpm and excipient particle size.

A multivariate methodology for material sparing characterization and blend design in drug product development

This study developed a material and time saving method for powder characterization. Building on an earlier developed raw material property database for use towards development of pharmaceutical dry powder processes, blends were selected in an efficient way to include maximal variability of the underlying raw material dataset. For both raw materials and blends, powder characterization methods were kept to a minimum by selecting the testing methods that described the highest amount of variability in physical powder properties based on principal component analysis (PCA). This method selection was made by identifying the overarching properties described by the principal components of the PCA model. Ring shear testing, powder bed compressibility, bulk/tapped density, helium pycnometry, loss on drying and aeration were identified as the most discriminating characterization techniques from this dataset to detect differences in physical powder properties. This ensured a workload reduction while most of the powder variability that could be detected was still included. The methodology proposed in this paper could be used as a material-saving alternative to the current “Design of Experiment” approach, which will be investigated further for applicability to speed up the development of formulations and processes for new drug products and building an end-to-end predictive platform.

Using a Model-based Material Sparing Approach for Formulation and Process Development of a Roller Compacted Drug Product.

The present work details a material sparing approach that combines material profiling with Instron uniaxial die-punch tester and use of a roller compaction mathematical model to guide both formulation and process development of a roller-compacted drug product. True density, compression profiling, and frictional properties of the pre-blend powders are used as inputs for the predictive roller compaction model, while flow properties, particle size distribution, and assay uniformity of roller compaction granules are used to select formulation composition and ribbon solid fraction. Using less than 10g of a model drug compound for material profiling, roller compacted blend in capsule formulations with appropriate excipient ratios were developed at both 1.4% and 14.4% drug loadings. Subsequently, scale-up batches were successfullymanufactured based on the roller compaction process parameters obtained from predictive modeling. The measured solid fractions of roller compaction ribbon samples from the scale-up batches were in good agreement with the target solid fraction of the modeling. This approach demonstrated considerable advantages through savings in both materials and number of batches in the development of a roller-compacted drug product, which is of particular value at early development stages when drug substance is often limited and timelines are aggressive.

Development of an amorphous based sustained release system for apremilast a selective phosphodiesterase 4 (PDE4) inhibitor

Apremilast is a selective PDE4 inhibitor and has been approved for several inflammatory disorders. It is classified as a BCS-IV drug and has 7 polymorphic forms. In this research we report the development of an ASD based sustained-release (SR) drug delivery system. A simplified material sparing ASD formulation approach was employed to identify ideal carrier polymers for optimum drug loadings. HPMCAS-M at 20% and Copovidone at 40% drug loadings were selected as the lead formulations. A stable single-phase amorphous system of apremilast via spray drying was created and fully characterized by mDSC, XRPD, DMA, micro-dissolution, dissolution, and accelerated stability analysis. Micro-dissolution study of ASD confirmed attainment and maintenance of supersaturated state over 3 h. ASD showed 8-fold higher solubility relative to its crystalline counterpart. Novel monolithic and bilayer SR HPMC tablet matrices containing 30 mg or 60 mg of ASD system were manufactured. Tablets during dissolution exhibited gradual swelling, erosion, and disentanglement over 15–20-hours with over 90% drug released. The designed SR amorphous based matrix system showed ability to increase apremilast solubility, dissolution rate, and inhibit recrystallization or polymorphic interconversion by stabilizing its amorphous form. This new development may allow for once-daily drug administration and improve both bioavailability and patient compliance.

Ex Vivo Fluorescence Confocal Microscopy in Specimens of the Liver: A Proof-of-Concept Study.

Simple SummaryFluorescence confocal microscopy (FCM) is a novel micro-imaging technique providing optical sections of native tissue. The method is increasingly used for the routine diagnosis of tumors and inflammatory lesions of the skin and shows promising results for the diagnosis of other organ tumors. Very few publications exist about examinations of liver tissue thus far. In this study, we compare findings of FCM-examinations of biopsies and surgical specimens of the liver with the final diagnoses from conventional histology.Ex vivo Fluorescence Confocal Microscopy (FCM) is a technique providing high-resolution images of native tissues. The method is increasingly used in surgical settings in areas of dermatology and urology. Only a few publications exist about examinations of tumors and non-neoplastic lesions of the liver. We report on the application of FCM in biopsies, surgical specimens and autopsy material (33 patients, 39 specimens) of the liver and compare the results to conventional histology. Our preliminary examinations indicated a perfect suitability for tumor diagnosis (ĸ = 1.00) and moderate/good suitability for the assessment of inflammation (ĸ = 0.4–0.6) with regard to their severity and localization. Macro-vesicular steatosis was reliably detected, micro-vesicular steatosis tended to be underestimated. Cholestasis and eosinophilic granules in granulocytes were not represented in the scans. The tissue was preserved as native material and maintained its quality for downstream histological, immunohistological and molecular examinations. In summary, FCM is a material sparing method that provides rapid feedback to the clinician about the presence of tumor, the degree of inflammation and structural changes. This can lead to faster therapeutic decisions in the management of liver tumors, treatment of hepatitis or in liver transplant medicine.

