Performance Of Tablets Research Articles

Continuous, simultaneous cocrystallization and formulation of Theophylline and 4-Aminobenzoic acid pharmaceutical cocrystals using twin screw melt granulation

In this work a cocrystal of Theophylline and 4Aminobenzoic acid was successfully produced and formulated using a hydrophilic binder with a novel continuous melt granulation approach. This melt granulation was followed with direct compression to generate oral solid dosage forms. The study revealed that the processing temperature, molecular weight of the binder and binder concentration were the most effective parameters for the production and formulation of high purity cocrystals. Superior tableting performance was observed for melt granulated cocrystals as compared with extruded cocrystals and pure theophylline. Moreover the prepared THP-4ABA melt granulated cocrystals were stable for 14 days (50 °C and 75% RH).

Balance with the interactive size effects of display, target, and key spacing in tablet tapping, dragging, and typing tasks

AbstractThis study aimed to expand the current demonstration of display size effects from pointing tasks to dragging and tap‐typing tasks to investigate the effects of influential factors on the performance of touchscreen tablets. From 7‐ to 11‐in. displays, the index of difficulty was kept constant by increasing the target amplitudes and widths (6.0–9.5 mm) proportionally, and the key spacing were, respectively, 13.5 × 7.3–21.5 × 11.5 mm with 0‐mm key gaps. The results demonstrated that simple task types (complexities) reinforced the display size effects and that the effects interacted with target sizes (including amplitude/width scaling) and key spacing to reflect increasing efficiency and usability with increasing sizes. Gender effects were only significant in subjective assessments. Display sizes approaching 10 in., target sizes not less than 7 mm (optimal 9–10 mm) and key spacing larger than 17.5 mm induced the effects of motor scale (the scale of the upper limb joint coordination) and interacted with one another to result in the optimal performance and usability.

Continuous high-shear granulation: Mechanistic understanding of the influence of process parameters on critical quality attributes via elucidating the internal physical and chemical microstructure

Over the past decade, continuous wet granulation has been emerging as a promising technology in drug product development. In this paper, the continuous high-shear mixer granulator, Lӧdige CoriMix® CM5, was investigated using a low-dose formulation with acetaminophen as the model drug. Design of experiments was deployed in conjunction with multivariate data analysis to explore the granulator design space and comprehensively understand the interrelation between process parameters and critical attributes of granules and tablets. Moreover, several complementary imaging techniques were implemented to unveil the underlying mechanisms of physical and chemical microstructure in affecting the tablet performance. The results indicated that L/S ratio and impeller speed outweighed materials feeding rate in modifying the granule and tablet properties. Increasing the degree of liquid saturation and mechanical shear input in the granulation system principally produced granules of larger size, smaller porosity, improved flowability and enhanced sphericity, which after compression generated tablets with slower disintegration process and drug release kinetics due to highly consolidated physical microstructure. Besides, in comparison to batch mixing, continuous mixing integrated with a conical mill enabled better powder de-agglomeration effect, thus accelerating the drug dissolution with increased surface area.

Tableting performance of various mannitol and lactose grades assessed by compaction simulation and chemometrical analysis

Mannitol and lactose are commonly used fillers in pharmaceutical tablets, available in several commercial grades that are produced using different manufacturing processes. These grades significantly differ in particulate and powder properties that impact tablet manufacturability. Choice of sub-optimum type or grade of excipient in tablet formulation can lead to manufacturing problems and difficulties, which are magnified during a continuous manufacturing process. Previous characterization of tableting performance of these materials was limited in scope and under conditions not always realistic to the commercial production of tablets. This work seeks to comprehensively characterize the compaction properties of 11 mannitol and 5 lactose grades using a compaction simulator at both slow and fast tableting speeds. These include tabletability, compressibility, tablet brittleness, die-wall stress transmission, and strain rate sensitivity. A chemometrical analysis of data, using the partial least square technique, was performed to construct a model to provide accurate prediction of tablet tensile strength for mannitol grades. Such knowledge facilitates the selection of suitable tablet filler to attain high quality tablet products.

