Direct Tablet Research Articles

An Agile and Accurate Approach for N-Nitrosamines Detection and Quantification in Medicines by DART-MS.

N-nitrosamines (NAs) are prevalent mutagenic impurities in various consumer products. Their discovery in valsartan-containing medicines in 2018 prompted global regulatory agencies to set guidelines on their presence and permissible levels in pharmaceuticals. In order to determine the NAs content in medicines, efficient and sensitive analytical methods have been developed based on mass spectrometry techniques. Direct analysis in real time-mass spectrometry (DART-MS) has emerged as a prominent ambient ionization technique for pharmaceutical analysis due to its high-throughput capability, simplicity, and minimal sample preparation requirements. Thus, in this study DART-MS was evaluated for the screening and quantification of NAs in medicines. DART-MS analyses were conducted in positive ion mode, for both direct tablet analysis and solution analysis. The analytical performance was evaluated regarding linearity, precision, accuracy, limits of detection, and quantification. The DART-MS proved to be suitable for the determination of NAs in medicines, whether through direct tablet analysis or solution analysis. The analytical performance demonstrated linearity in the range from 1.00 to 200.00 ng mL-1, limits of quantification about 1.00 ng mL-1, precision and accuracy lower than 15%, and no significant matrix effect for six drug-related NAs. In conclusion, the DART-MS technique demonstrated to be an alternative method to determine NAs in medicines, aligning with the principles of green chemistry.

Improved flowability, mechanical and dissolution properties of metronidazole obtained from crystallo coagglomeration technique for direct tableting

Improved flowability, mechanical and dissolution properties of metronidazole obtained from crystallo coagglomeration technique for direct tableting

Precise particle size control during spherical agglomeration of benzoic acid by modification of the bridging liquid phase using TWEEN 20

The interest in spherical agglomeration processes in the pharmaceutical industry is rising due to the possibility of direct tableting of Active Pharmaceutical Ingredients and enhancements in bulk powder properties translating into improved powder processability. While agglomerating needle-shaped particles into spheres offers numerous advantages, such as improved flowability, filterability, and particle density, achieving precise control over the particle size and shape of the agglomerates remains a significant challenge. More specifically, the obtained agglomerate size rarely reaches values below 500 μm, which is the desired size range for pharmaceutical applications. To address this challenge, the current research investigates the effectiveness of incorporating surfactants at varying concentrations as a means to control the particle size and shape of the resulting agglomerates. Reversed addition antisolvent crystallization experiments were performed in ethanol/water using benzoic acid as a model compound, followed by the addition of a bridging liquid (toluene), which wets and bridges the single crystals into agglomerates. To modify the interfacial tension between the two immiscible liquid phases, different concentrations of the tween 20 surfactant were used, leading to a range of interfacial tensions spanning from 0.50 to 16.38 × 10−3 N/m. Both crystallization and agglomeration processes were monitored in situ using in-process microscopy tools. The experimental results demonstrated that by adjusting the surfactant concentration and thus the corresponding interfacial tension of the bridging liquid, highly tunable agglomerate sizes were achieved, ranging from 160 μm to 4412 μm. A higher surfactant concentration is correlated with smaller agglomerates and is key to control the final agglomerate size. However, it should be noted that the introduction of surfactants in the spherical agglomeration process negatively impacted the agglomerate's strength. Nonetheless, this method remains a promising and innovative technique for controlling the final particle size during spherical agglomeration.

