Direct Compression Tablet Formulation Research Articles

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.

A study of solid-state epimerisation within lactose powders and implications for milk derived ingredients stored in simulated tropical environmental zones

Isolated from milk, lactose is a food ingredient and an excipient in medicines. Its chiral forms are known to undergo epimerisation in solution but understanding whether this chemical reaction occurs in lactose powders exposed to tropical environments is of great importance for medicine stability and food quality. Thus, the aim of this study was to investigate epimerisation within lactose powders stored under specified conditions that model hot and humid climates. Powdered α-lactose monohydrate was stable under all conditions, whereas β-lactose stored at 40 °C and 75 % RH suffered epimerisation, falling to 3.9 ± 0.3 β-content after 6-months. Zero-order kinetics observed by NMR, indicated a shelf-life (5 % degradation) of 4.55-days for β-lactose containing powders. Thermal analysis revealed monohydrate formation as β-lactose epimerised, seen as tomahawk shaped α-lactose monohydrate crystals by SEM. Therefore, it is recommended β-rich lactose containing powders, e.g., infant formula or direct compression tablet formulations, are stored hermetically in tropical zones.

Direct compression tablet formulation of celecoxib enabled with a pharmaceutical solvate

Celecoxib, an anti-inflammatory drug for pain and arthritis, is currently only available in capsule form. To reduce the onset time for a faster action and to lower the manufacturing cost, the tablet dosage form is more preferred. However, the commercial celecoxib (Form III) is not suitable for direct compression (DC) tablet manufacture due to poor flow, low bulk density, and tablet lamination. In this work, we overcome these challenges using a pharmaceutically acceptable dimethyl sulfoxide (DMSO) solvate of celecoxib. Aided with the DMSO solvate, an acceptable DC tablet formulation was successfully developed to manufacture tablets containing 200 mg celecoxib, with satisfactory manufacturability, disintegration, and in vitro dissolution performance.

A compression behavior classification system of pharmaceutical powders for accelerating direct compression tablet formulation design.

In this paper, a compression behavior classification system (CBCS) for direct compression (DC) pharmaceutical powders is presented. Seven descriptors from a series of compression models for powder compressibility, compactibility and tabletability analysis were included in the CBCS. A new tabletability index d was proposed to differentiate three categories of tensile strength (TS) vs. pressure relationships, and its physical meaning was explained thoroughly. 130 materials containing diverse pharmaceutical excipients and natural product powders (NPPs) were fully characterized and were compiled into an in-house developed material library, in which 70 materials with potential DC applications were used to justify the effectiveness of the CBCS. Principle component analysis (PCA) was used to uncover the latent structure of compression variables. Moreover, partial least squares (PLS) regression models are established in prediction of both tablet TS and solid fraction (SF) based on the raw materials' physical characteristics, the compression behavior indices and the compression force. The obtained scores and loadings are used to group the materials and the compression variables, respectively. Different categories of tabletability for DC powders were clearly clustered along two orthogonal directions pointing to the index d and the compression force. Finally, a multi-objective design space was identified under the latent variable space, summarizing the operationally possible region for both material properties and compression pressure required in DC tablet formulation design.

The Use of Nata de Coco Derived Bacterial Cellulose as a Potential Excipient for Directly Compressed Tablets

Nata de coco is produced through the fermentation of coconut water using Acetobacter xylinum bacteria. Chemically, Nata de coco is high in fiber, consisting of bacterially derived cellulose. Bacterial celluloses present a number of unique physical properties compared with plant celluloses including a relatively high purity and crystallinity, with mechanical strength. These properties lend Nata de coco to be extremely amenable to research. The current study attempts to assess the suitability of Nata de Coco derived bacterial cellulose in direct compression tablet formulation. Nata de coco, at various states of hydration, defined here as 0%, ‘low’ and ‘high’, achieved by both oven-drying and freeze-drying is incorporated into a low-dose loratadine powder blend for direct compression into tablets. The dissolution profile of these novel tablets were evaluated for release properties. The resulting tablets reveal freeze-drying, compared with oven-drying, markedly improve the properties of Nata de Coco for inclusion in a tablet formulation, producing tablets with improved disintegration times and dissolution profiles and retaining physical stability. Oven dried Nata de Coco, resulting in physically weaker tablets, with poor friability and hardness. The upper limit for water-content in both cases, similar to HPMC, appears to be 11%. Freeze-dried Nata de Coco therefore presents considerable promise for use as a tablet excipient to produce a rapid-release formulation.

