Tablet Weight Variation Research Articles

The effect of material properties and process parameters on die filling at varying throughputs: A PLS-model-based analysis

When tablets are manufactured on a rotary tablet press and the throughput is increased, it leads to changes in powder dynamics during die filling due to formulation characteristics and changing powder flow in the feed frame. This may result, a.o. in increased tablet weight variability, poorer content uniformity, capping and lamination. This research focuses on explaining the die filling performance depending on material properties and process settings, including throughput for small and large tablets. It was concluded that throughput had a negative impact on die filling variability, which is related to reduced residence time and lower fill fraction of the feed frame and dies. Furthermore, the die filling mechanism was inherently different for large tablets in comparison to small tablets. Higher die filling consistency was observed for dense, less porous, less compressible and better flowing powders. As a result of this work, a model was developed to predict the impact of formulation properties and process settings on die filling variability and its dependency on changes in throughput. This model will benefit formulation development at an early stage when active ingredient availability may be challenging as it will avoid the need to conduct experiments at high throughputs.

Continuous direct compression of a commercially batch-manufactured tablet formulation with two different processing lines

The transfer from batch-based to continuous tablet manufacturing increases the quality and efficiency of processes. Nonetheless, as in the development of a batch process, the continuous process design requires optimization studies to ensure a robust process. In this study, processing of a commercially batch-manufactured tablet product was tested with two continuous direct compression lines while keeping the original formulation composition and tablet quality requirements. Tableting runs were conducted with different values of process parameters. Changes in parameter settings were found to cause differences in tablet properties. Most of these quality properties could be controlled and maintained within the set limits effortlessly already at this stage of studies. However, the API content and content uniformity seemed to require more investigation. The observed content uniformity challenges were traced to individual tablets with a high amount of API. This was suspected to be caused by API micro-agglomerates since tablet weight variability did not explain the issue. This could be solved by adding a mill between two blenders in the process line. Overall, this case study produced promising results with both tested manufacturing lines since many tablet properties complied with the test result limits without optimization of process parameter settings.

Modified Release of Acetaminophen from Matrix Tablet Formulations: Influence of Tablet Geometry

Background: Acetaminophen (APAP) or paracetamol is a widely used over-the-counter, analgesic (common conditions treated include headaches, backache, toothache, muscle aches, arthritis, sore throat etc.) and antipyretic drug. It can be administered orally, in the form of a tablet (plain, effervescent, orodispersable, etc.) or liquid, rectally in the form of a suppository or by injection (intravenously or intramuscularly). It is well absorbed orally with a plasma elimination half-life ranging from 1 to 4 h. The modified release oral formulation can prolong its therapeutic effects by maintaining APAP average plasma concentrations. Objective: In the context of this work, two APAP formulation tablets with different geometries were produced from standard pharmaceutical excipients to investigate the role of altered tablet geometry in modified oral drug delivery. Methods: APAP tablets were prepared by direct compression, using hydroxypropyl methylcellulose (HPMC K15M), polyvinylpyrrolidone (PVP, MW: 55,000) and magnesium stearate, as ingredients. The release profiles were probed in aqueous dissolution media (pH 1.2 and 6.8) to simulate the conditions in the gastrointestinal tract in a United States Pharmacopeia (USP) dissolution paddle apparatus II and analyzed using an ultraviolet (UV) spectrophotometer (λmax = 244 nm). Results: The results indicated that the tablets were within the acceptable range of all evaluation parameters (tablet dimensions, drug content, weight variation, and breaking force) as defined by the international standards stated in the US Pharmacopoeia. The dissolution results showed that the APAP’s release profile was controlled by the tablets’ different geometries and, specifically the surface area (SA) and the surface area/volume (SA/V) ratio of the different tablets. The tablets with smaller SA/V ratios and SA showed slower drug release, indicative of a modified release motif. Conclusion: Altered tablet geometry plays an important role in APAP-modified oral drug delivery.

