Effects of Manufacturing Process Variables on the Tablet Weight Variation of Mini-tablets Clarified by a Definitive Screening Design.

This study investigated the effect of manufacturing process variables of mini-tablets, in particular, the effect of process variables concerning fluidized bed granulation on tablet weight variation. Test granules were produced with different granulation conditions according to a definitive screening design (DSD). The five evaluated factors assigned to DSD were: the grinding speed of the sample mill at the grinding process of the active pharmaceutical ingredient (X1), microcrystalline cellulose content in granules (X2), inlet air temperature (X3), binder concentration (X4) and the spray speed of the binder solution (X5) at the granulation process. First, the relationships between the evaluated factors and the granule properties were investigated. As a result of the DSD analysis, the mode of action of granulation parameters on the granule properties was fully characterized. Subsequently, the variation in tablet weight was examined. In addition to mini-tablets (3 mm diameter), this experiment assessed regular tablets (8 mm diameter). From the results for regular tablets, the variation in tablet weight was affected by the flowability of granules. By contrast, regarding the mini-tablets, no significant effect on the variation of tablet weight was found from the evaluated factors. From this result, this study further focused on other important factors besides the granulation process, and then the effect of the die-hole position of the multiple-tip tooling on tablet weight variation was proven to be significant. Our findings provide a better understanding of manufacturing mini-tablets.

Predictive Approach to Understand and Eliminate Tablet Breakage During Film Coating.

Pharmaceutical tablets can be susceptible to damage such as edge chipping or erosion of the core during the tablet coating process. The intersection of certain process parameters, equipment design, and tablet properties may induce more significant tablet damage such as complete tablet fracture. In this work, a hybrid predictive approach was developed using discrete element method (DEM) modeling and lab-based tablet impact experiments to identify conditions that may lead to tablet breakage events. The approach was extended to examine potential modifications to the coating equipment and process conditions in silico to mitigate the likelihood of tablet breakage during future batches. The approach is shown to enhance process understanding, identify optimal process conditions within development constraints, and de-risk the manufacture of future tablet coating batches.

Artificial Neural Network (ANN) Approach to Predict an Optimized pH-Dependent Mesalamine Matrix Tablet.

BACKGROUND: Severe bleeding and perforation of the colon and rectum are complications of ulcerative colitis which can be treated by a targeted drug delivery system. PURPOSE: Development of colon-targeted delivery usually involves a complex formulation process and coating steps of pH-sensitive methacrylic acid based Eudragit®. The current work was purposefully designed to develop dicalcium phosphate (DCP) facilitated with Eudragit-S100-based pH-dependent, uncoated mesalamine matrix tablets. MATERIALS AND METHODS: Mesalamine formulations were compressed using wet granulation technique with varying compositions of dicalcium phosphate (DCP) and Eudragit-S100. The developed formulations were characterized for physicochemical and drug release profiles. Infrared studies were carried out to ensure that there was no interaction between active ingredients and excipients. Artificial neural network (ANN) was used for the optimization of final DCP-Eudragit-S100 complex and the experimental data were employed to train a multi-layer perception (MLP) using quick propagation (QP) training algorithm until a satisfactory root mean square error (RMSE) was reached. The ANN-aided optimized formulation was compared with commercially available Masacol®. RESULTS: Compressed tablets met the desirability criteria in terms of thickness, hardness, weight variation, friability, and content uniformity, ie, 5.34 mm, 7.7 kg/cm2, 585±5 mg (%), 0.44%, and 103%, respectively. In-vitro dissolution study of commercially available mesalamine and optimized formulation was carried out and the former showed 100% release at 6 h while the latter released only 12.09% after 2 h and 72.96% after 12 h which was fitted to Weibull release model with b value of 1.3, indicating a complex release mechanism. CONCLUSION: DCP-Eudragit-S100 blend was found explicative for mesalamine release without coating in gastric and colonic regions. This combination may provide a better control of ulcerative colitis.