Food effect risk assessment in preformulation stage using material sparing μFLUX methodology.

The intake of food and meal type can strongly impact the bioavailability of orally administered drugs and can consequently impact drug efficacy and safety. During the early stages of drug development, only a small amount of drug substance is available, and the solubility difference between fasted state simulated intestinal fluid and fed state simulated intestinal fluid may provide an early indication about the probable food effect. But higher drug solubility in fed state simulated intestinal fluid may not always results in an increased oral absorption. In the present research, we demonstrated using 11 model compounds that in addition to the drug dissolution in biorelevant media, the evaluation of the diffusion flux of a drug in solution, across artificial lipid coated membrane, where only the unbound drug crosses the membrane, is a reliable way to predict the food effect. Although, the combination of dissolution and diffusion flux may not reliably predict the food effect in case of drugs undergoing intestinal metabolism or when transporters are involved in the drug absorption, the technique generally provides good information about the food effect at very early stages of drug development that may help in designing a clinical plan by adjusting the drug dose in the fed state.

NIR spectroscopic methods for monitoring blend potency in a feed frame - calibration transfer between offline and inline using a continuum regression filter

A material sparing method for near-infrared (NIR) calibration was developed using an offline apparatus coupled with a calibration transfer method to enable a partial least squares (PLS) model to monitor the concentration of active pharmaceutical ingredients (API) in the feed frame of a rotary tablet press. The offline apparatus was designed to simulate the powder flow dynamic and NIRS measurement environment of a tablet-press feed frame. A comprehensive experimental design, including calibration and testing, was employed to determine blend inhomogeneity. NIR spectra were collected at both the feed frame (inline) conditions and the simulator (offline) conditions. The simulator conditions were designed to mimic the density and powder flow in the feed frame during the actual tableting process. The offline data were pretreated by an orthogonalization-based calibration transfer algorithm, a continuum regression filter (CR filter), before being subjected to PLS modeling. This study demonstrated: (1) calibration for inline application can be generated using an offline apparatus, and (2) the CR filter, as an innovative calibration transfer method, can generalize the offline method for multiple feed frame conditions.

Oro- and Nasopharyngeal Swab for Detection of SARS-CoV-2 - Step-by-step Approach

Oro- and nasopharyngeal swab specimens by quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) to detect SARS-CoV-2 is currently the main diagnostic tool during the ongoing COVID-19 pandemia. Accurate performance of the procedure to avoid false negative results, adequate personal protective equipment and material sparing algorithms are mandatory while obtaining swab specimens. In the current stey-by-step review a feasible approach will be presented.

Benchtop NIR method development for continuous manufacturing scale to enable efficient PAT application for solid oral dosage form

A Near Infrared (NIR) method was developed using a small benchtop feed frame system to quantify Saccharin potency in a powder blend during continuous manufacturing process. A 15-point Design of Experiments (DoE) was created based on the NIR spectral response and compositions of the formulation to develop a calibration set. The calibration set was designed to create compositional and raw material lots variation using minimum resources. The calibration experiments utilized around 0.5 kg Saccharin (Active Pharmaceutical Ingredient (API) surrogate) and 1.8 kg of excipients. Partial Least Square (PLS) modeling was used to develop a quantitative NIR method from the calibration data. The NIR method was implemented during 5 test batches in two different manufacturing sites across different potency levels at a continuous manufacturing platform for direction compression. Acceptable prediction performance was achieved from the NIR method at both sites. The NIR method was robust against changes in process scale and NIR instruments. The variance information built into the calibration set was found to be critical to successful model performance. This study shows a benchtop feed frame can be used for material sparing calibration method development without operating at a full-scale process line and applied across multiple sites, instruments at different potency levels.

