Formulation Development Of Tablets Research Articles

Relative Bioavailability Assessment of Solid Forms by An Artificial Stomach and Duodenum Apparatus

In this work, the ability of the artificial stomach and duodenum (ASD) model to predict bioavailability in rats was investigated using a poorly soluble model compound, BI-639667. A solution and four suspensions of different solid forms of BI-639667 were tested both in an ASD and rats. Rank order of the bioavailability estimated from an ASD apparatus is consistent with that of in vivo result in rats, i.e., solution > salicylic acid cocrystal > malate salt > maleate salt > monohydrate, which correlates with the ability of the different solid forms to maintain supersaturation with respect to the stable form in aqueous solution. The results support the use of an ASD for characterizing dissolution performance of solid forms to aid their selection for tablet formulation development.

Polymer Tablet Matrix Systems for the Controlled Release of Dry Betula pendula Leaf Extract.

The aim of the study was to develop polymer matrix tablets with modified release of dry Betula pendula leaf extract and to investigate basic parameters influencing the drug release pattern. To fully assess the statistical significance of the influence of the individual factors in the tablet formulation development as well as the combination of them, Tukey's tests and a complete 33 factor analysis of variance (ANOVA) were applied. The following three factors were studied at three levels (low, medium and high): influence of the hydrophobic/hydrophilic polymer ratio Ethylcellulose (EC)/Hydroxypropyl methylcellulose (HPMC) (40/60, 25/75 and 10/90), influence of HPMC molecular weight (500 kDa, 750 kDa and 1150 kDa), and influence of the compression force applied (1 t, 1.5 t and 2 t). The effect of these varied parameters on the drug release parameter t80 was evaluated statistically. Twenty-seven tablet models were formulated, including all possible combinations of the variables. The obtained drug release profiles demonstrated that a 25/75 (EC/HPMC) ratio was the most suitable for prolonging the release process. Increasing the molecular weight of HMPC from 500 kDa to 750-1150 kDa and applying higher compression force significantly influenced the studied t80 values and caused sustained drug release (t80 up to 7.97 h). The combination of the hydrophilic HPMC polymer with the hydrophobic EC can result in the formation of a promising drug-carrying matrix, offering effective control of the drug release process.

Effect of Material Properties and Variability of Mannitol on Tablet Formulation Development.

Using a high level of mannitol as adiluent in oral formulations can potentially result in tablet defects (e.g., chipping, cracking) during compression. This work aims to scrutinize the linkage between the mechanical properties and material attributes of mannitol and also uncover how variations between vendors and lots can lead to significant changes in the compaction performance of tablet formulations containing mannitol. The mechanical properties (Poisson's ratio, fracture energy) and mechanical performance (ejection force, pressure transmission ratio, residual radial die-wall stress, and tensile strength) of mannitol compacts were assessed on a compaction simulator for four lots of mannitol from two different vendors. The variation of material attributes of each lot, including particle size distribution (PSD), crystal form, primary crystal size and morphology, specific surface area (SSA), powder flow, and moisture absorption were investigated. The variability of material attributes in mannitol lots, especially primary crystal size and SSA, can result in significant changes in mechanical properties and mechanical performance such as ejection force and residual radial die-wall stresses, which potentially led to chipping during compression. The study elucidated the linkage between fundamental material attributes and mechanical properties of mannitol, highlighting their impact on tablet defects and compaction performance in compression. A comprehensive understanding of the variability in mannitol properties between vendors and lots is crucial for successful formulation development, particularly when high percentages of mannitol are included as a brittle excipient.