Individualized in vitro and in silico methods for predicting in vivo performance of enteric-coated tablets containing a narrow therapeutic index drug

The efficacy of narrow therapeutic index (NTI) drugs is closely related to their plasma concentration-time profile. Particularly for these compounds interindividual variability of gastrointestinal (GI) parameters relevant to in vivo drug release may result in fluctuations of the plasma concentration. The present study focused on assessing the influence of individual GI pH- and transit profiles on drug release of enteric valproate tablet formulations by means of individualized in vitro dissolution experiments. After initial experiments simulating GI passages in average healthy adults, a novel in vitro dissolution model was used to simulate individual GI pH- and transit profiles with physiologically relevant dissolution media. Based on the dissolution profiles obtained in these experiments, individual in silico plasma profiles were generated and compared to fasted in vivo data applying a mean Euclidean distance approach. Simulated individual gastric residence time was identified as crucial parameter determining the onset of absorption, whereas the shape of the plasma profile is mainly influenced by individual valproate pharmacokinetics. The novel in vitro and in silico methods used in this study are promising tools for estimating in vivo drug release and plasma concentration in individual subjects and thus may contribute to a prospective risk assessment for NTI formulations.

Prediction of the Long-Term Dissolution Performance of an Immediate-Release Tablet Using Accelerated Stability Studies

A slowdown in dissolution performance has been observed for an immediate release tablet formulation during long-term stability testing. The slowdown was successfully predicted using an accelerated stability study in which the dissolution was tested over a range of temperatures, humidity conditions and storage times. The slowdown was quantified using a calculated parameter referred to as the “acceleration factor” (AF); this is the degree by which the timescale (x-axis) of a dissolution profile needs to be scaled to overlay it on to the dissolution profile obtained at the initial timepoint. The “AF” approach was applicable because it was observed that the shape of the dissolution profile remains consistent even though different dissolution rates were obtained. Under the accelerated stability conditions, the AF is observed to follow an “exponential decay” curve. A predictive model for the long-term stability dissolution was obtained by modeling both the plateau level and the rate constant for the exponential decay curve as functions of temperature and humidity. The long-term stability of product A in packaging was successfully predicted using this model in combination with simulations of the changing relative humidity conditions inside the packaging.

Revealing the Role of Structural Features in Bulk Mechanical Performance of Ternary Molecular Solids of Isoniazid.

Mechanical performance in ternary (3n) molecular solids has been rarely studied, and hence it is an interesting topic of investigation in the direct compression method of tableting. The structural features of 3n-eutectic (3n-Eu: INZ-ADP-NIC) and 3n-cocrystal (3n-Co: INZ:SUC:NIC) were explored to understand the bonding area-bonding strength (BA-BS) interplay. Higher compressibility and lower values of the Heckel parameter of 3n-Co as compared to 3n-Eu suggested its better deformation behavior, with BA being the predominant factor. The higher tensile strength and Walker analysis indicated a higher compressibility coefficient ( W) and lower pressing modulus ( L) for 3n-Eu, which was consistent with its better tabletability over 3n-Co. The higher compressibility and plastic energy, and higher value of L of 3n-Co, were attributed to the facile propagation (⟨-1' 0' 5'⟩) of the shearing molecular slip (-1 0 5) when subjected to the external mechanical stress. Thus, the overall higher tableting performance of 3n-Eu over 3n-Co was found due to the predominant BS and limited contribution of BA. The latter was the dominant factor in 3n-Co. Cohesive interactions, like the 3D mechanically interlocked structure of conglomerates of 3n-Eu, contributed toward the higher BS. Moreover, the prediction of better tabletability solely based on crystallographic feature slip planes (0D/1D/2D H-bonded layer (h k l) ⊥ vdW interactions) is warranted in pharmaceutical molecular solids. Eutectics with varying microstructural variants ( nLα + nLβ + nLγ) may open up the opportunity to manipulate the physicomechanical performance.