Evaluation of Co-Processed Excipients for Fast Disintegration of Aspirin Tablets Prepared by Direct Compression

Background: Co-processed excipients are popular for direct tablet compression and give added economic value to product formulation. Specific benefits of co-processed excipients include improved flow, compressibility, disintegrating effect, and masking undesirable properties of individual excipients.
 Objective: The aim of this study is to co-process physically modified (pregelatinized) Musa sapientum starch with lactose by fusion and evaluate the effect of the co-processed excipients on the disintegration properties of Aspirin tablet.
 Methods: Co-processed excipients were prepared from pregelatinized Musa sapientium starch and lactose by fusion in ratios of 1:1, 1:2 and 2:1 (BL1, BL2, and BL3 respectively) and evaluated for particle size, pH, moisture content, flow and swelling properties. Aspirin tablets were formulated using the excipients at ratio 5% W/W by direct compression. (FM1, FM2, FM3 respectively). Sodium starch glycolate (FSG) tablet was also prepared as the standard and the formulations were assessed for hardness, friability and disintegration time. Data were analyzed using ANOVA.
 Results: The co-processed excipients possessed excellent flow having a Carr’s index between 18.39-20.78 and Hausner’s ratio ≤ 1.25.BL1 had the highest swelling profile while BL3 had the lowest. Formulation FM1 and FM2 had the highest tensile strength of (0.16 N/cm2). Disintegration time of FM3 (4.28 min) was comparable to that of FSG (4.15 min).
 Conclusion: Co-processing pregelatinized Musa sapientium starch and lactose by fusion influenced tablet disintegration and has potential to be used in manufacture of fast dissolving tablet formulations.

Effect of process parameters in high shear granulation on characteristics of a novel co-processed mesoporous silica material

In this study, insights into the development and optimization of a co-processed excipient based on mesoporous silica are presented. The main advantage of such a material is that it is appropriate for direct tablet compression and has a sufficiently large specific surface area to be suitable for potential subsequent drug loading and formulation of (amorphous) solid dispersions. Our aim was to use a Design of Experiments approach to investigate which process parameters in high shear granulation affect the characteristics of such a co-processed material. The parameters included were the amount of binder (isomalt), the amount of water (granulation liquid), the water addition rate and the speed of the impeller. The responses evaluated and modelled were particle size and its distribution, specific surface area, bulk density, flowability, compressibility and compactibility. The models obtained showed good quality in terms of goodness of fit and predictive power. Active effects were identified for all responses, giving a thorough insight into factors affecting the material characteristics. Optimization experiments resulted in products with the desired characteristics (high specific surface area, large particle size, good flow and compression properties) and confirmed the validity of the generated models.

Direct Tableting on a Continuous Manufacturing Line—Impact of Mixing Parameters, Material Densities, and Drug Load on Subsequent Process Parameters and Tablet Quality

The continuous manufacturing (CM) of solid oral dosage forms has received increased attention in recent years and has become a leading technology in the pharmaceutical industry. A model has been developed based on process data from two design of experiments (DoEs), where the impact of the mixer process parameters, throughput (THR), hold up mass (HUM), impeller speed (IMP), and the input raw material bulk density (BDi), on the continuous process and the resulting drug product has been investigated. These statistical models revealed equations, describing process parameter interactions for optimization purposes. For the exit valve opening width (EV) at the bottom of the continuous mixer (CMT), the combination of high throughput (30 kg/h) and low impeller speed (300 rpm) resulted in optimal process conditions. Apparent bulk density of the blend (BD) within the process, fill depth (FD), and tensile strength (TS) were mainly impacted by input bulk density (BDi) of the tableting mixture, emphasizing the role of material attributes on the continuous manufacturing process. The apparent bulk density itself was, other than from the input bulk density, equally dependent from THR and IMP in opposite deflections. However, process parameters (THR and IMP) revealed a minor impact on the apparent BD compared to the input bulk density. FD was impacted mainly by THR ahead of IMP and the TS by IMP and THR to a similar extend, in opposite deflections. A simplified linear model to estimate the input bulk density revealed satisfactory prediction quality when included in the derived statistical model equations.