In vitro and In vivo Assessment of the Effect of Okra Gum Solid Dispersion in Atorvastatin Solubility

Background: Atorvastatin is BCS class II drug; it is lipid-lowering medication. Okra gum (OKG), from the pods of Abelmoschus esculentus, is natural product contain polymers having advantages over synthetic ones as it is safe, chemically inert, nonirritant, biodegradable, and does not require toxicological studies. Aim: This study aimed to assess the effect of okra gum solid dispersion in atorvastatin solubility. Method: The gum was extracted by hot water extraction and the dry extract was evaluated for percentage practical yield, flow properties, pH values and FTIR spectroscopy. Then solid dispersions with different drug to polymer ratios were prepared from OKG, and hydroxy propyl methyl cellulose (HPMC) by solvent evaporation method. Saturation solubility was tested for the solid dispersions prepared, the physical mixtures and atorvastatin. Tablets were prepared from solid dispersions with the highest saturation solubility, then tablets were tested and evaluated. Finally, in vivo test was done using Swiss albino mice and data were analyzed using one way Anova test followed by T test. Results: The content percent of atorvastatin in the solid dispersion prepared were 99,9- 100.1%, the tablets showed satisfactory physicochemical properties as 1.29% RSD in tablet weight variation, 24 min disintegration time, 5.24±0.457 Hardness and OKGSD tablets showed sustained release manner and 87% of drug released in 6 hrs. Lipid profile results showed significant decrease in total cholesterol level with marked decrease in LDL when using OKGSD tablets. Conclusion: It was concluded that OKG is promising excipient that can be used in dosage forms formulation to enhance solubility of low soluble drugs.

Preparation and in vitro evaluation of donepezil hydrochloride orodispersible tablets

Objective: The present study was aimed to prepare and evaluate Donepezil HCl Orodispersible tablets (DO-ODTs) using natural and synthetic superdisintegrants to increase patient compliance. Methods: Direct compression was adapted using crospovidone, croscarmellose sodium as synthetic and mucilage isolated from fruits of Abelmoschus esculentus as natural superdisintegrants at different concentrations along with microcrystalline cellulose and aerosil. The powder mixture were subjected for pre and post compression evaluation including FTIR spectroscopy, micromeritic properties, tablet weight variation, hardness, friability, drug content, wetting time, dispersion time, water absorption ration, disintegration time and in vitro drug release. Results: The low SD indicate the drug content was uniform, FTIR suggest no interaction between the drug and the excipients used. The DO-ODTs prepared with croscarmellose at higher concentration shows better in vitro drug release and relative properties than the DO-ODTs prepared with crospovidone and Abelmoschus esculentus. Conclusion: The results of this work reveals that DO-ODTs shows water absorption, dispersion, rapid disintegration time, fast drug release and good hardness, further conclude that DO-ODTs can be efficiently and successfully formulated by direct compression method.

Solubility Enhancement of Atorvastatin Tablets by Solid Dispersions Using Fenugreek Seed Mucilage

Fenugreek seed mucilage (FSM) is isolated from the seeds of Trigonella Foenum-graecum, commonly known as Fenugreek, which is herbaceous plant. Fenugreek seeds contain high percentage of mucilage, which does not dissolve in water, but swell up and become slick when exposed to fluids. Atorvastatin is one of the HMG-CoA reductase inhibitors (statins), which are lipid-lowering medications used in the primary and secondary prevention of coronary heart disease. Atorvastatin is poorly absorbed orally, its oral bioavailability is very low (about14%) because it is very slightly soluble in distilled water and pH 7.4 phosphate buffer, which would limit its clinical application. The objective of this study is to enhance atorvastatin solubility in order to increase its bioavailability by the formulation of solid dispersion using fenugreek seed mucilage. Mucilage was extracted from the seed and evaluated for flow properties, pH value, FTIR spectroscopy and percentage practical yield. Then solid dispersions with different drug to polymer ratios were prepared from fenugreek mucilage and hydroxy propyl methyl cellulose (HPMC), after that saturation solubility was tested for fenugreek seed mucilage solid dispersion (FSMSD), hydroxxy propyle methyl cellulose solid dispersion (HPMCSD) and pure drug. Tablets were prepared from solid dispersion with the highest saturation solubility, then tablets were tested and evaluated. The tablets showed satisfactory physicochemical properties as 1.77%RSD in tablet weight variation, 1 min disintegration time, 5.24±0.457 Hardness and 89% drug release in 45 min. it is concluded that FSM is a promising excipient that can be used in dosage forms formulation to enhance solubility of low soluble drugs.