A platform direct compression formulation for low dose sustained-release tablets enabled by a dual particle engineering approach

Content uniformity (CU) is a well-recognized challenge for low-dose direct compression (DC) tablet formulations. Using a dual particle engineering approach that involves a) forming a segregation-resistant drug-carrier composite to improve CU and b) nanocoating HPMC to enhance flowability, we have developed a platform DC formulation for preparing low-dose drug sustained-release (SR) tablets with excellent CU. In addition to demonstrated robustness in manufacturability, this platform formulation has the flexibility for modifying drug release rate. Thus, it is useful for expedited and material-sparing development of low dose SR tablets using the economical DC process.

Modulating Sticking Propensity of Pharmaceuticals Through Excipient Selection in a Direct Compression Tablet Formulation.

To investigate how excipient matrix affects punch sticking propensity of active pharmaceutical ingredients (API), with the focus on the effect of bonding interactions between API-API (F2) and API-excipient (F3). Sticking kinetics of direct compression formulations, consisting of 20% of celecoxib (CEL) or ibuprofen (IBN) in different excipient matrices, i.e., microcrystalline cellulose (Avicel PH102 and Avicel PH105 dry coated with nano-sized silica (PH105(n)), hypromellose (K15M), and a 3:1 mixture between starch and Avicel PH102 (S3P1), was assessed using a removable punch tip on a compaction simulator. The amount of material transferred to punch was determined gravimetrically every 10 compressions up to 50 compactions. CEL exhibited higher F2 than IBN. CEL also exhibited more sticking under otherwise identical compaction conditions in the same excipient matrix. Among different excipient matrices, sticking propensity of both APIs followed the ascending order: PH105(n) < PH102 < K15M < S3P1. This order was exactly opposite to the order of F3, confirming that greater bonding strength of the formulation favors lower sticking propensity of a given API. For an API prone to punch sticking, judicious use of excipients to render higher tablet mechanical strength can mitigate severity of punch sticking.

Investigation of the Sensitivity of Transmission Raman Spectroscopy for Polymorph Detection in Pharmaceutical Tablets.

Polymorph detection is critical for ensuring pharmaceutical product quality in drug substances exhibiting polymorphism. Conventional analytical techniques such as X-ray powder diffraction and solid-state nuclear magnetic resonance are utilized primarily for characterizing the presence and identity of specific polymorphs in a sample. These techniques have encountered challenges in analyzing the constitution of polymorphs in the presence of other components commonly found in pharmaceutical dosage forms. Laborious sample preparation procedures are usually required to achieve satisfactory data interpretability. There is a need for alternative techniques capable of probing pharmaceutical dosage forms rapidly and nondestructively, which is dictated by the practical requirements of applications such as quality monitoring on production lines or when quantifying product shelf lifetime. The sensitivity of transmission Raman spectroscopy for detecting polymorphs in final tablet cores was investigated in this work. Carbamazepine was chosen as a model drug, polymorph form III is the commercial form, whereas form I is an undesired polymorph that requires effective detection. The concentration of form I in a direct compression tablet formulation containing 20% w/w of carbamazepine, 74.00% w/w of fillers (mannitol and microcrystalline cellulose), and 6% w/w of croscarmellose sodium, silicon dioxide, and magnesium stearate was estimated using transmission Raman spectroscopy. Quantitative models were generated and optimized using multivariate regression and data preprocessing. Prediction uncertainty was estimated for each validation sample by accounting for all the main variables contributing to the prediction. Multivariate detection limits were calculated based on statistical hypothesis testing. The transmission Raman spectroscopic model had an absolute prediction error of 0.241% w/w for the independent validation set. The method detection limit was estimated at 1.31% w/w. The results demonstrated that transmission Raman spectroscopy is a sensitive tool for polymorphs detection in pharmaceutical tablets.