Design of Xylitol Granules for Direct Tableting by Using Cellulose Nanofiber

Design of Xylitol Granules for Direct Tableting by Using Cellulose Nanofiber

EVALUATION OF ORO-DISPERSIBLE TABLETS (ARTEMETHER- LUMEFANTRINE AND AMOXICILLIN TRIHYDRATE) USED FOR SOME COMMON CHILDHOOD DISEASES (MALARIA AND PHEUMONIA)

Background: Generic substitution of a brand of medicine for others, with the hope that they have the same therapeutic effect is difficult for health care providers and consumers.
 Aim: This study was able to evaluate the authenticity of label claim of eight samples of artemether-lumefantrine and two samples of amoxicillin trihydrate tablets available at Ogige market Nsukka and Ogbete main market, Enugu.
 Method: The following tests were carried out; hardness, friability, modified disintegration time, wetting time, water absorption ratio and weight uniformity. The compliance of each sample to the United States Pharmacopoeia (USP) requirements were recorded.
 Results: The friability test showed that all the tablets passed the test with less than 1% friability loss. The mean hardness ranged from 1.65±0.47 to 5.35±0.67 kgf for artemether-lumefantrine tablets, while that of amoxicillin trihydrate tablets ranged from 4.00±0.93 to 6.10±0.91 kgf respectively. The tablet diameter and mean thickness of artemether-lumefantrine tablets ranged from 9.00±1.53 to 11.00±1.0 mm and 2.00±1.15 to 4.00±1.53 mm respectively, while that of amoxicillin trihydrate ranged from 8.00± 0.9 to 10.00±1.0mm and 3.00±2.08 to 4.00±1.53mm respectively. The disintegration time of artemether-lumefantrine tablets ranged from 1.50±0.1 to 3.52±0.01 min and 2.06±0.02 to 3.30±0.03 min for amoxicillin trihydrate respectively. The study discovered that several generic brands of artemether-lumefantrine and amoxicillin trihydrate tablets in Nigeria could be sub-standard products.
 
 Peer Review History: 
 Received: 28 June 2022; Revised: 1 August; Accepted: 5 September, Available online: 15 September 2022
 Academic Editor: Prof. Dr. Gorkem Dulger, Duzce University, Turkey, gorkemdulger@yandex.com
 UJPR follows the most transparent and toughest ‘Advanced OPEN peer review’ system. The identity of the authors and, reviewers will be known to each other. This transparent process will help to eradicate any possible malicious/purposeful interference by any person (publishing staff, reviewer, editor, author, etc) during peer review. As a result of this unique system, all reviewers will get their due recognition and respect, once their names are published in the papers. We expect that, by publishing peer review reports with published papers, will be helpful to many authors for drafting their article according to the specifications. Auhors will remove any error of their article and they will improve their article(s) according to the previous reports displayed with published article(s). The main purpose of it is ‘to improve the quality of a candidate manuscript’. Our reviewers check the ‘strength and weakness of a manuscript honestly’. There will increase in the perfection, and transparency. 
 Received file: Reviewer's Comments:
 Average Peer review marks at initial stage: 5.5/10
 Average Peer review marks at publication stage: 7.0/10
 Reviewers:
 Dr. Mohammad Bayan, Faculty of Pharmacy, Philadelphia University, P.O. Box: 1 Philadelphia University 19392 Jordan, mbayan01@qub.ac
 Dr. Sally A. El-Zahaby, Pharos University in Alexandria, Egypt, sally.elzahaby@yahoo.com
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Development of Nafamostat Mesylate Immediate-Release Tablet by Drug Repositioning Using Quality-by-Design Approach.

We aimed to develop nafamostat mesylate immediate-release tablets for the treatment of COVID-19 through drug repositioning studies of nafamostat mesylate injection. Nafamostat mesylate is a serine protease inhibitor known to inhibit the activity of the transmembrane protease, serine 2 enzyme that affects the penetration of the COVID-19 virus, thereby preventing the binding of the angiotensin-converting enzyme 2 receptor in vivo and the spike protein of the COVID-19 virus. The formulation was selected through a stability study after manufacturing by a wet granulation process and a direct tableting process to develop a stable nafamostat mesylate immediate-release tablet. Formulation issues for the selected processes were addressed using the design of experiments and quality-by-design approaches. The dissolution rate of the developed tablet was confirmed to be >90% within 30 min in the four major dissolutions, except in the pH 6.8 dissolution medium. Additionally, an in vivo pharmacokinetic study was performed in monkeys, and the pharmacokinetic profiles of nafamostat injections, oral solutions, and tablets were compared. The half-life during oral administration was confirmed to be significantly longer than the reported literature value of 8 min, and the bioavailability of the tablet was approximately 25% higher than that of the oral solution.