Enabling direct compression tablet formulation of celecoxib by simultaneously eliminating punch sticking, improving manufacturability, and enhancing dissolution through co-processing with a mesoporous carrier

The development of a high quality tablet of Celecoxib (CEL) is challenged by poor dissolution, poor flowability, and high punch sticking propensity of CEL. In this work, we demonstrate a particle engineering approach, by loading a solution of CEL in an organic solvent into a mesoporous carrier to form a coprocessed composite, to enable the development of tablet formulations up to 40% (w/w) of CEL loading with excellent flowability and tabletability, negligible punch sticking propensity, and a 3-fold increase in in vitro dissolution compared to a standard formulation of crystalline CEL. CEL is amorphous in the drug-carrier composite and remained physically stable after 6 months under accelerated stability conditions when the CEL loading in the composite was ≤ 20% (w/w). However, crystallization of CEL to different extents from the composites was observed under the same stability condition when CEL loading was 30–50% (w/w). The success with CEL encourages broader exploration of this particle engineering approach in enabling direct compression tablet formulations for other challenging active pharmaceutical ingredients.

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).

Effect of Hydrophobic Powders on the Tensile Strength of the Tablet

Zoe Chu1,2, Christopher Windows-Yule¹, Ian Gabbott², Gavin Reynolds², Rachael Shinebaum² and Andy Ingram¹1. School of Chemical Engineering, University of Birmingham, Edgbaston, B15 2TT2. Oral Product Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Macclesfield, UKEmail: zhc906@student.bham.ac.ukIntroductionA tablet consists of the active pharmaceutical ingredients (API), and the other components, excipients. A tablet needs to withstand coating, packing and shipping stresses whilst maintaining the dissolution time; therefore, the tensile strength is of great importance. Currently, there is a lack of understanding on why excipients improve the bulk powder properties and the bonding mechanisms of the powder during compression. This makes tablet formulation development an inefficient trial-and-error process that is required for every new API (1). Literature has shown that the surface energy of the powders contributes a significant amount towards the tablet tensile strength. Hydrophobic powders have a lower surface energy (2) and are seen to disrupt this tablet strength (3,4).Experimental Aim and MethodThe aim was to investigate the impact of the hydrophobicity of excipient powders on tabletability of microcrystalline cellulose. This was done by mixing powders of varying hydrophobicity with MCC at varying mass fractions. There was focus on a lower mass fraction (0.02-0.1 m/m) with increasing increments of 0.02 m/m of added additive as well as gaining a global picture (0.2-1 m/m) with increments of 0.2 m/m.ResultsIt was found that at low mass fractions (0.02-0.4 m/m) of additive added the hydrophobic powders disrupted the tablet strength more compared to hydrophilic powders which could be attributed to the levels of surface energy of the additive. In contrast, at higher mass fractions (0.6-0.8 m/m), the surface energy is not as important and it is hypothesised that the deformation mechanisms of the additives governs the tablet strength.1. Reynolds GK, Campbell JI, Roberts RJ. A compressibility based model for predicting the tensile strength of directly compressed pharmaceutical powder mixtures. Int J Pharm [Internet]. 2017;531(1):215–24. Available from: http://dx.doi.org/10.1016/j.ijpharm.2017.08.0752. Sunkara D, Capece M. Influence of Material Properties on the Effectiveness of Glidants Used to Improve the Flowability of Cohesive Pharmaceutical Powders. AAPS PharmSciTech. 2018;19(4):1920–30. 3. Zuurman K, Maarschalk KVDV, Bolhuis GK. Effect of magnesium stearate on bonding and porosity expansion of tablets produced from materials with different consolidation properties. 1999;179:107–15. 4. Mishra SM, Rohera BD. Mechanics of tablet formation: a comparative evaluation of percolation theory with classical concepts. Pharm Dev Technol [Internet]. 2019;24(8):954–66. Available from: https://doi.org/10.1080/10837450.2019.1599913

Synthesis of Celecoxib-Eutectic Mixture Particles via Supercritical CO2 Process and Celecoxib Immediate Release Tablet Formulation by Quality by Design Approach.