Crystal anisotropy explains structure-mechanics impact on tableting performance of flufenamic acid polymorphs

Anisotropic features with other crystallographic properties like d-spacing, and attachment energy (Eatt) can predict material performance during the secondary pharmaceutical processing. A newly developed state-of-the-art compression cell lodged in a powder X-ray diffractometer was used to measure anisotropic Young’s moduli (YM) of flufenamic acid (FFA) polymorphs in this study. Methodology is based on the generation of a single crystal deformation in this cell, which reflects as a change in the d-spacing in the PXRD pattern. Anisotropic YM was calculated from such information gathered along different FFA planes. Measured FFA crystallographic molecular features were concatenated to understand macroscopic compaction (Heckel and Shapirao’s parameters) and tableting performance. Block shaped crystals of FFA form I, and III after initial characterization with SEM, DSC, PXRD, and FTIR were compressed normal to X, Y, and Z-planes, identified from calculated PXRD pattern using the reported single crystal structure. YM of X and Y planes of form I was significantly higher than corresponding planes of form III. Z plane of form III showed significantly higher YM than that for form I. Low YM of form III can be attributed to its large d-spacing regardless of their high Eatt than form I, as well as orientation of supramolecular acid dimer (OH⋯O) homosynthon chains in the FFA planes. FFA form I stiffness was further confirmed with lower densification and higher yield pressure of deformation than form III. Clearly, form III exhibited better compressibility, compactibility, and tableting performance than form I due to favorable molecular and macroscopic features. Thus, developed anisotropic measurement approach can be used to distinguish material performance in the early development stage of the pharmaceutical processes.

Effect of batch age on potency and dissolution of levothyroxine sodium tablets: impact of BP and USP monograph differences on dissolution results

Controversies surround levothyroxine sodium as a drug and product, and are reflected in compendia (USP vs BP) differences in levothyroxine sodium tablets specifications concerning potency limit and dissolution test conditions, and in lack of consensus on several issues such as whether the drug BCS class I or III. We have recently published a clinical study in patients comparing the efficacy of multisource 100 mcg levothyroxine sodium tablets (three sources, two brands, a total of five batches). Clinical efficacy and dissolution rate data varied among the tablet batches studied and indicated that brand/source interchangeability could not be claimed. The efficacy parameters showed good correlation with dissolution data generated under BP 2014, but not under USP 2014 dissolution test conditions. In the present study, we decided to expand the number of tablet batches studied in vitro to a total of 12, to report potency and content uniformity data missing in the clinical study, and to further examine the discrepancy in dissolution results based on the medium used. The wide range of batch age in the studied samples allowed investigating the effect of batch age on in-vitro tablet performance parameters. Generated potency values indicated the prevalence of super-potent tablet batches. The dissolution data reflected the effect of compendia monograph differences in dissolution medium. The results also indicated an inverse relationship between tablet potency and batch age and, between dissolution and batch age. The possible effect of potency results on the generated dissolution data was discussed. Statistical significance of correlations examined was assessed by linear and non-linear regression analysis. Statistical significance was evident for the relation between batch age and BP 2014 dissolution data, compared to USP 2014 dissolution results.

The effect of roller compaction and tableting stresses on pharmaceutical tablet performance

In this research the effect of two fundamental stresses, i.e. the tableting load and roller compaction pressure, on tablet disintegration were investigated. Excipient materials were roller compacted using a range of pressures, and tablets were produced by compressing the consequent granules at varying tableting loads. For this study mannitol, a brittle and soluble material, and microcrystalline cellulose, a deformable and insoluble material, were investigated at varying binary ratios. The tablets were characterised by analysis of the compactibility and a flow cell imaging method was utilised to investigate tablet disintegration in real-time. It was found that the effect of roller compaction (RC) pressure on tablet tensile strength and porosity was dependent on the tableting load used. At low tableting load, the tablet porosity varied depending on the RC pressure used, whereas the tensile strength was largely unaffected. The use of a high tableting load leads to the opposite effect being observed. The tensile strength was highly dependent on the RC pressure used. In terms of the tablet disintegration the RC pressure did not influence the disintegration behaviour when low tableting loads were used as the process was rapid. When higher tableting loads were used, tablets containing granules roller compacted using lower pressure expanded in size larger than when a low RC pressure was used. A low RC pressure also lead to a faster particle release rate was observed.

Preparation of Colon-Targeted Acetylharpagide Tablets and its Release Properties in vivo and in vitro.