Enhancing the Dissolution of Oral Dasatinib Tablets Using Zein–Hydroxypropyl Methylcellulose Solid Dispersions

Zein has been used in several pharmaceutical applications because of its unique composition. It is an amphiphilic molecule that is biodegradable, biocompatible, and has adhesive, matrix-forming, and film-coating properties, making it a promising pharmaceutical excipient. Zein-based formulations have been investigated in tablet-coating, nanoparticulate delivery systems, and controlled-release formulations. However, to date, very few studies have been performed on the inclusion of zein in solid dispersion formulations to enhance drug dissolution. This study aimed to improve the dissolution of the weakly basic and poorly soluble oral dasatinib (used as a model) using zein–hydroxypropyl methylcellulose (HPMC) solid dispersion to achieve rapid disintegration and dissolution in the gastric pH. Using the spray-drying technique, four solid dispersions were prepared with different zein, HPMC, and dasatinib ratios. Subsequently, five different tablets were directly compressed using the previously prepared solid dispersions along with basic excipients. Various in vitro characterization analyses were performed to predict their behavior in vivo. Particle size measurement, tablet weight variation and content assay, disintegration, and dissolution studies were also performed. The results indicated that zein solid dispersion improved the disintegration and dissolution of dasatinib in the gastric media by reducing the drug particle size and the formation of the dasatinib amorphous state. Moreover, the tablets exhibited desirable properties in terms of high drug content, friability, and tensile strength. In conclusion, tablets comprising zein–HPMC solid dispersion showed improved properties; however, including a higher ratio of zein in the solid dispersion adversely affected the disintegration and release properties of formulations.

Improving the Manufacturability of Cohesive and Poorly Compactable API for Direct Compression of Mini-tablets at High Drug Loading via Particle Engineering.

To utilize a particle engineering strategy to improve the manufacturability of a cohesive and poorly compactable API at high drug loading for direct compression of mini-tablets. A high-shear mixer was used for wet milling during the API manufacturing process to obtain target particle size distributions. The targeted particles were characterized and formulated into blends by mixing with excipients. The formulated blends were compressed directly into mini-tablets using a compaction simulator. The tablet hardness, weight variation, and friability of the mini-tablets were characterized and compared with mini-tablets prepared with hammer milled APIs. Compared to the hammer milled APIs, the wet milled APIs, had smoother surface, narrower particle size distributions and demonstrated a better flow properties. Moreover, the mini-tablets produced with the wet milled APIs exhibited better weight uniformity, robust tablet mechanical strength and ultimately better friability. In addition, unlike the hammer milled process, the wet milling process is controllable and easy to scale up. This study successfully implemented API particle engineering through a high shear wet milling process to produce particles suitable for robust drug product manufacturing.