Significant improvements in the wettability and dissolution rate of celecoxib (CEL), a poorly soluble selective cyclooxygenase-2 (COX-2) inhibitor, have been shown by Huyn et al., 2019 by combining the binary pharmaceutical compositions including CEL and one of the two co-formers, adipic acid (ADI) and saccharin (SAC), into eutectic mixtures (EM). Purpose: In this study, we developed a therapeutic eutectic system for CEL which is a promising approach for oral delivery to enhance bioavailability. CEL EM were synthesized by novel techniques including supercritical CO2 techniques and new tablet formulations were purposed. Methods: CEL EM were synthesized by evaporation crystallization method, spray drying, supercritical fluid (SCF) techniques. The CEL EM particles were then characterized by differential scanning calorimetry, powder X-ray diffraction, Fourier-transform infrared spectroscopy, scanning electron microscope, and particle size analysis. Dissolution studies were carried out. With a quality by design approach, a statistical method through design of experiment and data analysis by JMP® (SAS institute) was applied to CEL EM immediate release tablet formulation development. Results: CEL EM produced by spray drying technique, supercritical fluid (SCF) techniques were identified and characterized. The enhancement of dissolution was observed for SCF processed samples. The design space for CEL-ADI EM IR tablet and control limits for individual parameters were determined.

A new parameter for characterization of tablet friability based on a systematical study of five excipients

In this paper, a new parameter highly relevant to tablet friability is proposed based on a systematical study of the tablet quality attributes and texture performances of five different direct compression excipients, including microcrystalline cellulose, starch, lactose, mannitol, and dicalcium phosphate anhydrous. The new parameter, named Strain/Stress Max, could indicate the tablet’s ability against external force to maintain integrity. It was directly obtained from the diametrical breaking test which is extensively used to assess tablet mechanical strength, and thus no extra work is required. The values varied significantly among the tablets formed by materials with different mechanical properties under the same compression pressure. A design space was developed to achieve <1% tablet friability at various combinations of Strain/Stress Max and tensile strength. Additionally, data from binary mixture tablets validated the availability of the constructed design space. And the upper limit of Strain/Stress Max value was advisable for 1.5 MPa−1 for pharmaceutical tablets. In conclusion, the new parameter and design space are available for fast identification of the tablets with acceptable friability to facilitate the development of tablet formulation using as few active pharmaceutic ingredients as possible.

Tablet formulation development focusing on the functional behaviour of water uptake and swelling

The functional behaviour of tablets is strongly influenced by their manufacturing process and the choice of excipients. Water uptake and swelling are prerequisites for tablet disintegration, dispersion and hence active pharmaceutical ingredient (API) dissolution. High proportions of polymeric excipients in tablets, which are typically used as API carriers in amorphous solid dispersions (ASDs), may be challenging due to the formation of a gelling polymer network (GPN). In this study, systematic investigations into the formulation development of tablets containing polymeric and other excipients are performed by water uptake and swelling analysis. The impact of tablet composition and porosity as well as pH of the test medium are investigated. The pH affects the analysis results for Eudragit L100–55 and Eudragit EPO. HPMC and Kollidon VA64 inhibit water uptake and swelling of tablets due to the formation of a GPN. High tablet porosity, coarse particle size of the polymer and the addition of fillers and disintegrants can reduce the negative impact of a GPN on tablet performance. The application of lubricants slows down the analysed processes. Water uptake and swelling data are fitted to an empirical model obtaining four characteristic parameters to facilitate the simple quantitative assessment of varying tablet formulations and structural properties.