Auxilliary Dry Binding Properties of Some Hydrogenated Vegetable Oils in Direct Compression Tabletting

The ability of some hydrogenated vegetable oils to act as dry binder in direct compression tablet formulations was investigated using an instrumented rotary tablet press. The effect of these widely used tablet lubricants was compared to Avicel® PH 102, a standard, dry binding excipient in direct compression tablet formulations. The effects of the hydrogenated vegetable oils on the hardness, friability, disintegration time and dissolution of tablets made from the direct compression tablet formulations were evaluated. Dika fat, Lubritab®, Sterotex®, Stearolac-S® and stearic acid improved the hardness and friability profiles of a model direct compression tablet formulation as well as ascorbic acid and aspirin-acetaminophen tablet formulations. Prolonged mixing had no deleterious effect on the properties of the hydrochlorothiazide, ascorbic acid and aspirin-paracetamol tablets prepared. The hydrogenated vegetable oils appear to be a good alternative to Avicel® PH 102 as dry binder in the formulations evaluated.Keywords: Hydrogenated vegetable oils, Auxiliary dry binding, Hardness, Friability, Disintegration time, Dissolution, Direct compression tablet formulations

The tabletting properties of Stearolac-S

The tabletting properties of STEAROLAC-S was evaluated in this study and compared to those of stearic acid and magnesium stearate in three direct compression tablet formulations. An instrumented rotary tabletpress was used to determine the unit ejection force of tablets made from the direct compression formulations. The effects of the excipients on tablet hardness, friability, disintegration and dissolution rate were also evaluated. Tablets containing 3 - 4 % w/w STEAROLAC-S gave unit ejection force values comparable to those of tablets containing 2% w/w magnesium stearate. Tablets containing 4% STEAROLAC-S exhibited better physical properties than those containing 2% magnesium stearate. Prolonged mixing improved the lubricating efficiency of STEAROLAC-S and had no deleterious effect onthe disintegration of hydrochlorothiazide and ascorbic acid tablets. STEAROLAC-S does not possess the lubricating ability of magnesium stearate but appears to be a useful candidate for the formulation of sustained release chlorpheniramine maleate and phenylpropanolamine hydrochloride tablets.

In-line quantification of micronized drug and excipients in tablets by near infrared (NIR) spectroscopy: Real time monitoring of tabletting process

The objectives of this study were to assess the utility of near infrared (NIR) spectroscopy for simultaneous in-line quantification of the contents of drug and excipients in tablets and to monitor the tabletting process in real time. Direct compression tablet formulations comprising micronized chlorpheniramine maleate, lactose, microcrystalline cellulose and magnesium stearate were used. A custom built NIR setup was used for in-line spectral acquisition (980–1900 nm with 1 nm resolution) during the tabletting process. Calibration models using dynamic spectral acquisition were prepared and validated using design of experiment approach. During tabletting, stratified sampling of tablets was also carried out to compare the NIR prediction results and subsequent UV analysis results for drug content. The results obtained with calibration and validation statistics confirmed the accuracy of models used to predict contents of tablet components. Stratified sampling results for drug content did not exhibit any significant statistical variation. However, in-line quantification enabled the content analysis of individual tablets in the production batch and detection of content uniformity problems towards the end of the tabletting process. Furthermore, it provided the assurance of in-process content uniformity monitoring of the individual excipients during the tabletting process.

Application of the SeDeM Diagram and a new mathematical equation in the design of direct compression tablet formulation

Application of the new SeDeM Method is proposed for the study of the galenic properties of excipients in terms of the applicability of direct-compression technology. Through experimental studies of the parameters of the SeDeM Method and their subsequent mathematical treatment and graphical expression (SeDeM Diagram), six different DC diluents were analysed to determine whether they were suitable for direct compression (DC). Based on the properties of these diluents, a mathematical equation was established to identify the best DC diluent and the optimum amount to be used when defining a suitable formula for direct compression, depending on the SeDeM properties of the active pharmaceutical ingredient (API) to be used. The results obtained confirm that the SeDeM Method is an appropriate system, effective tool for determining a viable formulation for tablets prepared by direct compression, and can thus be used as the basis for the relevant pharmaceutical development.