Wireless Electrochemotherapy by Selenium-Doped Piezoelectric Biomaterials to Enhance Cancer Cell Apoptosis.

Cancer residues around the surgical site remain a significant cause of treatment failure with cancer recurrence. To prevent cancer recurrence and simultaneously repair surgery-caused defects, it is urgent to develop implantable biomaterials with anticancer ability and good biological activity. In this work, a functionalized implant is successfully fabricated by doping the effective anticancer element selenium (Se) into the potassium-sodium niobate piezoceramic, which realizes the wireless combination of electrotherapy and chemotherapy. Herein, we demonstrate that the Se-doped piezoelectric implant can cause mitochondrial damage by increasing intracellular reactive oxygen species levels and then trigger the caspase-3 pathway to significantly promote apoptosis of osteosarcoma cells in vitro. Meanwhile, its good biocompatibility has been verified. These results are of great importance for future deployment of wireless electro- and chemostimulation to modulate biological process around the defective tissue.

Evaluation of using spray-dried glutinous rice starch as a direct compression hydrophilic matrix tablet.

BACKGROUND: Our previous study found that spray-dried glutinous rice starch (sGRS) is larger in size, rounder in shape and better in flowability than native GRS. It has the potential to be used for direct compression hydrophilic matrix (HM) tablets. OBJECTIVE: This study aimed to investigate the factors that affect the propranolol release from directly compressed sGRS HM tablets. METHODS: The effects of the amount of sGRS, the compaction pressure and the amount of magnesium stearate on the drug release rate from sGRS directly compressed HM were investigated. In vitro drug releases were performed. The dilution potential of sGRS was investigated. RESULTS: The higher the sGRS content, the slower the release rate of propranolol. The compaction pressure and the amount of magnesium stearate did not significantly affect the release rate of the drug. The sGRS showed plastic deformation under compaction with a dilution potential of 46%. CONCLUSIONS: sGRS can be used as a direct compression HM. The amount of sGRS significantly affected the release rate of the drug from the matrix.

Real-time monitoring of pharmaceutical properties of medical tablets during direct tableting process by hybrid tableting process parameter-time profiles.

BACKGROUND: Real-time monitoring is required for the pharmaceutical manufacturing process to produce high-quality pharmaceutical products. OBJECTIVE: Changes in the critical tableting process parameters of single-punch tableting machine due to variability in the moisture content of the raw powders were monitored by hybrid tableting pressure-time profiles. METHODS: After mixing of the raw powders, which consisted of theophylline, anhydrous lactose, potato starch and crystalline cellulose, they were stored at 0%, 45%, or 75% relative humidity (RH) for 24 h, respectively. Continuous tablet productions were carried out using the mixed powder samples at 10%, 45%, or 75% RH, respectively. The critical process parameters, such as upper and lower puncture pressures, die wall pressures, and inter-punch distances were recoded with the tableting machine, and then, tablet hardness (H), weight (W) and disintegration time (DT) of the tablets were measured. RESULTS: Hybrid tableting pressure-time profiles were obtained from various critical process parameters, and calibration models to predict pharmaceutical properties were calculated based on the hybrid profiles using a partial-least-squares regression (PLSR) method. In addition, the consistency of the calibration models were verified by constructing robust calibration models. CONCLUSION: Informetrical analysis for tablets based on hybrid tableting pressure-time profiles could evaluate the change of tablet properties dependent on the moisture content in the raw powders during the tableting process. The changes of tableting properties and elasticity were caused by agglomeration of powder particles at moisture content.

Preparation and In vitro Evaluation of FDM 3D-Printed Ellipsoid-Shaped Gastric Floating Tablets with Low Infill Percentages.