Parameter optimization in a continuous direct compression process of commercially batch-produced bisoprolol tablets

Continuous tablet manufacturing is a competitive option to replace the traditional batch manufacturing approach. The aim of this study was to evaluate technology transfer from batch-based direct compression of a commercial tablet formulation to continuous direct compression without changes to the composition of the formulation. Some powder studies were conducted with the raw materials and multi-tip punches were utilized in the tableting studies. To lower the high level of tablet weight variability that was evident during preliminary tests, a process parameter optimization was performed using an experimental design with different rpm values of force feeder and mixer impeller. By selecting the most appropriate settings of these parameters for the studied product, the weights of the tablets could be controlled adequately to meet the specification criteria. The functionality of the best-performing parameter settings was investigated with a three-hour-long tableting run. The tablets were evaluated with the same quality criteria as the commercial batch-produced tablets, and they passed all the tests performed in this study. Despite the challenging material properties according to the flowability tests, production of tablets with the desired quality was achieved using the original composition with continuous direct compression.

Simultaneous modeling prediction of three key quality attributes of tablets by powder physical properties

Tensile strength (TS), solid fraction (SF), and tablet weight variability (TWV) are all key quality factors to be considered during the tablet manufacturing process. For predicting them, a novel powder texture measurement methodology was proposed to study the texture attributes of 32 types of powders, and 10 types of unknown powders were used to validate the model. Principal component analysis (PCA) was used to classify the powders. Standard least-squares models were constructed to predict the TS and SF of tablets using texture properties as independent variables, with model R2 values of 0.9188 and 0.8672, respectively. Moreover, due to the advantages of decision trees in classification performance and computation time, multi-node decision trees were constructed, and the approximate range of the TS and SF can be quickly predicted by using only 2-4 key texture attributes. Partial least squares-discriminant method (PLS-DA) algorithm was used to determine whether TWV was qualified by using texture and other physical attributes of powders. In conclusion, the constructed models predicted TS, SF, and TWV well and provide an effective reference for facilitating the development of tablet formulation for direct compression (DC).

INFLUENCE OF PARTIALLY AND FULLY PREGELATINIZED STARCH ON THE PHYSICAL AND SUSTAINED-RELEASE PROPERTIES OF HPMC-BASED KETOPROFEN ORAL MATRICES

Objective: This study aims to investigate the effect of two types of pregelatinized starch on the physical performance of HPMC matrices containing Ketoprofen as a model drug. Methods: The design of the experiment was inspired by the monothetic analysis, in which testing factors or causes is done one factor or cause at a time, to achieve system improvements. Tablets were prepared by direct compression. The impact of the type of modified starch on the tablet's physicochemical properties was studied by testing for weight variation, friability, hardness, and drug release properties. PCP dissolution software was used to investigate the kinetics of drug release from matrix tablet formulation. Results: The impact of the type of modified starch on tablet physicochemical attributes revealed that the weight variation of tablets was affected by the amount of modified starch used and that the combination of 64.7% partially pregelatinized starch (StarchÒ 1500) with 9.5% HPMC (F8) was found to be the better in terms of weight variation (%RSD= 1.73%) when compared with those containing fully pregelatinized starch (LYCATABÒ). All formulation runs have friability that complies with pharmacopeial limits of less than 1% loss upon test conduction except for (F1). Formulations containing LYCATABÒ showed better friability than those containing StarchÒ 1500, and similar results were observed in tablet hardness as well, in which the formulation containing the highest LYCATABÒconcentration showed a significant increase in mechanical strength (P = 0.0004) than those containing the highest concentration of StarchÒ 1500. Finally, all formulations containing LYCATABÒexhibited sustained-release behavior, less than 60% of the drug was released from matrices over 14 h, and it is believed that the drug is transported via Fickian diffusion and followed either Higuchi or Peppas model (n>0.5), while all formulations containing StarchÒ 1500 released ~90% of the drug around 2 h, this might probably be due to the high disintegration effect of the partially pregelatinized starch, which is lost upon full pregelatinization. Conclusion: Tablet weight variation, hardness, friability, and T50% were found to be influenced by both the type and concentration of modified starch used. While drug release characteristics were greatly affected by the type of modified starch used. For sustain-release formulations, only fully pregelatinized starch is thought to be suitable.

