Optimization of diluents on the basis of SeDeM-ODT expert system for formulation development of ODTs of glimepiride

The present study aimed to optimize diluents characteristics (rheological characteristics, compressibility and disintegration behavior) using SeDeM-ODT expert system, to mask poor characteristics of APIs and will help in development of a formulation which is to be processed by direct compression technique. On the basis of SeDeM-ODT experts system, various parameters were determined for glimepiride, diluents and other excipients, and evaluated their suitability for direct compression and bucco-dispersibility. Diluents were selected and powder blend of all the developed formulations were tested as per SeDeM-ODT expert system. Powder blends were compressed to ODTs and cross carmellose sodium was used as super dissintegrant. Different parameters of the powder blend related to flow were evaluated while compressed tablets were subjected to various official and un-official quality control tests. SeDeM-ODT Experts system was successfully applied for optimization of diluents and all the formulations exhibited better flow, disintegration behavior and sufficient mechanical strength, irrespective of the addition of other excipients having poor characteristics. Results of the developed formulations was same as predicted in terms of rapid disintegration (disintegration < 60sec) and high mechanical strength (crushing strength greater than 40 N) of the tablets. SeDeM-ODT expert system can help in selection of diluents with optimum characteristics, required for tablet preparation by direct compression, facilitating the process of formulation development and avoided extensive experimentation, as carried out in conventional statistical optimization.     

The Effect of Agglomeration Methods on the Micromeritic Properties of a Maltodextrin Product, Maltrin 150™

Maltrin M150 is a fine powder of maltodextrin which is a carbohydrate product made by controlled hydrolysis of corn starch. Agglomerated Maltrin was prepared using a fluidized bed granulation process and a roller compaction method, respectively. The micromeritic properties of these two granular products were compared. Three different sizes of granules (20/30, 40/50 and 80/100 mesh size) were used in the evaluation. Granules produced by the fluidized bed method showed a relatively low bulk density as compared to the roller compacted granules. As the granule size was reduced, the roller compacted granules showed a decrease in bulk density while an increase in bulk density was seen in the fluidized bed granulated product. A better flowability of the roller compacted granules was demonstrated by a higher flow rate and a lower compressibility index. For a given compression pressure, roller compacted granules produced compacts with a lower tensile strength. A significant work-hardening effect was exhibited by the roller compacted product.     

Comparative binder efficiency modeling of dry granulation binders using roller compaction

Roller compaction parameters’ impact on granules and tableting properties of coprocessed Avicel^® DG [ADG], a physical mixture of the two components at the same composition present in ADG [PADCP], and microcrystalline cellulose and Kollidon^® VA-64 Fine physical mixture [KVA64] was quantified by analysis of variance (ANOVA) and multivariate methods. Roller force, roller gap, and roller speed levels were selected for evaluation. A 3³ full-factorial experimental design with three center points for roller force, roller gap, and roller speed was used. The response parameters studied were granule-to-fines (GF) ratio, compressibility index (CI), tablet thickness (TT), tablet friability (TF), tablet breaking force (TBF) and disintegration time (DT). A model acetaminophen tablet formulation was roller granulated and tableted at 10?kg scale. Principal component analysis of ADG and PADCP formulations were separated from KVA64 formulations, indicating different granule and tableting properties were binder dependent. This difference in binder performance was also confirmed by ANOVA. The ANOVA also showed that there were no statistical performance differences between coprocessed ADG and its comparable physical blend with the exception of TT. Principal component regression (PCR) analyses of ADG and PADCP revealed that these excipients exhibited a statistically significant negative effect on granules-to-fine (GF) ratio, TT, TBF, and DT. KVA64 demonstrated a positive effect on these parameters. The KVA64 physical mixture demonstrated an overall better performance and binding capability. This study strongly suggests that there is no performance advantage of coprocessed Avicel^® DG when compared to a physical mixture of the two components at the same composition.     