Laser diffraction and image analysis as a supportive analytical tool in the pharmaceutical development of immediate release direct compression formulations

Immediate release direct compression tablet formulations require a strict control of the particle characteristics (i.e. particle size (distribution) and shape) of both the active pharmaceutical ingredient (API) and the excipients. In this publication, the development of a dry dispersion laser diffraction (LD) method has been outlined. With this method, the chemical development of an API meant for the manufacturing of an immediate release direct compression tablet formulation can be supported. Comparison with static image analysis (SIA) and scanning electron microscopy (SEM) data often shows laser diffraction to generate different size data. However, since LD is fast and frequently shows an adequate precision over a wide particle size range, the technique is still considered as a valuable analytical tool in the screening of the particle size distribution of API batches. In the future, automated (static) image analysis and dynamic image analysis are believed to become more and more important, since these techniques will allow the fast analysis of large amounts of particles with a minimum intervention of the operator.

Rapid release tablet formulation of micronized danazol powder produced by spray-freezing into liquid (SFL)

To prepare a rapid release tablet formulation containing SFL micronized powders by direct compression and to investigate the effects of SFL powder compositions and tabletting excipient compositions on drug release. Three SFL micronized powder formulations were studied including danazol/polyvinylpyrrolidone (PVP) K-15 (2:1), danazol/PVP K-15/poloxamer 407 (4:1:1), and danazol/PVP K-15/sodium lauryl sulfate (SLS) (4:1:1). The physicochemical properties of SFL micronized powders were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), surface area analysis, contact angle, and dissolution. Five tablet formulations containing SFL micronized powders were investigated. The excipients used in the study included microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, sodium starch glycolate, and low-substituted hydroxypropyl cellulose. Tablets containing SFL micronized powder were analyzed for hardness, disintegration, friability, and dissolution. XRD results indicated that danazol was amorphous regardless of excipient type used in the SFL micronized powder. The surface area of SFL danazol/PVP K-15 powder, 79.9 m 2 /g, exceeded that of danazol/PVP K-15/SLS (48.0 m 2 /g) and danazol/poloxamer 407 (30.0 m 2 /g). Each of these powders exhibited similar and significantly enhanced dissolution rates compared to the micronized crystalline danazol. A rapid release tablet formulation containing SFL danazol/PVP K-15/SLS (4:1:1) was developed. The dissolution rate of micronized crystalline danazol control from the tablet was slow; only 40% of danazol dissolved in 10 min. However, 94% dissolved in only 10 min from tablets containing SFL micronized danazol/PVP K-15/SLS powder. This rapid dissolution rate was similar to the value for the SFL danazol/PVP K-15/SLS powder prior to tableting. Amorphous SFL powders with high glass transition temperatures (T g ), were physically stable during the direct compression process, based on dissolution rates and DSC measurements. Direct compression tablet formulation of SFL amorphous micronized powder led to desirable mechanical properties and a very rapid release profile approaching that of the SFL powder before tableting. A high T g excipient was utilized to prevent crystallization of the danazol during the process.

Investigation of Flow Properties of Powders by Means of a Uniaxial Tester, in Relation to Direct Tablet Compression

ABSTRACTUnexpected poor flowability during commercial production of a direct compression tablet formulation initiated an investigation of the flow properties of the powder mixture and its components by means of a uniaxial tester. The failure function—a curve describing the strength of the powder bed as a function of the maximum main stress that has consolidated the bed—of the powder mixture and its components was determined. The drug was more cohesive than the filler, which was somewhat more cohesive than the powder mixture. Three excipients—a binder, a glidant and a lubricant—constituting 3.5 w/w% of the formulation improved the flowability of the mixture of active ingredient and filler. The failure function discriminated powder mixtures with poor flow from mixtures with medium or good flow. However, it was not possible to discriminate medium from good flow by means of the failure function. Attempts to correlate univariately the flow property parameters of the powder mixtures with particle size data or flow property data of included active ingredient and filler batches failed. Therefore a multivariate approach was tested. Principal component analysis (PCA) and projection to latent structures by means of partial least squares (PLS) were employed. An excellent PCA model was obtained with the flow properties of the powder mixture. A good PCA model of tableting performance—based on tablet weight variation and tablet machine speed—was obtained.