The aim of the study is to investigate the feasibility of fabricating FDM 3D-printed gastric floating tablets with low infill percentages and the effect of infill percentage on the properties of gastric floating tablets in vitro. Propranolol hydrochloride was selected as a model drug, and drug-loaded polyvinyl alcohol (PVA) filaments were produced by hot melt extrusion (HME). Ellipsoid-shaped gastric floating tablets with low infill percentage of 15% and 25% (namely E-15 and E-25) were then prepared respectively by feeding the extruded filaments to FDM 3D printer. Thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffraction (XRD), and scanning electron microscopy (SEM) were employed to characterize the filaments and 3D-printed tablets, and a series of evaluations were performed to the 3D-printed tablets, including the weight variation, drug content, hardness, in vitro floating behavior, and drug release of the tablets. The SEM results showed that the drug-loaded filaments and 3D-printed tablets appeared intact without defects, and the printed tablets were composed of filaments deposited uniformly layer by layer. The model drug and the excipients were thermally stable under the process temperature of extruding and printing, with a small amount of drug crystals dispersing in the drug-loaded filaments and 3D-printed tablets. Both E-15 and E-25 could float on artificial gastric fluids without any lag time and released in a sustained manner. Compared with E-15, the E-25 presented less weight variation, higher tablet hardness, shorter floating time, and longer drug release time.

Novel Orally Disintegrating Tablets Produced Using a High-Pressure Carbon Dioxides Process.

It is well known that high-pressure carbon dioxide (CO2) lowers the glass transition temperature (Tg) of polymers. We therefore investigated whether Tg depression of high-pressure CO2 results in interparticle bridging of a polymer and the tablet characteristics that makes the manufacture of an orally disintegrating tablet (ODT) possible. Copolyvidone (Kollidon®) and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®) were examined and found to exhibit a large Tg depression. Placebo ODTs were prepared and hardness, disintegration rate, porosity, and change in thickness and appearance were evaluated before and after the high-pressure CO2 treatment. This enabled the establishment of the optimal conditions for pressure, temperature, and treatment time under pressure. Experimental results showed that it was possible to manufacture ODTs comprising Kollidon® as a water-soluble polymer with CO2 treatment under the suitable conditions such as temperature at 45°C, pressure lower than 8 MPa, and a treatment time shorter than 30 min, which is a new ODT manufacturing process called "Carbon Dioxide Assisted Tablet Formation Scheme" (CATS). In comparison to the conventional processes, which require high temperatures or humidity, CATS is expected to be applicable to drugs that are unstable at high temperature and humidity, and to functional drug particles used for bitter taste masking, sustained release, and other uses.

Strength Simulation of Scored Tablets Based on the Finite Element Method Using an Extreme Vertices Design.

The mechanical strain distribution of scored tablets was simulated using the finite element method (FEM). The score was fabricated as a triangular runnel with the pole on the top surface of flat tablets. The effect of diametral compression on the tablet surface strain was evaluated by changing the angle between the scored line and the diametral compression axis. Ten types of granules were prepared according to an extreme vertices design. Young's modulus and the Poisson ratio for the model powder bed were measured as elastic parameters. The FEM simulation was then applied to the scored tablets represented as a continuous elastic model. Strain distributions in the inner structure of the tablets were simulated after the application of external force. The maximum principal strain (ε1) value was obtained with tablets containing a large amount of corn starch, in all scored line positions. In contrast, the ε1 value of the tablets containing a large amount of microcrystalline cellulose was minimal. The adequacy of the simulation was evaluated by experiments with scored tablets. The results indicated a fairly good agreement between the FEM simulation and experiments. Moreover, it was found that the ε1 value correlated negatively with the value of tablet hardness. These results suggest that the FEM simulation was advantageous for designing scored tablets.

Co-Processed Excipients for Dispersible Tablets-Part 1: Manufacturability.