Oro- and nasopharyngeal swab for detection of SARS-CoV-2 - step-by-step approach

Oro- and nasopharyngeal swab specimens by quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) to detect SARS-CoV-2 is currently the main diagnostic tool during the ongoing COVID-19 pandemia. Accurate performance of the procedure to avoid false negative results, adequate personal protective equipment and material sparing algorithms are mandatory while obtaining swab specimens. In the current stey-by-step review a feasible approach will be presented.

The efficient development of a sildenafil orally disintegrating tablet using a material sparing and expedited approach.

The purpose of this work is to develop an orally disintegrating tablet (ODT) of sildenafil (SIL) using a materials sparing and expedited development approach, enabled by the materials science tetrahedron principle and predictive technologies. To overcome the problem of bitter taste of SIL, an artificial sweetener, acesulfame (Acs), was used to form a sweet SIL salt (SIL-Acs) using an effective reaction crystallization process to prepare phase pure bulk SIL-Acs with a high yield. The SIL-Acs salt shows excellent thermal stability (Tm=200.2°C), low hygroscopicity, and acceptable dissolution rate. Formulation and process parameters were optimized based on powder flowability, tabletability, tablet disintegration time, and expedited friability. A particle engineering approach, i.e., nanocoating, was employed to attain adequate flowability of the SIL-Acs ODT formulation required for the direct compression process. The wide range of compression forces for making tablets exhibiting both fast disintegration time (≤30s) and low friability (≤0.8%) suggested excellent flexibility in manufacturing SIL-Acs ODT. The development of a sildenafil ODT formulation, including solid form selection and characterization, crystallization method development, formulation development, and DC process optimization, only required 5g of SIL citrate and 2weeks of time.

Five-Stage Approach for a Systematic Screening and Development of Etravirine Amorphous Solid Dispersions by Hot-Melt Extrusion

The aim of this study was to develop a fast, effective, and material sparing screening method to design amorphous solid dispersions (ASDs) of etravirine to drive more effectively the development process, leading to improved bioavailability (BA) and stability. A systematic step-by-step approach was followed by combining theoretical calculations with high-throughput screening (HTS) and software-assisted multivariate statistical analysis. The thermodynamic miscibility and interaction of the drug in several polymers were predicted using Hansen solubility parameters (δ). The selected polymers were evaluated by HTS, using solvent evaporation. Binary compositions were evaluated by their solubilization capacity and physical stability over 2 months. JMP 14.0 was used for multivariate statistical analysis using principal components analysis. Extrusion was performed in Thermo Scientific HAAKE MiniLab II, and extrudates were characterized by assay, related substances, dissolution, and physical state (polarized light microscopy (PLM), Raman spectroscopy, and X-ray powder diffraction (XRPD)). A short stability study was performed where milled extrudates were exposed to 25 °C/60%RH and 40 °C/75%RH for 3 months. Through thermodynamic predictions, five main polymers were selected. The HTS enabled the evaluation of 42 formulations for solubilization capacity and physical stability. The three most promising compositions were selected for hot-melt extrusion (HME) tests. In general, a good correlation was found among the results of theoretical predictions, HTS, and HME. Poly(vinylpyrrolidone) (PVP)-based formulations were shown to be easily extrudable, with low degradation and complete amorphicity, whereas in Soluplus, the drug was not miscible, leading to a high crystalline content. The drug release rate was improved more than two times with PVP, and the manufactured ASD was demonstrated to be stable physically and chemically. A fast and effective screening technique to develop stable ASDs for a poorly soluble drug was successfully developed as applied to etravirine. The given method is easy to use, requires a low amount of drug, and is fairly accurate in predicting the amorphization of the drug when formulated. The success of HME formulation development of etravirine was undoubtedly enhanced with this high-throughput tool, which led to the identification of extrudates with improved biopharmaceutical properties. The structural characterization performed by PLM, XRPD, and Raman spectroscopy demonstrated that the HME prototype was essentially amorphous. The unexpected stability at 40 °C/75%RH was correlated with the presence of molecular interaction characterized by Raman spectroscopy.

A Miniaturized Extruder to Prototype Amorphous Solid Dispersions: Selection of Plasticizers for Hot Melt Extrusion.