A Novel Preparation Method for Effervescent Tablets of Xianganfang Containing Fresh Juice using a Semi-Solid Extrusion 3D Printer with Three Cartridge Holders.

This study aimed to prepare effervescent tablets of traditional Chinese medicine Xianganfang with fresh juice using a semi-solid 3D printer with three cartridge holders to seperate acid and alkali source by drug paste through model design to avoid sticking impact and premature effervescence during the tableting in the conventional preparation process. The powder of Xianganfang including fresh juice of Phyllanthus emblica and licorice extract was obtained by vacuum freeze-drying with 50% mannitol as cryoprotectant. Then, the formulation of 3D-printed effervescent tablets was investigated. Further 5% HPMC hydroalcoholic gel was mixed with sodium bicarbonate and freeze-dried Xianganfang powder to prepare alkali source and drug paste respectively while 30% PVP ethanol solution was mixed with tartaric acid to prepare acid source paste; these three pastes had good printability. The pastes of drug, acid, and alkali were loaded into three syringe cartridges separately and numbered as "3," "5," and "7," according to cartridge holders of the 3D printer, and printed in the order of "537,353,735" for separating acid and alkali by drug to avoid premature effervescence. And the basic printing parameters were optimized. The tablets were evaluated by the appearance, tablet weight variation, hardness, disintegration time, friability, pH, and stability. The physicochemical properties all conformed to the Chinese Pharmacopoeia 2020 edition. The content of the active ingredient gallic acid was 0.769 ± 0.019mg/g. This study provided a new method to prepare effervescent tablets of traditional Chinese medicine with fresh juice using 3D printing technology.

Prediction of tablet weight variability from bulk flow properties by sparse modeling

Die filling is a critical step in the pharmaceutical tableting process as it determines the uniformity in tablet weight, which affects the drug content uniformity and appearance of tablets. With the progress in powder flow characterization, a wide variety of bulk flow properties can be obtained, and several studies have been conducted to predict tablet weight variability (TWV) from bulk flow properties by applying multivariate analysis; however, there is still room for improvement in the selection of properties for predictive model construction. In this study, least absolute shrinkage and selection operator regression, a type of sparse modeling, was applied to select the critical flow properties from various ones, and TWV was predicted. To obtain blends with a wide range of properties, 27 powder blends were prepared by changing the active pharmaceutical ingredients (APIs), API loading in the formulation, and the grade of the lubricant. Bulk flow properties were evaluated, and a good prediction model was obtained by selecting five out of 14 bulk flow properties. The constructed model also predicted TWV well in the validation dataset. The applied approach is useful for constructing a simple model to better understand the phenomenon (die filling in this case), and the constructed model can be expanded further by including blends manufactured by dry or wet granulation.

Design and invitro evaluation of gastro retentive oral matrix tablet formulations of ketorolac tromethamine

Ketorolac Tromethamine floating tablets were prepared by using combination of hydrophilic polymers such as Hydroxy Propyl Methyl Cellulose 4000 cps grade and 100000 cps grade. Eight set of formulations were prepared by gradual increasing and decreasing concentrations of above two polymers. The floating pattern was found to be instant for all the formulations and best controlled release profile was achieved for few set of formulations. The drug content, tablet weight, friability and weight variation were found to be within the limits. Validated UV spectrophotometric method was developed and standard linear regression was used to determine the concentration of released drug during the course of dissolution. The release studies were subjected to zero order, first order, higuchi and ritger-peppas kinetics and the parameters for controlled release were calculated.

Study of weight variation and dissolution of Edoxaban split tablets in pharmacy practice

Study of weight variation and dissolution of Edoxaban split tablets in pharmacy practice

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.