Investigation of the effect of impeller speed on granules formed using a PMA-1 high shear granulator

Impeller speed was varied from 300 to 1500?rpm during the wet high shear granulation of a placebo formulation using a new vertical shaft PharmaMATRIX-1 granulator. The resulting granules were extensively analysed for differences caused by the varying impeller speed with emphasis on flowability. Microscopy showed that initial granules were formed primarily from microcrystalline cellulose at all tested impeller speeds. At low impeller speed of 300?rpm in the "bumpy" flow regime, forces from the impeller were insufficient to incorporate all the components of the formulation into the granules and to promote granule growth to a size that significantly improved flowability. The "roping" flow regime at higher impeller speeds promoted granule growth to a median particle size of at least 100 μm that improved the flowability of the mixture. Particle size distribution measurements and advanced indicators based on avalanching behavior, however, showed that an impeller speed of 700?rpm produced the largest fraction of optimal granules with the best flowability potential. This impeller speed allowed good development of "roping" flow for sufficient mixing, collision rates and kinetic energy for collisions while minimizing excessive centrifugal forces that promote buildup around the bowl perimeter.     

Investigation of the effect of impeller speed on granules formed using a PMA-1 high shear granulator

Impeller speed was varied from 300 to 1500?rpm during the wet high shear granulation of a placebo formulation using a new vertical shaft PharmaMATRIX-1 granulator. The resulting granules were extensively analysed for differences caused by the varying impeller speed with emphasis on flowability. Microscopy showed that initial granules were formed primarily from microcrystalline cellulose at all tested impeller speeds. At low impeller speed of 300?rpm in the “bumpy” flow regime, forces from the impeller were insufficient to incorporate all the components of the formulation into the granules and to promote granule growth to a size that significantly improved flowability. The “roping” flow regime at higher impeller speeds promoted granule growth to a median particle size of at least 100 µm that improved the flowability of the mixture. Particle size distribution measurements and advanced indicators based on avalanching behavior, however, showed that an impeller speed of 700?rpm produced the largest fraction of optimal granules with the best flowability potential. This impeller speed allowed good development of “roping” flow for sufficient mixing, collision rates and kinetic energy for collisions while minimizing excessive centrifugal forces that promote buildup around the bowl perimeter.     

Comparative Evaluation of A New Direct Compression Excipient, SoludexTM 15

Soludex^TM15, a new corn-based maltodextrin, has been evaluated and compared to nine frequently used commercial excipients for direct compression. The properties of the excipients reported are median size, particle size distribution, bulk density, flow rate, repose angle, moisture content, and hardness and compressibility at several compaction pressures. The influence of concentration of lubricant and mixing time with a lubricant on hardness of Soludex 15 compacts were determined. The effect of 1% magnesium stearate on the hardness of compacts was determined for the ten excipients. Model formulations for direct compression tablets using Soludex 15 are presented, and for a batch of these tablets the weight variation, friability, hardness, disintegration and dissolution are reported. Soludex 15 exhibited excellent flow and compressibility, and model tablets using Soludex 15 as the direct compression diluent met USP specifications and provided a rapid dissolution of the active ingredient.     

Pharmaceutical Evaluation of Multipurpose Excipients for Direct Compressed Tablet Manufacture: Comparisons of the Capabilities of Multipurpose Excipients with Those in General Use

Recently, a novel type of multipurpose excipient (MPE) with high binding characteristics and high fluidity has been developed. In this study, the capabilities of MPEs (Ludipress and Microcelac) were compared with those of excipients in general use. Also, the effects on powder and tableting characteristics of the physical properties and contents of active ingredients were examined in tablets prepared with these MPEs by the direct compression method. Multipurpose excipients mixed with adjuvants such as fillers, binders, lubricants, disintegrants, and the like show superior fluidity and compressibility. Tablets containing very small amounts of highly active ingredients with little dispersion were prepared. However, with increases in active ingredient content, each of the physical properties was affected strongly by the properties of the active ingredient. Tablets with appropriate hardness and disintegration characteristics could be prepared by mixing of different types of MPEs.     

Tricalcium citrate – a new brittle tableting excipient for direct compression and dry granulation with enormous hardness yield

Objectives: Tricalcium citrate (TCC) was characterized as a tableting excipient for direct compression (DC) and dry granulation (DG).

Significance: Brittle materials usually lead to tablets of inferior mechanical strength compared to plastic deforming materials. A brittle material exhibiting a high tabletability with the ability to retain that behavior during recompression would represent a valuable alternative to the commonly used microcrystalline cellulose.

Methods: Tablets of TCC and other common fillers were directly compressed for the purpose of compression analysis including Heckel analysis, speed dependency, and lubricant sensitivity. DG by roller compaction of TCC was first simulated via briquetting and experiments were subsequently repeated on a roller compactor.