Co-processed excipients may enhance functionality and reduce drawbacks of traditional excipients for the manufacture of tablets on a commercial scale. The following study aimed to characterise a range of co-processed excipients that may prove suitable for dispersible tablet formulations prepared by direct compression. Co-processed excipients were lubricated and compressed into 10.5-mm convex tablets using a Phoenix compaction simulator. Compression profiles were generated by varying the compression force applied to the formulation and the prepared tablets were characterised for hardness, friability, disintegration and fineness of dispersion. Our data indicates that CombiLac, F-Melt type C and SmartEx QD100 were the top 3 most suitable out of 16 co-processed excipients under the conditions evaluated. They exhibited good flow properties (Carr's index ˂ 20), excellent tabletability (tensile strength > 3.0 MPa at 0.85 solid fraction), very low friability (< 1% after 15 min), rapid disintegration times (27-49 s) and produced dispersions of ideal fineness (< 250 µm). Other co-processed excipients (including F-Melt type M, Ludiflash, MicroceLac, Pharmaburst 500 and Avicel HFE-102) may be appropriate for dispersible tablets produced by direct compression providing the identified disintegration and dispersion risks were mitigated prior to commercialisation. This indicates that robust dispersible tablets which disintegrate rapidly could be manufactured from a range of co-processed excipients.

Tablets made from paper.

The possibility to compress ordinary paper into tablets was systematically investigated in this study. Results proved that tablets can be made from paper, independent of the type of paper used. The tablets appear shiny and with a smooth surface. The pharmaceutical quality was acceptable, i.e. all tablets fulfilled the requirements for tablets according to the European Pharmacopeia. Drug-loaded tablets were produced by compression of drug-loaded paper. Drug loading did not alter the pharmaceutical quality. However, the uncoated tablets possessed an extremely fast disintegration, i.e. intense swelling upon contact with water, which might hamper the swallowing after oral administration. To avoid swelling tablets were successfully coated with a polymer film, leading to a prevention of swelling but immediate disintegration in simulated gastric fluid. In fact, tablets made from paper are a novel and promising strategy for improved oral drug delivery. They can be easily produced without any further excipients and possess pharmaceutical quality according to the European Pharmacopeia.

Transient Temperature Monitoring of Pharmaceutical Tablets During Compaction Using Infrared Thermography.

Manufacturing of pharmaceutical tablets from powders is always accompanied by the conversion of irreversible mechanical work of compaction into heat. The heat is generated due to friction between powder particles, particles and the die wall, plastic deformation of particles, bonding, and other irreversible processes. The resulting temperature increase potentially might have significant effects on a tablet's mechanical properties, disintegration time, and drug release. In the present work, we show that using infrared thermography as a nondestructive and noncontact process analytical technology (PAT) tool to measure the tablet's rate of cooling, in contrast to the temperature evolution, can be directly related to the tablet's thermal diffusivity. Results show the potential capabilities of this technique to discriminate and toward predicting tensile strength of tablets between same formulations produced at same compaction force but experienced different process shear conditions. Correlation of the tablet's tensile strength, relative density, and rate of cooling at regular regime with respect to different process shear is also discussed.

Optimization of Premix Powders for Tableting Use.

Direct compression is a popular choice as it provides the simplest way to prepare the tablet. It can be easily adopted when the active pharmaceutical ingredient (API) is unstable in water or to thermal drying. An optimal formulation of preliminary mixed powders (premix powders) is beneficial if prepared in advance for tableting use. The aim of this study was to find the optimal formulation of the premix powders composed of lactose (LAC), cornstarch (CS), and microcrystalline cellulose (MCC) by using statistical techniques. Based on the "Quality by Design" concept, a (3,3)-simplex lattice design consisting of three components, LAC, CS, and MCC was employed to prepare the model premix powders. Response surface method incorporating a thin-plate spline interpolation (RSM-S) was applied for estimation of the optimum premix powders for tableting use. The effect of tablet shape identified by the surface curvature on the optimization was investigated. The optimum premix powder was effective when the premix was applied to a small quantity of API, although the function of premix was limited in the case of the formulation of large amount of API. Statistical techniques are valuable to exploit new functions of well-known materials such as LAC, CS, and MCC.

Sticking and Picking in Pharmaceutical Tablet Compression: An IQ Consortium Review.