Process Model Approach to Predict Tablet Weight Variability for Direct Compression Formulations at Pilot and Production Scale

Optimizing processing conditions to achieve a critical quality attribute (CQA) is an integral part of pharmaceutical quality by design (QbD). It identifies combinations of material and processing parameters ensuring that processing conditions achieve a targeted CQA. Optimum processing conditions are formulation and equipment-dependent. Therefore, it is challenging to translate a process design between formulations, pilot-scale and production-scale equipment. In this study, an empirical model was developed to determine optimum processing conditions for direct compression formulations with varying flow properties, across pilot- and production-scale tablet presses. The CQA of interest was tablet weight variability, expressed as percentage relative standard deviation. An experimental design was executed for three model placebo blends with varying flow properties. These blends were compacted on one pilot-scale and two production-scale presses. The process model developed enabled the optimization of processing parameters for each formulation, on each press, with respect to a target tablet weight variability of <1%RSD. The model developed was successfully validated using data for additional placebo and active formulations. Validation formulations were benchmarked to formulations used for model development, employing permeability index values to indicate blend flow.

QbD approach to downstream processing of spray-dried amorphous solid dispersions – a case study

In the current study, we demonstrate a structured approach to downstream process development for spray dried amorphous solid dispersions. Direct compression is generally not suitable due to typically poor flow of spray dried powders in tablets. Roller compaction (RC) is therefore the method of choice to enable spray dried dispersion downstream processing. Here, a structured experimental design of RC process parameters was used. The objective was to identify process conditions that lead to improved powder flow without compromising tablet robustness. Ten blends were compacted using different process parameters, and subsequently compressed into tablets. The impact of process parameters on granules and tablet properties was analyzed. We demonstrate that compaction force, gap and mesh aperture have major impact on RC outcomes. A combination of large gap and low force was identified as optimum combination of RC process parameters leading to powder flow improvement that could guarantee low tablet weight variation and at the same prevented loss of blend compressibility.

FORMULATION AND EVALUATION OF ORODISPERSIBLE TABLETS OF DONEPEZIL HYDROCHLORIDE

Objective: The present study was aimed to develop the formulation and in vitro evaluation of Orodispersible tablets by wet granulation method using Donepezil HCl as a model drug to enhance patient compliance.&#x0D; Methods: In the wet granulation method, a mixture of microcrystalline cellulose and hydroxypropyl methylcellulose were used along with superdisintegrants, i.e., croscarmellose sodium and crospovidone. The prepared granules were subjected to both pre and post-compression evaluation parameters including; FTIR spectroscopy, micromeritics properties, tablet weight variation, hardness, friability, drug content, disintegration time and in vitro drug release.&#x0D; Results: FTIR studies indicated that there was nointeraction between the drug and the excipients used. The formulation containing high concentration of crospovidone and mixture as the best formulation F2 based on in vitro drug release characteristics of tablet formulation.&#x0D; Conclusion: The results of this work suggested that orodispersible tablets of Donepezil hydrochloride with rapid disintegration time, fast drug release and good hardness can be efficiently and successfully formulated by wet granulation method.

Image-based characterization of powder flow to predict the success of pharmaceutical minitablet manufacturing.

Powder flowability plays an important role in die filling during tablet manufacturing. The present study introduces a novel small-scale measuring technique for powder flow. Based on image analysis, the flow was defined depending on the variation of luminous intensity and the movement of powder inside the measurement cuvette. Using quantities around 100mg it was possible to characterize a wide range of common pharmaceutical powders, especially in distinguishing subtle differences in flow caused by minor changes in samples characteristics. The method was compared with powder rheometry, which is widely used in the pharmaceutical literature, and showed a significant improvement in predicting the success of pharmaceutical minitablet manufacture (d=5mm). Tablet weight variation (RSD) was defined as the most efficient way to assess relevant powder flow behaviour in tablet production when using the novel device. The proposed method was distinguished from others by its ability to classify different grades of microcrystalline cellulose in the die-filling process. Subsequently, eight common pharmaceutical powders, both excipients and APIs, were properly ranked as a function of flowability based on their physical properties. The method showed a high repeatability, with a relative standard deviation not more than 10%.