Studies on Fruit Pectin in the Development of Tablet Formulations of Ibuprofen

Background: Pectin, a naturally occurring polysaccharide is more than a food additive and has got amazing properties as a gelling agent and as a binder.&#x0D; Objective: The current research entails the extraction and identification of pectin from peels of selected fruits mango (Magnifera indica) and banana (Musa paradisiaca) by direct heating and using alcohol as precipitating agent. The potential of pectin as a binding agent in tablet formulation was evaluated by screening its micromeritics and post compression properties.&#x0D; Method: quadruple formulations of ibuprofen with crude peel pectin extracted from mango and banana in concentration of 50, 75, 100 and 125 mg respectively were employed in the tablet manufacture process by wet granulation method.&#x0D; Results: Successful formulation of tablet was done with the extracted pectin from the two fruit peels. The micromeritics properties showed good binding and flowing properties. An increase in concentration of pectin increased the hardness and also the dissolution of tablets up to a certain extent. The disintegration time was suitable for all formulations.&#x0D; Conclusion: It was concluded that pectin extracted from mango and banana peels can be used as a super disintegrating agent in pharmaceutical formulations, where needed.

Discovery, Characterization, and Pharmaceutical Applications of Two Loratadine–Oxalic Acid Cocrystals

Loratadine (Lor) is an antihistamine drug commonly used to relieve the symptoms of allergy. It has high permeability but low solubility under physiological conditions. To overcome the problem of low solubility, we synthesized and characterized two Loratadine multi-component crystalline phases with oxalic acid (Oxa), i.e., a 1:1 Lor-Oxa conjugate acid-base (CAB) cocrystal (Lor-Oxa CAB) and a 2:1 Lor-Oxa cocrystal monohydrate (Lor-Oxa hydrate). Both cocrystals exhibited an enhanced solubility and intrinsic dissolution rate (IDR) compared to Lor and adequate physical stability. The intrinsic dissolution rate of Lor-Oxa CAB is 95 times that of Lor, which makes it a promising candidate for tablet formulation development.

Development of piroxicam mini-tablets enabled by spherical cocrystallization.

We examined the potential of the spherical cocrystallization (SCC) technology in simultaneously enhancing tablet manufacturability and dissolution of poorly soluble drugs by developing a mini-tablet formulation of piroxicam. The manufacturing of mini-tablets using a direct compression (DC) process is more challenging than conventional tablets because of the much stricter requirement on the micromeritic properties of formulated powders. The SCC process in this work involved two steps: 1) preparing a new piroxicam-ferulic acid (PRX-FA) cocrystal, and 2) forming spherical agglomerates with the aid of a suitable bridging liquid. The PRX-FA cocrystal exhibited enhanced solubility as well as improved plasticity. The bridging liquid, a mixture of chloroform and ethyl acetate (EA) (1: 2, v/v), was chosen based on the high computed adsorption energy of chloroform and EA on morphologically dominating crystal faces of PRX-FA. The improved flowability, tabletability, and dissolution rate of spherical PRX-FA enabled the successful development of a DC mini-tablet formulation with a high PRX loading (41wt%). This example shows that SCC is a powerful enabling technology for DC tablet formulation development of challenging drugs.

To Maintain Formulation Composition Similarity of Coated Tablets of Different Strengths: Should Coating be Based on Core Tablet Weight or Surface Area?

As per the Japanese or SUPAC guidance to maintain formulation composition similarity across tablet strengths, the coating should be applied based on the core tablet surface area or weight, respectively. These two coating approaches were compared by evaluating protective effects of coating on the light stability of three model compounds. Core tablets of three light sensitive drugs, nifedipine, rosuvastatin calcium, and montelukast sodium were coated either with PVA-based Opadry® II white or Opadry® II beige. The coated tablets were exposed to light up to three ICH cycles. For Opadry® II white, the surface area based coating provided consistent light protection across tablet strengths when the coating amount was more than 0.1mg/mm2 compared to that based on core tablet weights. For Opadry® II beige, both approaches gave comparable and better light protection due to presence of iron oxides. The light protection by Opadry® II white could be because of physical barrier of coating, which was uniform across the strengths when it was based on core tablet surface area. For a routine tablet formulation development with Opadry color coating, it does not matter whether the coating is applied based on the core tablet surface area or weight.