Sticking and picking during tablet manufacture has received increasing interest recently, as it causes tablet defects, downtime in manufacturing, and yield losses. The capricious nature of the problem means that it can appear at any stage of the development cycle, even when it has been deemed as low risk by models, tests, and previous experience. In many cases, the problem manifests when transferring the process from one manufacturing site to another. Site transfers are more common now than in previous times because of the multinational nature of drug product manufacturing and the need for redundancy in manufacturing networks. Sticking is a multifactorial problem, so one single "fix" is unlikely to solve it completely, and "solutions" addressing one problem may exacerbate another. A broad-based strategy involving the API, formulation, tablet tooling, and the manufacturing process is the most likely approach to provide a robust and lasting solution. When faced with a sticking problem for the first or subsequent time, the formulator should address, in a structured way, a range of possible causes and remedies. In this article, we focus on current research and practice; on some of the common causes of sticking; mitigation and resolution strategies and solutions; and possible future directions in research.

"Tampering to Death": A Fatal Codeine Intoxication Due to a Homemade Purification of a Medical Formulation.

Many homemade tamper processes of medical codeine formulations are available on selected "forums" on the Internet, where recreational codeine users claim to be able to purify codeine by removing additives, such as acetaminophen, to avoid or limit adverse effects. In this work, it is reported and discussed a fatal case of codeine intoxication. The findings of objects such as jars, filters, and tablets, and amounts of unknown liquid material at the death scene investigation suggested a fatal codeine intoxication after the tampering procedure called "cold water extraction." Toxicological results obtained from the analysis of both the nonbiological material and the body fluids of the decedent integrated with the information collected at the death scene investigation confirmed the above-mentioned hypothesis. This report underlines the importance of a tight interconnection between criminalistics and legal medicine to strengthen the identification of the cause of death and the reconstruction of the event.

A Demonstration of Mixing Robustness in a Direct Compression Continuous Manufacturing Process.

The purpose of this work was to assess the impact of continuous mixing on tablet critical quality attributes (CQAs) manufactured using a continuous, direct compression process. A 9-run design of experiments (DoE) that bracketed the range of commercially relevant mixer speeds, mixer orientations, and mass flow rates was executed using a formulation containing a cohesive drug substance at relatively low drug load. Drug substance dispensed concentration using loss-in-weight feeders was within 1% of target for each experiment with 30-s mass flow relative standard deviation values of 3.5% or less. Higher mass flow rates resulted in first off tablets closer to target potency, a shorter tablet potency startup phase, and greater assurance of passing content uniformity testing. Dissolution profiles from the DoE runs that bracketed mixer shear conditions were similar, indicating mixing had minimal impact on drug substance release from the tablets. None of the DoE parameters had a practical impact on the description CQA (tablet breaking force, friability, and appearance). Collectively, these results highlight that for this study continuous mixing within a direct compression process is robust and is assessed as low risk of adversely impacting drug product CQAs provided there is appropriate control of the continuous feeders.

Effect of the Curvature of the Punches on the Shape of the Interface and the Delamination Tendency of Bilayer Tablets.

Bilayer tablets are of special interest in the pharmaceutical industry. The main problem during their manufacturing is the occurrence of delamination during or after the ejection from the die. This work studies the influence of using punches with a curvature on the interfacial strength and thus on the delamination tendency of bilayer tablets. Bilayer tablets were produced with a compaction simulator using different flat and concave punches with different radii of curvature. The main compaction pressure was kept constant but the tamping force was varied. Two bilayer model systems were studied. The interfacial strength was determined using a previously described indentation test. The factors studied were analyzed for statistical significance with respect to the responses. The curvature of the interface was found to be higher when the curvature of the punch and the tamping force increased. Breaking tests then demonstrated that, for bilayer tablets obtained using the same compression parameters, the interfacial strength was lower when the curvature of the interface increased. As a consequence, when producing bilayer tablets with concave punches, it is important to choose properly the tableting parameters in order to have an interface between the layers as flat as possible to avoid delamination issues.

Solving manufacturing problems for L-carnitine-L-tartrate to improve the likelihood of successful product scale-up.