Ethno Pharmacological Relevance: Acetylharpagide is a monomeric compound extracted from Ajuga decumbens, widely used for remedying infectious and inflammatory diseases in Southern China.Aim of the Study: The present study designed and investigated the formulation of colon-targeted acetylharpagide tablets according to the dual controlled release mechanisms of time-delay and pH-sensitivity.Materials and Methods: The core tablets of acetylharpagide were coated with the material used in time-delay systems such as ethyl cellulose and suitable channeling agent, followed by pH-dependent polymers, polyacrylic resin II and III in a combination of 1:4. Furthermore, the release and absorption performance of colon-targets tables were evaluated in vitro and in vivo. In the in vitro tests, the optimized formulation was not released in simulated gastric fluid in 2 h; the release was <5% at pH 6.8 simulated intestinal fluids for 4 h; the drug was completely released within 5 h at pH 7.6 simulated colon fluid. In the in vivo tests, pharmacokinetic characteristics of the colon-targeted tablets were investigated in dogs.Results: The results indicated that the acetylharpagide tablets with the technology of colon-targeting caused delayed Tmax, prolonged absorption time, lower Cmax, and AUCINF_obs. Meanwhile, the apparent volume of distribution (Vz_F_bs) of the colon-target tablets was higher than the reference.Conclusions: These results suggested that colon-targeted acetylharpagide tablets deliver the drug to the colon. The in vitro performance of colon-targeted acetylharpagide tablet was appropriately correlated with its performance in vivo.

3022Relative bioavailability and pharmacokinetic (PK) performance of a ralinepag extended-release (XR) tablet oral formulation and the effect of food and gender in healthy human subjects

3022Relative bioavailability and pharmacokinetic (PK) performance of a ralinepag extended-release (XR) tablet oral formulation and the effect of food and gender in healthy human subjects

Life cycle assessment of industrial scale production of spirulina tablets

Spirulina platensis has been successfully commercialized as functional food ingredients, animal feed and medicine due to its high contents of protein, beta-carotene, vitamins, and minerals. In this study, we investigated the environmental performance (cradle-to-gate) of edible Spirulina tablets using Life Cycle Assessment (LCA). A comparative analysis with other three traditional foods or diets was conducted by using various nutrient values as functional units (e.g., protein content and a composite nutrient score) in the analysis. This research showed that Spirulina tablets production for protein caused environmental impacts mainly in fossil fuel use, acidification, climate change, smog formation, and eutrophication. The impact of the cultivation stage was the highest environmental impacts among all production stages resulting from the extensive use of chemicals, nutrients, and energy. The impacts of algae food production are around 2–5 times to algae production for biofuels which was also modeled in this study. In terms of protein production, algae tablet cause higher impacts than traditional terrestrial crops but lower impacts than protein from animal products. However, as the algae contain a wide variety of nutrients, especially high micronutrients such as the beta-carotene, the environmental impacts of producing the same nutrient combinations of protein and beta-carotene from carrot + tofu were higher than producing Spirulina tablets. The results in this work can be used to assess edible algae production inventories and provide reliable information for development of more sustainable products and processes.

Formulation and evaluation of controlled-release matrix systems of ciprofloxacin.

Ciprofloxacin is a broad-spectrum fluoroquinolone antibacterial drug to which most Gram-negative and many Gram-positive bacteria are highly susceptible. Fluoroquinolones are administered repeatedly, twice a day for 5 days, during the course of therapy. Hence, they require repeated administration. Ciprofloxacin qualifies as a drug candidate for a controlled-release drug delivery system. The present work was aimed to develop ciprofloxacin hydrochloride-containing matrix tablets by the wet granulation method. The tablets were prepared using EthocelTM 100 Premium and Eudragit® RS PO (Evonik Laboratory, Mumbai, India) as a rate-controlling polymer. Granular dioctyl phthalate (DCP) was used as a diluent. An isopropyl alcohol and dichloromethane (1:1) mixture was used as a granulating agent. The effect of the formulation variables on tablet performance was examined based on weight variation, hardness, friability, thickness, and drug release profiles. The results suggested that the tablets had good integrity. The tablets were stable for 18 months. Formulation F7 gave a linear release pattern up to 12 h. The release of ciprofloxacin from formulation F7 followed zero-order kinetics. The release mechanism was found to be diffusion-controlled as the Higuchi equation was obeyed. Ciprofloxacin hydrochloride-containing matrix tablets were prepared successfully. The tablets had good integrity and were found stable for 18 months.