Predictive evaluation of multicomponent direct compress model tablets by integrating sphere UV-Vis spectroscopy and chemometrics.

Control of the pharmaceutical manufacturing process and active pharmaceutical ingredients (API) is essential to product formulation and bioavailability. The aim of this study is to predict tablet surface API concentration by chemometrics using integrating sphere UV-Vis spectroscopy, a non-destructive and contact-free measurement method. Riboflavin, pyridoxine hydrochloride, dicalcium phosphate anhydrate, and magnesium stearate were mixed and ground with a mortar and pestle, and 100mg samples were subjected to direct compression at a compaction pressure of 6MPa at 7mm diameter. The flat surface tablets were then analyzed by integrating sphere UV-Vis spectrometry. Standard normal variate (SNV) normalization and principal component analysis were applied to evaluate the measured spectral dataset. The spectral ranges were prepared at 300-800nm and 500-700nm with SNV normalization. Partial least squares (PLS) regression models were constructed to predict the API concentrations based on two previous datasets. The regression vector of constructed PLS regression models for each API was evaluated. API concentration prediction depends on riboflavin absorbance at 550nm and the excipient dicalcium phosphate anhydrate. Integrating sphere UV-Vis spectrometry is a useful tool to process analytical technology.

Effect of Moisture of Pharmaceutical Material MCC Avicel PH102 and Tablet Diameter on the Compression Process and Tablet Strength

Abstract This paper focuses on the effect of moisture of powder material on the process of tablet compression and on tablet mechanical strength. The powder used in the experiments was Avicel PH102 microcrystalline cellulose, as it is the most widely used excipient in direct tablet compression. The compression process is described using the Heckel equation and the strength of the tablets was determined using a Brazilian test. To introduce the reader to the issue, the first part of the paper is devoted to a theoretical introduction. The second part of the work is devoted to the description of experimental equipment and work procedure. The last part of the paper presents the results of the experiment and their evaluation. The reason for this experiment was the assumption that the moisture of the raw material significantly affects the compression process and the mechanical strength of the tablet. A series of experiments demonstrated this effect, which can be seen in the respective graphs.

Design of Erythritol Granules for Direct Tableting by Improving Compressibility

Design of Erythritol Granules for Direct Tableting by Improving Compressibility

Investigation of the Tableting Properties of Modified Dioscorea dumetorum Starch in Direct Compressed Diclofenac Tablet Formulations

Background: Modification of starch enhances their performance and improves properties such as compressibility, visco-stability, texture and dissolution. Objectives: The aim of the study was to investigate the direct compression properties of modified starch of Dioscorea dumetorum in diclofenac tablet formulations. Method: Isolated starch from Dioscorea dumetorum tubers was subject to two forms of modification and the modified products characterized with the native starch for their physicochemical and powder properties. The modified starches (5, 7.5 and 10%w/w) and microcrystalline cellulose (MCC) (10%w/w) were used in the formulation of batches of diclofenac potassium tablets via slugging and direct compression. Flowability of granules from their slugs and tablet parameters from their tablet were evaluated using standard procedures. Drug-excipient interaction studies was carried out using FTIR analysis. Results: The extracted starch was white, while the modified forms were off-white in colour. All the starches were smooth in texture and insoluble in water with swelling capacities ≤ 2.85, hydration capacities ≥ 1.22 and moisture contents ≤ 14.5%. Granules gave Carr’s indices, Hausner’s ratios and angles of repose values ranging from 10.71-18.03%, 1.12-1.22 and 20.16- 28.15°, respectively, indicating good flow. Tablet’s friability ranged from 0.01-0.04% while their hardness values was between 4.20-5.50 kp and disintegration times < 7.0 min. Dissolution profiles of the tablets showed over 70% diclofenac release within 45 min. FTIR studies showed no interaction between diclofenac and formulation excipients. Conclusion: Modified Dioscorea dumetorum starch possesses binding and disintegrating properties comparable with MCC, hence it can be used as an alternative to MCC in direct compression of tablets.