Results: TCC appears as an excellent flowing powder of large agglomerates consisting of lower micron to submicron platelets. Despite the brittle deformation mechanism identified in the Heckel analysis, TCC demonstrated a very high mechanical strength up to 11?MPa in conjunction with an astonishingly low solid fraction of 0.85 at a compression pressure of 400?MPa. This was seen along with hardly any speed and lubricant sensitivity. Nevertheless, disintegration time was very short. TCC tablets suffered only a little from the re-compression: a slight loss in tensile strength of 1–2?MPa was observed for granules produced via roller compaction.

Conclusions: TCC was found to be suitable for DC as a predominantly brittle deforming filler, nevertheless demonstrating an enormous hardness yield while being independent of lubrication and tableting speed. TCC furthermore retained enough bonding capacity after DG to maintain this pronounced tabletability.     

Co-proccessed excipients with enhanced direct compression functionality for improved tableting performance

It is necessary to have excipients with excellent functional properties to compensate for the poor mechanical properties and low aqueous solubility of the emerging active ingredients. Therefore, around 80% of the current drugs are not suitable for direct compression and more advanced excipients are required. Further, conventional grades of excipients cannot accommodate the technologically advanced high speed rotary tablet presses which require a powder with excellent flow, good compressibility, compactibility, particle size distribution and homogeneity of the ingredients. Co-processed excipients have been created to enhance the functional properties of the excipients and reduce their drawbacks. Co-processing is defined as the combination of two or more excipients by a physical process. Co-processed excipients are adequate for direct compression since they become multifunctional and thus, their dilution potential is high eliminating the need for many excipients in a formulation. In some cases, they are able to hold up to 50% of the drug in a formulation rendering compacts of good tableting properties. This study describes and discusses the functionality enhancement of commercial and investigational excipients through co-processing.     

Evaluation of Era-Tab as a Direct Compression Excipient

The physical and compressional properties of a modified rice starch, Era-Tab, were evaluated and compared with those of 4 commercially available direct compression excipients, namely, microcrystalline cellulose (Avicel PH-101), partially pregelatinized starch, spray-dried lactose (Super-Tab Lactose), and granular dicalcium phosphate dihydrate (Emcompress). It was found that Era-Tab possessed high flowability and adequate compressibility. The compacted material made with Era-Tab has a higher crushing strength and a lower friability than 3 other direct compression excipients, except microcrystalline cellulose. Tablets containing terfenadine of the same degree of hardness (10 kg) were also prepared using different direct compression excipients. The disintegration time of the tablets made with Era-Tab was approximately 2.5 min. The maximum of the accumulated percentage of terfenadine released from the tablet reached 90%, and 63.2% of it was released within 20 min. Both the powder characteristics and tablet properties show that the modified rice starch, Era-Tab, is a useful product as a direct compression tablet excipient.     

To prepare and characterize microcrystalline cellulose granules using water and isopropyl alcohol as granulating agents and determine its end-point by thermal and rheological tools

Microcrystalline cellulose (MCC-102) is one of the most commonly used excipient in the pharmaceutical industry. For this research purpose, authors have developed a different technique to determine the end point for MCC-102 using water and isopropyl alcohol 70% (IPA) as granulating agent. Wet and dry granules obtained were characterized for their flow properties using the powder rheometer and thermal analysis. Powder rheometer was used to measure basic flowability energy (BFE), specific energy (SE), percentage compressibility, permeability and aeration. Thermal analysis includes effusivity and differential scanning calorimetry (DSC) measurements. BFE and SE results showed water granules requires high energy as compared to IPA granules. Permeability and compressibility results suggest IPA forms more porous granules and have better compressibility as compared to water granules. Hardness data reveals interesting phenomena in which as the amount of water increases, hardness decreases and vice-versa for IPA. Optimal granules were obtained in the range of 45–55% w/w. DSC data supported the formation of optimal granules. Empirical measurements like angle of repose did not reveal any significant differences between powder flow among various granules. In this paper, with the help of thermal effusivity and powder rheology we were able to differentiate between various powder flows and determine the optimal range for granule formation.     