L-carnitine-L-tartrate, a non-essential amino acid, is hygroscopic. This causes a problem in tablet production due to pronounced adhesion of tablets to punches. A 33 full factorial design was adopted to suggest a tablet formulation. Three adsorbents were suggested (Aerosil 200, Aerosil R972, talc) to reduce stickiness at three concentrations (1, 3 and 5 %), and three fillers (mannitol, Avicel PH 101, Dibasic calcium phosphate) were chosen to prepare 27 formulations. Micromeritic properties of formulations were studied, and tablets were prepared by wet granulation. Absence of picking, sticking or capping, recording of sufficient hardness, acceptable friability and tablet ejection force indicated formulation success. The resulting formulation prepared using Avicel PH 101 and 1 % Aerosil 200 was submitted to further investigation in order to choose the most suitable compression conditions using a 33 full factorial design. Variables included compression force, tableting rate and magnesium stearate (lubricant) concentration. The formulation prepared at compression force of 25 kN, using 2 % magnesium stearate, at a production rate of 30 tablets/ minute, was found to be the most appropriate scale up candidate.

Preparation of Orally Disintegrating Tablets Containing Powdered Tea Leaves with Enriched Levels of Bioactive Compounds by Means of Microwave Irradiation Technique.

In the present study, a microwave treatment process has been applied to prepare orally disintegrating tablets (ODTs) containing powdered tea leaves with enriched levels of the anti-inflammatory compounds such as chafuroside A (CFA) and chafuroside B (CFB). The use of distilled water as the adsorbed and granulation solvents in this preparation process afforded tablets with a long disintegration time (more than 120 s). The CFA and CFB contents of these tablets did not also change after 4 min of microwave irradiation due to the tablet temperature, which only increased to 100°C. In contrast, the tablet temperature increased up to 140°C after 3 min of microwave irradiation when a 1.68 M Na2HPO4 solution instead of distilled water. Notably, the disintegration time of these tablets was considerably improved (less than 20 s) compared with the microwave-untreated tablets, and there were 7- and 11-fold increases in their CFA and CFB contents. In addition, the operational conditions for the preparation of the tablets were optimized by face-centered composite design based on the following criteria: tablet hardness greater than 13 N, disintegration time less than 30 s and friability less than 0.5%. The requirements translated into X1 (the amount of granulation solvent), X2 (tableting pressure) and X3 (content of the powdered tea leaves) values of 45%, 0.43 kN and 32%, respectively, and the ODTs containing powdered tea leaves prepared under these optimized conditions were found to show excellent tablet properties and contain enriched levels of CFA and CFB.

Blend uniformity evaluation during continuous mixing in a twin screw granulator by in-line NIR using a moving F-test.

This study focuses on the twin screw granulator of a continuous from-powder-to-tablet production line. Whereas powder dosing into the granulation unit is possible from a container of preblended material, a truly continuous process uses several feeders (each one dosing an individual ingredient) and relies on a continuous blending step prior to granulation. The aim of the current study was to investigate the in-line blending capacity of this twin screw granulator, equipped with conveying elements only. The feasibility of in-line NIR (SentroPAT, Sentronic GmbH, Dresden, Germany) spectroscopy for evaluating the blend uniformity of powders after the granulator was tested. Anhydrous theophylline was used as a tracer molecule and was blended with lactose monohydrate. Theophylline and lactose were both fed from a different feeder into the twin screw granulator barrel. Both homogeneous mixtures and mixing experiments with induced errors were investigated. The in-line spectroscopic analyses showed that the twin screw granulator is a useful tool for in-line blending in different conditions. The blend homogeneity was evaluated by means of a novel statistical method being the moving F-test method in which the variance between two blocks of collected NIR spectra is evaluated. The α- and ß-error of the moving F-test are controlled by using the appropriate block size of spectra. The moving F-test method showed to be an appropriate calibration and maintenance free method for blend homogeneity evaluation during continuous mixing.