Design and characterization of a surfactant-enriched tablet formulation for oral delivery of a poorly water-soluble immunosuppressive agent

The feasibility of incorporating significant quantities of the anionic surfactant, sodium lauryl sulfate (SDS), into an immediate release tablet formulation of a poorly water-soluble immunosuppressive agent was investigated. Despite the extremely poor compressibility of SDS and poor chemical stability of the drug, a commercializable, direct-compression tablet formulation with satisfactory mechanical properties and acceptable chemical stability was achieved. Optimal in vitro release of the drug from the tablet formulation was achieved by establishing the minimum molar uptake ratio necessary to achieve complete micellar solubilization of the drug, after which formulation studies were conducted to determine the influence of formulation and process variables on the rate and extent of drug release. A model-independent analysis of dissolution results in a reduced volume (250 ml) of modified simulated gastric fluid demonstrated that the rate and extent of drug release was highly dependent on the mean particle size of the bulk drug, but independent of compression force above that required to achieve a compact of acceptable mechanical strength. Employing the Korsmeyer–Peppas model of Fickian and non-Fickian drug release, it was further shown that release of the drug from the dosage form was governed largely by surface erosion of the surfactant-enriched tablet matrix.

L-649,923 — The selection of an appropriate salt form and preparation of a stable oral formulation

L-649,923 is an orally active leukotriene D 4 antagonist and the salt of a γ-hydroxy acid. It was formulated as a physically and chemically stable compressed tablet dosage form. Because the free acid was inherently unstable, the physical and chemical properties of the sodium, calcium, ethylenediamine and benzathine salts were evaluated and the calcium salt selected as the most pharmaceutically acceptable form of the drug for formulation development. The principal route of degradation was through an intramolecular esterification to yield the γ-lactone. Degradation could be monitored by following the appearance of the γ-lactone with an HPLC assay. A mechanism of degradation was proposed resembling acid-catalyzed solution esterificatiom occuring in the sorbed moisture. This postulate was used as a predictive model. Formation of γ-lactone was minimized in a direct compression tablet formulation by reducing the amount of free acid in the drug substance, avoiding an aqueous granulating process, using excipients with low water content and adding sodium carbonate as an alkalizing agent.

The application of canonical analysis to the evaluation of the influence of changes in components of standard direct compression tablet formulations

Different types of microcrystalline and microfine celluloses are often used in direct tabletting mixtures. An evaluation has been undertaken of the connection between the pharmaceutical behaviour of a range of the cellulose products and the powder and tablet properties of the tabletting mixtures, using the multivariate statistical technique of canonical analysis. The cellulose properties were reflected in the behaviour of the tabletting mixtures, in particular the bulk volume, the particle size range, the formation energy (force-displacement-curves, E 2) and the elastic recovery energy ( E 3). The approach demonstrated that an exchange of the cellulose product in direct tabletting mixtures is only possible in special cases.

The Stability of Aspirin in a Moisture Containing Direct Compression Tablet Formulation

Studies were conducted on the stability of a direct compression tablet formulation containing aspirin as a model hydrolabile drug. EmdexR (a mixed-sugar diluent containing approximately 8 percent m...

Optimization of Direct Compression Tablet Formulations for Use in Tropical Countries

AbstractWith the aid of a combined mixture- and factorial- design, 2 standard tablet formulations were selected suitable for use in tropical countries. The formulations were based on native ingredients or ingredients that are available worldwide. The selection of the standard formulations was based on both the initial tablet properties of the formulations one day after preparation as well as the physical stability after storage under tropical conditions.The selected formulations were evaluated by adding model drugs (diazepam, 2 mg per tablet or hydrochlorthiazide, 100 mg per tablet) and measuring tablet properties, not only one day after preparation, but also after storage under tropical conditions. Both selected tablet formulations were suitable standard formulations for tablets prepared by direct compression for use in tropical countries.