Application of the Kuenz–Leuenberger Equation as a Predictive Model of the Direct Tablet Compression Process

Application of the Kuenz–Leuenberger Equation as a Predictive Model of the Direct Tablet Compression Process

Development and evaluation of a composite dosage form containing desmopressin acetate for buccal administration

Desmopressin acetate (DDAVP) is an oligopeptide indicated for the treatment of primary nocturnal enuresis, for example. The poor oral bioavailability of DDAVP accelerated a shift to alternative routes of administration like nasal and oromucosal, whereby nasal administration results in high fluctuations increasing the risk of undesirable side effects. Aim of the study was to use a new composite dosage form (solid matrix attached to a bilayer mucoadhesive film) to make DDAVP available via oromucosal route, reducing the risk of undesirable side effects through precise dosing. DDAVP was incorporated into a solid matrix in the form of a minitablet, and both direct tableting (AV > 30) and granulation followed by tableting (AV = 17.86) were compared. Minitablets with content uniformity could only be obtained by granulation and loss supplementation (AV = 11.27) with immediate drug release (>80% after 7–8 min) and rapid disintegration (<49 s). Permeation studies were performed with a clinically relevant dose (200 μg) in a time interval of up to one hour, resulting in apparent permeation coefficients of 4.90 × 10−6 cm/s (minitablet) and 2.04 × 10−6 cm/s (composite). Comparable fluctuations showed no inferiority of composite and minitablet regarding dosing accuracy. Thus, a step towards controlled and dose-accurate transmucosal delivery of systemically active DDAVP could be achieved.

Continuous downstream processing of milled electrospun fibers to tablets monitored by near-infrared and Raman spectroscopy

Electrospinning is a technology for manufacture of nano- and micro-sized fibers, which can enhance the dissolution properties of poorly water-soluble drugs. Tableting of electrospun fibers have been demonstrated in several studies, however, continuous manufacturing of tablets have not been realized yet. This research presents the first integrated continuous processing of milled drug-loaded electrospun materials to tablet form supplemented by process analytical tools for monitoring the active pharmaceutical ingredient (API) content. Electrospun fibers of an amorphous solid dispersion (ASD) of itraconazole and poly(vinylpyrrolidone-co-vinyl acetate) were produced using high speed electrospinning and afterwards milled. The milled fibers with an average fiber diameter of 1.6 ± 0.9 µm were continuously fed with a vibratory feeder into a twin-screw blender, which was integrated with a tableting machine to prepare tablets with ~ 10 kN compression force. The blend of fibers and excipients leaving the continuous blender was characterized with a bulk density of 0.43 g/cm3 and proved to be suitable for direct tablet compression. The ASD content, and thus the API content was determined in-line before tableting and at-line after tableting using near-infrared and Raman spectroscopy. The prepared tablets fulfilled the USP <905> content uniformity requirement based on the API content of ten randomly selected tablets. This work highlights that combining the advantages of electrospinning (e.g. less solvent, fast and gentle drying, low energy consumption, and amorphous products with high specific surface area) and the continuous technologies opens a new and effective way in the field of manufacturing of the poorly water-soluble APIs.

A study on the influence of the formulation factors on in vitro release of ketoprofen from sustained release tablets