Novel Quasi-Emulsion Solvent Diffusion-Based Spherical Cocrystallization Strategy for Simultaneously Improving the Manufacturability and Dissolution of Indomethacin

Successful development of tablet formulations of many active pharmaceutical ingredients (APIs) is challenged by their poor manufacturability (e.g., flowability, tabletability) and dissolution chara...

Material-Sparing and Expedited Development of a Tablet Formulation of Carbamazepine Glutaric Acid Cocrystal- a QbD Approach.

To efficiently develop a tablet formulation of carbamazepine using a soluble cocrystal with excess coformer to maintain phase stability during dissolution. The carbamazepine - glutaric acid cocrystal (CBZ-GLA, 1:1) and excess glutaric acid (GLA) were mixed with suitable tablet excipients, which were selected to address powder flowability and tabletability deficiencies specifically. Tablet friability and dissolution profiles were evaluated to guide formulation optimization. Dry granules were prepared by milling simulated ribbons. A binary blend of CBZ-GLA and GLA had poor flowability and marginal tabletability. Therefore, silica coated Avicel PH-102 (sMCC) was applied as a binder to improve the flow property and tabletability. A formulation consisting of sMCC, CBZ-GLA, and GLA exhibited good manufacturability but did not show improved dissolution because of rapid precipitation of CBZ dihydrate when CBZ-GLA came in contact with water. Dry granulation of CBZ-GLA and GLA dramatically improved dissolution profile due to the intimate contact between CBZ-GLA and GLA. Such cocrystal - coformer granules also led to much improved tablet manufacturability and dissolution. The successful tablet development of CBZ-GLA, using < 3 g of the cocrystal in <3 weeks, demonstrates an efficient workflow for tablet formulation development based on material-sparing and predictive powder characterization techniques. This workflow is useful for early tablet development using enabling solid form, such as cocrystal, when only a small amount of material is available.

A Precise Prediction Method for the Properties of API-Containing Tablets Based on Data from Placebo Tablets.

We previously reported a novel method for the precise prediction of tablet properties (e.g., tensile strength (TS)) using a small number of experimental data. The key technique of this method is to compensate for the lack of experimental data by using data of placebo tablets collected in a database. This study provides further technical knowledge to discuss the usefulness of this prediction method. Placebo tablets consisting of microcrystalline cellulose, lactose, and cornstarch were prepared using the design of an experimental method, and their TS and disintegration time (DT) were measured. The response surfaces representing the relationship between the formulation and the tablet properties were then created. This study investigated tablets containing four different active pharmaceutical ingredients (APIs) with a drug load ranging from 20–60%. Overall, the TS of API-containing tablets could be precisely predicted by this method, while the prediction accuracy of the DT was much lower than that of the TS. These results suggested that the mode of action of APIs on the DT was more complicated than that on the TS. Our prediction method could be valuable for the development of tablet formulations.

Simulation of Unit Operations in Formulation Development of Tablets Using Computational Fluid Dynamics.

Tablets are the most customarily used solid oral unit dosage form for its better patient compliance. Preparation of these tablets include granulation, granule drying, die filling, and tablet coating as few unit operations and evaluation tests like dissolution test and disintegration test. These are the most crucial segments influencing the quality of the tablet. Critical analysis of the impact of factors like flow pattern, temperature, velocity, and other properties of fluid affecting the unit operations is obligatory to enhance their efficiency. Computational fluid dynamics (CFD), a combined mathematical and numerical approach, is used to analyze the process parameters of fluid affecting the abovementioned processes during tablet formulation. The equations governing the laws of conservation of energy, mass, and momentum are solved numerically utilizing CFD software for better understanding of the role of fluids within the tablet processing steps. This review not only focuses on discrete explanations on how CFD is utilized in formulation and evaluation of tablet but it is also a compilation of multiple research works performed on each unit operation by applying CFD.

Reduction of Punch-Sticking Propensity of Celecoxib by Spherical Crystallization via Polymer Assisted Quasi-Emulsion Solvent Diffusion.