EFFECT OF COMPONENTS AND DEPOSITION ON TECHNOLOGICAL PERFORMANCE OF IBUPROFEN TABLETS

Objective: This work evaluated the influence of the technological properties of polyvinylpyrrolidone (PVP), calcium phosphate (CP) and cross-linked sodium carboxymethylcellulose (CC) as well as the deposition of a solid dispersion, through the solvent evaporation method, on the technological parameters that define the properties of ibuprofen tablets. Methods: The powder flow rate through an orifice, bulk volume and tapped volume of powders, tablet hardness, disintegration time and dissolution profile of the tablets were determined on individual components, their physical mixtures, granules obtained by deposition and solvent evaporation, and tablets obtained at different compaction pressures. Results: The very poor flowability of CP and the high compactibility of PVP were transferred to the powder mixtures, which showed poor flowability, and ibuprofen tablets with twice the compactibility. The tablets disintegration was high with a low proportion of CC (0.5%), but decreased linearly by increasing the proportion of the disintegrant up to 10%. At the same time, the dissolution of the drug after 30 min increased from 3% to 80%. The agglomeration of CP through the deposition of an alcoholic solution of the drug and PVP improved the flow properties and tripled the hardness of the tablets. However, the dissolution after 30 min decreased from 80% to 18%. Conclusion: The physical mixture was the best option to improve the dissolution, while the deposition on an adsorbent, of a solid dispersion of drug-PVP, was the best option to improve the compactibility and flow properties.

Co‐Crystal of Paracetamol and Trimethylglycine Prepared by a Supercritical CO2 Anti‐Solvent Process

AbstractParacetamol (PCA) and trimethylglycine (TMG) were co‐crystallized and micronized by means of the supercritical anti‐solvent (SAS) process to improve the tabletability of PCA. The effects of operating conditions on particle properties were investigated in detail. Characterizations were performed to confirm the co‐crystal state of PCA‐TMG. The results indicated that the same crystal form with different crystal habits was prepared. The optimal PCA‐TMG co‐crystals presented a much larger tensile strength, higher drug content of PCA, and smaller particle size than those obtained using the ball milling (BM) process. The SAS‐processed PCA‐TMG co‐crystals showed an enhanced solubility, dissolution rate, and tableting performance compared to that of BM.

Molecular Understanding and Implication of Structural Integrity in the Deformation Behavior of Binary Drug-Drug Eutectic Systems.

In eutectic, a lamellar microstructure offers better tableting than that of the nonreacted physical mixture. However, bulk deformation remains elusive in two binary eutectics. We hypothesized that the binary eutectic of a drug with different components, having different H-bonding dimensionalities and crystal structure, shall allow the understanding of the structural integrity in the bulk deformation behavior. The shearing molecular solid (FXT Q) shared a common composition with the viscoelastic crystal (ASP I) and brittle (PCM I), forming EM-1 (ϕ1 = 41.27:58.73% w/w) and EM-2 (ϕ2 = 41.10:58.90% w/w), respectively. The excess thermodynamic functions were contributed by high energy microstructures (nonbonding interactions) along incoherent phase boundaries (visualized under CLSM). The energy dispersive analysis enabled the recognition of the relative distribution of higher atoms over the heterogeneous surface. EM-1 (FXT Q-ASP I) demonstrated higher compressibility, tensile strength, and compactibility (CTC profile) compared to those of EM-2 (FXT Q-PCM I) over a range of applied compaction pressures. The lower true yield strength (σ0(EM-1) = 138.66 MPa) of EM-1 as compared to that of EM-2 (σ0(EM-2) = 166.66 MPa) suggested a better deformation performance and incipient plasticity quantified from the "out-of-die" Heckel analysis. From Ryshkewitch analysis, the tensile strength at zero porosity (τ01 = 3.83 MPa) was predicted to be higher for EM-1 than EM-2 (τ02 = 2.54 MPa). The higher bonding strength of EM-1 was contributed to the additional influence of true density and isotropic van der Waals interactions of ASP I (0D). In contrast, EM-2 demonstrated lower compressibility and compactibility, having herringbone molecular packing of PCM I (1D) with a common shearing component (FXT Q (1D)). This study confirmed that the intrinsic deformational and chemical nature of the second component defined the compressibility and compactibility tendency to a greater extent in the tableting performance of conglomerates of crystalline solid solution.