Hot-melt extrusion is an option to fabricate amorphous solid dispersions and to enhance oral bioavailability of poorly soluble compounds. The selection of suitable polymer carriers and processing aids determines the dissolution, homogeneity and stability performance of this solid dosage form. A miniaturized extrusion device (MinEx) was developed and Hypromellose acetate succinate type L (HPMCAS-L) based extrudates containing the model drugs neurokinin-1 (NK1) and cholesterylester transfer protein (CETP) were manufactured, plasticizers were added and their impact on dissolution and solid-state properties were assessed. Similar mixtures were manufactured with a lab-scale extruder, for face to face comparison. The properties of MinEx extrudates widely translated to those manufactured with a lab-scale extruder. Plasticizers, Polyethyleneglycol 4000 (PEG4000) and Poloxamer 188, were homogenously distributed but decreased the storage stability of the extrudates. Stearic acid was found condensed in ultrathin nanoplatelets which did not impact the storage stability of the system. Depending on their distribution and physicochemical properties, plasticizers can modulate storage stability and dissolution performance of extrudates. MinEx is a valuable prototyping-screening method and enables rational selection of plasticizers in a time and material sparing manner. In eight out of eight cases the properties of the extrudates translated to products manufactured in lab-scale extrusion trials.

Surface engineered excipients: I. improved functional properties of fine grade microcrystalline cellulose

Excipients with good flowability, bulk density as well as compaction properties are desired for use in tableting since they play important roles in formulation development and processing, including, handling, mixing, feeding and compaction. The objective of this paper is to examine the feasibility of using dry coating based surface modification of microcrystalline cellulose, Avicel PH-105, to produce an engineered fine grade (<30 μm) excipient that has all three desired properties. Using a material sparing high-intensity vibrational mixer, Avciel PH-105 is dry coated with 1 wt% Aerosil 200, selected due to its relatively higher dispersive surface energy and lower particle size amongst other silica choices. The results indicated that as expected, the bulk density and flowability are significantly improved, while there was an appreciable loss of compaction. To minimize the loss of compaction, attributed to decreased surface energy after coating, while maintaining improved bulk density and flowability, the effect of reduced silica amount was examined. Remarkably, at reduced levels (0.5 wt% to 0.7 wt%) of Aerosil 200, significant improvements in bulk density and flowability were attained with only 9%–12% compaction reduction. The properties of the surface-engineered excipients were compared with several other commercially available pharmaceutical excipients using two different processibility or regime maps; tablet tensile strength versus bulk density or flow function coefficient (FFC). The surface engineered excipients exhibited the best overall performance establishing a promising pathway to engineer excipients using dry processing instead of complex processes such as spray drying.

Comparative Assessment of Miniaturized Screening Approaches for Selection of Polymers for Amorphous Drug Stabilization

The present work highlights the use of miniaturized approaches to screen and prioritize development of solid dispersions that provide stabilization of the amorphous drug against crystallization and enhanced dissolution over the crystalline form. The approaches evaluated include solvent casting and solvent displacement–based techniques. Four compounds were evaluated with both these screening approaches. A dual-pH dilution method using fasted state simulated gastric fluid and fasted state simulated intestinal fluid as media was used to evaluate solubility enhancement ratio in each well of the screen. The concentration at 15 mins after dilution with fasted state simulated intestinal fluid and super-saturation ratio at the end of the dissolution study is used as 2 descriptors of solubility enhancement. The empirical screening approaches were supplemented with theoretical calculations of solubility enhancement to gauge the best-performing amorphous solid dispersion (ASD). Physical stability of the amorphous systems was also evaluated, where applicable. Lead ASD compositions from the screens were scaled up to verify the predictions. To our knowledge, this is the first report where the 2 most common screening approaches for the development of ASDs are compared head to head. These approaches are rapid, material sparing, and can be adapted to accommodate screening of multiple variables such as polymer type, drug load, and ternary systems simultaneously. The strengths, limitations, and most suitable applications for each of the 2 methods are also discussed.

A robust quantitative near infrared modeling approach for blend monitoring

This study demonstrates a material sparing Near-Infrared modeling approach for powder blend monitoring. In this new approach, gram scale powder mixtures are subjected to compression loads to simulate the effect of scale using an Instron universal testing system. Models prepared by the new method development approach (small-scale method) and by a traditional method development (blender-scale method) were compared by simultaneously monitoring a 1kg batch size blend run. Both models demonstrated similar model performance. The small-scale method strategy significantly reduces the total resources expended to develop Near-Infrared calibration models for on-line blend monitoring. Further, this development approach does not require the actual equipment (i.e., blender) to which the method will be applied, only a similar optical interface. Thus, a robust on-line blend monitoring method can be fully developed before any large-scale blending experiment is viable, allowing the blend method to be used during scale-up and blend development trials.