Co-processing of cefuroxime axetil by spray drying technique for improving compressibility and flow property

The aim of the present investigation was to improve the compressibility and flow property of cefuroxime axetil by co-processing it with mannitol and chitosan chlorhydrate using spray drying method. 3² full factorial design, having inlet air temperature and mannitol: chitosan chlorhydrate ratio as independent variables was used for the optimization. Statistical analysis of obtained results revealed that both independent variables had significant effect on response variables (p value?<?.05). Evaluation of dependent variables suggested, excellent to good flow properties (angle of repose, Carr's index, and Hausner's ratio) for all prepared batches. Desirability function was used for the selection of the optimized batch which was evaluated for Kawakita’s equation, Heckel’s plot to assess compression behavior of co-processed product under applied pressure. Result of this analysis revealed that the optimized batch product had better compressibility than physical mixture. The tablets prepared by directly compressing spray-dried product, exhibited excellent tensile strength acceptable friability (<1%) and similar release profile when compared with marketed formulation (Similarity factor 89.24 and dissimilarity factor 1.79). So the results of the present investigation concluded that cefuroxime axetil was successfully co-processed with above mentioned excipients by using spray drying method to make it directly compressible.     

Pharmaceutical Evaluation of Multipurpose Excipients for Direct Compressed Tablet Manufacture: Comparisons of the Capabilities of Multipurpose Excipients with Those in General Use

Recently, a novel type of multipurpose excipient (MPE) with high binding characteristics and high fluidity has been developed. In this study, the capabilities of MPEs (Ludipress and Microcelac) were compared with those of excipients in general use. Also, the effects on powder and tableting characteristics of the physical properties and contents of active ingredients were examined in tablets prepared with these MPEs by the direct compression method. Multipurpose excipients mixed with adjuvants such as fillers, binders, lubricants, disintegrants, and the like show superior fluidity and compressibility. Tablets containing very small amounts of highly active ingredients with little dispersion were prepared. However, with increases in active ingredient content, each of the physical properties was affected strongly by the properties of the active ingredient. Tablets with appropriate hardness and disintegration characteristics could be prepared by mixing of different types of MPEs.     

Spherical crystallization of celecoxib

Celecoxib exhibits poor flow properties and compressibility. Spherical crystallization of celecoxib was carried out using the solvent change method. An acetone:dichloromethane (DCM):water system was used where DCM acted as a bridging liquid and acetone and water as good and bad solvent, respectively. Hydroxypropylmethylcellulose (HPMC) was used to impart strength and sphericity to the agglomerates. The effect of amount of bridging liquid and speed of agitation was studied using 3² factorial design. Primary properties of the agglomerates were evaluated by infrared spectroscopy, powder X-ray diffraction, and differential scanning calorimetry. The effect of variables on micromeritic, mechanical, compressional, and dissolution behavior was evaluated by response surface methodology. Particle size, bulk density, mean yield pressure (MYP), and drug release were found to be significantly affected by either of the two variables. Interaction of variables significantly affected the MYP.     

Spherical Crystallization of Celecoxib

ABSTRACT

Celecoxib exhibits poor flow properties and compressibility. Spherical crystallization of celecoxib was carried out using the solvent change method. An acetone:dichloromethane (DCM):water system was used where DCM acted as a bridging liquid and acetone and water as good and bad solvent, respectively. Hydroxypropylmethylcellulose (HPMC) was used to impart strength and sphericity to the agglomerates. The effect of amount of bridging liquid and speed of agitation was studied using 3² factorial design. Primary properties of the agglomerates were evaluated by infrared spectroscopy, powder X-ray diffraction, and differential scanning calorimetry. The effect of variables on micromeritic, mechanical, compressional, and dissolution behavior was evaluated by response surface methodology. Particle size, bulk density, mean yield pressure (MYP), and drug release were found to be significantly affected by either of the two variables. Interaction of variables significantly affected the MYP.     

A novel co-processing method to manufacture an API for extended release formulation via formation of agglomerates of active ingredient and hydroxypropyl methylcellulose during crystallization

A novel process for generating agglomerates of active pharmaceutical ingredient (API) and polymer by swelling the polymer in a water/organic mixture has been developed to address formulation issues resulting from a water sensitive, high drug load API with poor powder properties. Initially, the API is dissolved in water, following which hydroxypropyl methylcellulose (HPMC) is added, resulting in the imbibing of water, along with the dissolved API, into the HPMC matrix. The addition of acetone and isopropyl acetate (anti-solvents) then causes the API to crystallize inside and on the surface of HPMC agglomerates. The process was scaled up to 20?kg scale. The agglomerates of API and HPMC generated by this process are ～350?µm diameter, robust, and have significantly better flow than the API as measured by Erweka flow testing. These agglomerates exhibit improved bulk density, acceptable chemical stability, and high compressibility. The agglomerates process well through roller compaction and tableting, with no flow or sticking issues. This process is potentially adaptable to other APIs with similar attributes.     