Objectives. The aim of this study was to investigate the influence of formulation factors on in vitro release of ketoprofen from sustained release inert matrix tablets. Materials and methods. Laboratory scale, Ketoprofen sustained release inert matrix tablets were manufactured using Kollidon® SR as matrix formator, by direct tableting of powder blends. The influence of the formulation factors (X1 – matrix formator excipient and X2 – diluent type) on in vitro release of ketoprofen from sustained release tablets was studied by using a full factorial 23 experimental plan. Outcomes. Pharmacotechnical characterization of manufactured laboratory scale batches was performed and all 12 batches fulfilled European Pharmacopeia requests. In vitro release showed a sustained release profile in all cases. Variance analysis (ANOVA) showed a good correlation between experimental conditions and answers. In vitro release testing was performed in phosphate buffer pH = 7.4. Percentage release was determined spectrophotometrically at 258 nm. A decrease in the rate of in vitro release was registered, up to 4 h and 6 h when lactose DC and mannitol DC were used as diluents, respectively. Isomalt DC has increased the rate of in vitro release up to 6 h. Conclusions. In vitro release data, corresponding to formulation N1 shoed a good fitting with Weitbull, Korshmeyer-Peppas and Higuchi models while in vitro release data corresponding to formulation N8 presented a good fitting with Weitbull and Korsmeyer-Peppas. In case of formulations N1 and N8 a non-Fickian diff usion mechanism seems to be involved in drug release from the matrix tablets.

Evaluation of Lactose-Based Direct Tableting Agents' Compressibility Behavior Using a Compaction Simulator.

A compaction simulator (CS) is a single-punch instrument that records data during the powder compaction process. The aim of the study was to determine the behavior of lactose-based direct tableting agents (DTAs) by CS. The data recorded were used to evaluate the flowability and compressibility of powders. The focus of the study was on comparing the compressibility of StarLac® [alpha lactose monohydrate (85%) and white maize starch (15%)] and FlowLac®100 (spray-dried alpha lactose monohydrate) in order to make tablets containing poorly flowable paracetamol. Two lactose-based DTAs were used. Physical characterization of these powders was done by measuring bulk, tapped, and true densities alongside scanning electron microscopy analysis. Flow properties were then calculated by the angle of repose, Hausner ratio, and Carr's compressibility index. Force, in-die thickness, and punch displacement data produced by the CS were captured during in-die compression. Compressibility was calculated using the Heckel equation. The physical characterization test results showed no significant difference between the two DTAs. Hardness results revealed that tablet formulations containing FlowLac® had higher sensitivity to an increase in compression force in comparison with StarLac®. From the Heckel plots generated by the CS during the compression cycle, yield pressure (Py) values were calculated for FlowLac®100 and StarLac®. The Heckel parameter (Py) for FlowLac®100 and StarLac® was calculated as 87.5 MPa and 85.2 MPa, respectively, during the compaction cycle at 5 kN. These data indicated that both powders are compressible and have brittle behavior. StarLac® is less brittle, which was shown by its lower sensitivity to compression force. Py values obtained from the Heckel equation described the plasticity of particles, which gives distinct information on the compressibility of both DTAs in real time during the compaction cycle.

Development and evaluation of mucoadhesive buccal dosage forms of lidocaine hydrochloride by ex-vivo permeation studies.

Intraoral lidocaine formulations are applied in children and adults for pain relief. The potential risks associated with orally administered lidocaine due to accidental ingestions were highlighted in a warning letter by the US Food and Drug Administration (FDA). This increases the urgency for a need of a child-appropriate dosage forms. For risk minimization, a novel buccal composite dosage form was developed consisting of a lidocaine containing minitablet centered on top of a bilayered mucoadhesive buccal film, so called composite. The preparation included direct tableting of minitablets as well as film-casting technique. Within a comparability study, the permeation of this composite was classified against marketed lidocaine gel, a single-layer film, and a minitablet. These ex-vivo permeation studies under physiologically related conditions in combination with LC-MS/MS quantification enabled the evaluation of permeation in clinically relevant short-term application. The composite showed comparable permeation to marketed gel (104.26±30.15µg/cm2 vs 128.17±12.49µg/cm2 cumulative amount of drug) and a higher permeation compared to film (25.84±6.01µg/cm2). Therefore, a controlled drug application can be assumed by the composite, whereby the risk of inadvertent swallowing as well as uncontrolled absorbed amount of drug substance may be substantially minimized.

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

Real-time monitoring is required for the pharmaceutical manufacturing process to produce high-quality pharmaceutical products. 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. 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. 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. 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.