Punch-sticking during tablet compression is a common problem for many active pharmaceutical ingredients (APIs), which renders tablet formulation development challenging. Herein, we demonstrate that the punch-sticking propensity of a highly sticky API, celecoxib (CEL), can be effectively reduced by spherical crystallization enabled by a polymer assisted quasi-emulsion solvent diffusion (QESD) process. Among three commonly used pharmaceutical polymers, poly(vinylpyrrolidone) (PVP), hydroxypropyl cellulose (HPC), and hydroxypropyl methylcellulose (HPMC), HPMC was the most effective in stabilizing the transient emulsion during QESD and retarding the coalescence of emulsion droplets and the initiation of CEL crystallization. These observations may arise from stronger intermolecular interactions between HPMC and CEL, consistent with solution 1H NMR analyses. SEM and X-ray photoelectron spectroscopy confirmed the presence of a thin layer of HPMC on the surfaces of spherical particles. Thus, the sticking propensity was significantly reduced because the HPMC coating prevents direct contact between CEL and the punch tip during tablet compression.

Expedited Tablet Formulation Development of a Highly Soluble Carbamazepine Cocrystal Enabled by Precipitation Inhibition in Diffusion Layer.

To address the problem of precipitation of a poorly soluble drug during dissolution of highly soluble cocrystals by preparing granules intimately mixed with a water-soluble polymer. Effectiveness of polymers as precipitation inhibitors during the dissolution of carbamazepine-nicotinamide (CBZ-NCT) cocrystal was assessed based on induction time of crystallization from a supersaturated solution in presence of different polymers at two concentrations. Dissolution was evaluated by both intrinsic dissolution rate (IDR) and USP dissolution method. Powder manufacturability was assessed using a shear cell and compaction simulator to assess flowability and tabletability, respectively. Hydroxypropyl methylcellulose acetate succinate (HPMCAS) was the most effective polymer against precipitation of CBZ and the IDR of a 1:1 (w/w) CBZ-NCT/HPMCAS mixture was the highest. The final formulation of 1:1 CBZ-NCT/HPMCAS granule exhibited excellent flowability, good tabletability, and significantly improved drug release rate than cocrystal formulations without HPMCAS or the CBZ formulation. The particle engineering strategy of modifying the diffusion layer on the surface of highly soluble cocrystal with a polymer is effective for inhibiting premature precipitation of CBZ. Assisted with predictive tools for characterizing powder flowability and tabletability, the design of high quality tablet product with improved drug release rate and manufacturability can be achieved in an efficient manner.

Multivariate Statistical Optimization of Tablet Formulations Incorporating High Doses of a Dry Herbal Extract.

The development of oral tablet formulation for herbal medicines has been restricted by large drug loadings and the poor physicochemical and mechanical properties of dry herbal extracts (DHEs). Herein, statistical experimental designs were applied to herbal tablet formulation development and optimization using Wuzi Yanzong dry extract (WYE). The tablet disintegration time and hardness were identified as the critical quality attributes (CQAs) of the product. The tablet formulation was designed to achieve a high drug loading (50% or higher of WYE), shorter tablet disintegration time (less than 30 minutes), and suitable hardness (6.0 to 7.5 kp). A D-optimal mixture design was used to evaluate the effects of excipients on CQAs to minimize the risk compression failure and improve the tabletability in formulations containing WYE at 50% and 65% by weight. A partial least squares model was used to elucidate the multivariate relationships between a large number of formulation variables and product CQAs, and determine the maximum possible WYE loading. From overlaid plots of the effects of formulation variables on CQAs, it was found that a maximum WYE loading of 67% in tablet formulation satisfied the acceptance criteria of CQAs. In conclusion, this study shows that multivariate statistical tools are useful for developing tablet formulations containing high doses of herbal extracts and establishing control strategies that ensure product quality.