Solid State Characterization and Tableting Studies of Ethanol Based Cocrystals of Fenofibrate with Nicotinamide

Abstract: Objectives: The pharmaceutical cocrystals can be defined as dissociable “API-excipient” molecular complexes or Co-crystals are solids that are crystalline materials composed of two or more molecules in the same crystal lattice as per U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) April 2013. The objectives of present investigation were to formulate cocrystals of fenofibrate with nicotinamide by solution cocrystallization technique. Methods: The cocrystals were prepared by solution cocrystallization technique by using ethanol as a solvent and nicotinamide as a coformer in the ratio of 1:1 & 1:2. The prepared cocrystals were evaluate for, solid state characterization by FTIR, PXRD, Raman spectroscopy and evaluated for tableting performance. Results: The formation of cocrystals has been confirmed by FTIR and Raman spectroscopy. The formulations 1:1 and 1:2 ratios showed better flow properties. The order of tableting performance 1:2 ratio cocrystals > 1:1 ratio cocrystals > Recrystallized nicotinamide > Nicotinamide >> Recrystallized Fenofibrate >> Fenofibrate. Conclusion: The cocrystals showed superior tableting performance. This might be due to the co-crystals, contains hydrogen-bonded two dimensional flat slip planes which exhibits higher plasticity. Key words: Cocrystals, Crystallizaton, Fenofibrate, Nicotinamide, Tableting.

Development on porous particles of Pueraria lobatae Radix for improving its compactibility and dissolution.

Herein, we report a study on the influence of particles having different porosities on tablet performance. The ethanol extract of Pueraria lobatae Radix (EPL) was chosen as the model drug. A series of porous EPL particles were prepared by co-spray drying EPL with different amounts of ammonium bicarbonate (NH4HCO3), and their powder properties (particle morphology, particle size, porosity, flowability, bulk density, and tap density) and tablet properties (tensile strength, Esp, yield pressure, dissolution, etc.) were comparatively investigated. The results showed that there were significant differences in the fundamental and functional properties of the spray-dried and parent EPLs. First, the irregular and dense primary EPL particles were transformed into loose, hollow, and spheroidal particles via co-spray drying with NH4HCO3. Second, compared to parent EPL, porous EPLs showed a significant improvement (1.80–7.03 times) in compactibility. Third, the dissolution rates of porous EPLs were similar, and all were more than twice as fast as that of parent EPL. The increased porosity, on the one hand, led to the increase in interparticle and intraparticle bonding forces during tableting and, on the other hand, facilitated water intrusion into tablets for disintegration and dissolution. Porous particle design is therefore promising, especially for drugs with both poor compactibility and dissolution.

Isolation, Characterization and Evaluation of Ocimum Basilicum Seed Mucilage for Tableting Performance

Owing to multifarious potentialities and fine aroma chemicals, Ocimum basilicum possessed medicinal properties like antibiotic, antistress, diaphoretic, diuretic, antipyretic, stomachic, antimicrobial and insecticidal. The main aim of this study was to isolate and characterize mucilage obtained from Ocimum basilicum seeds as a pharmaceutical excipient. Phytochemical characterization of the isolated mucilage was performed and presence of carbohydrates, fats and oils was detected using identification tests. Compressibility performance of the isolated mucilage was evaluated using the Heckel plot study, which showed that the isolated mucilage has poor compressibility properties. Results indicated that the mucilage could be a potential superdisintegrant for formulating fast disintegrating tablets of metoprolol tartarate. The way of addition of mucilage, concentration and the method of preparation all were found to influence fast disintegrating tablet performance. From these results it is possible to conclude that Ocimum basilicum seed mucilage could be used in direct compression with other excipients and in wet granulation technology as a superdisintegrant.