“Rolling” phenomenon in twin screw granulation with controlled-release excipients

The developed knowledge regarding use of twin screw granulators for continuous wet granulation has been primarily limited to immediate release formulations in the literature. The present study highlights an issue previously unreported for wet granulation with twin screw extruders when using formulations containing controlled-release (CR) excipients. Long (3–10?mm), twisted noodle-like granules can be produced in the presence of these excipients that are difficult to control and are anticipated to create complications in downstream unit operations to the granulator. Working with two different CR excipients, METHOCEL? K4M and Kollidon® SR, each blended at different ratios with a mixture of 80% α-lactose monohydrate/20% microcrystalline cellulose, these unique particles were found to be produced in the conveying elements of the extruder, arising from a rolling action at the top of the screw flights. The CR excipients adhesively strengthen the wetted mass, forming this undesired granule shape such that they persisted to the exit of the machine; the shape appeared most strongly affected by screw speed, producing particles of higher aspect ratio as speed was increased. Adjusting the concentration of these CR excipients in the formulation, the flow rate or the type of compression element used in the screws proved ineffective in controlling the problem. Rather, a re-design of the extruder screws was required to prevent generation of these extended-form granules.     

Pharmaceutical production of tableting granules in an ultra-small-scale high-shear granulator as a pre-formulation study

Objective: In some of drug developments, the amount of bulk drug powder to use in early stages is limited and it is not easy to supply a sufficient drug amount for conventional preparation methods. Therefore, an ultra-small-scale high-shear granulator (less than 5?g) (USG) was developed and applied to small-scale granulation as a pre-formulation. Method: The sample powder consisted of 66.5% lactose, 28.5% microcrystalline cellulose and 5.0% hydroxypropylcellulose. The granules were obtained to agitate 5?g of the sample powder with 1.0?mL of water at 300?rpm for 5?min after pre-powder mixing for 3?min by the USG and the manual hand (HM) methods. Results: The granules were evaluated by the 10% and 90% accumulated particle size and the recoveries of the granules and the powder solid. Median particle size for the USG and the HM methods was 159.2?±?2.3 and 270.9?±?14.9 μm, respectively. The USG method had a narrower particle size distribution than those by the HM method. The recovery of the granules by USG was significantly larger than that by the HM method. Conclusion: Characteristics of all of the granules indicated that the USG method could produce higher quality granules within a shorter time than the HM methods.     

New gentle-wing high-shear granulator: impact of processing variables on granules and tablets characteristics of high-drug loading formulation using design of experiment approach

The aim of this work was to study the application of design of experiment (DoE) approach in defining design space for granulation and tableting processes using a novel gentle-wing high-shear granulator. According to quality-by-design (QbD) prospective, critical attributes of granules, and tablets should be ensured by manufacturing process design. A face-centered central composite design has been employed in order to investigate the effect of water amount (X₁), impeller speed (X₂), wet massing time (X₃), and water addition rate (X₄) as independent process variables on granules and tablets characteristics. Acetaminophen was used as a model drug and granulation experiments were carried out using dry addition of povidone k30. The dried granules have been analyzed for their size distribution, density, and flow pattern. Additionally, the produced tablets have been investigated for; weight uniformity, breaking force, friability and percent capping, disintegration time, and drug dissolution. Results of regression analysis showed that water amount, impeller speed and wet massing time have significant (p?相似文献   

Fabrication of Al–Si coating on Ti–6Al–4V substrate by mechanical alloying

Al–Si coatings were synthesized on Ti–6Al–4V alloy substrate by mechanical alloying with Al–Si powder mixture. The as-prepared coatings had composite structures. The effects of Al–Si ratio, milling duration and rotational speed on the microstructure and oxidation behavior of coating were investigated. The results showed that the continuity and the anti-oxidation properties of the coating were enhanced with the increase of Al–Si weight ratio. The thickness of the coating largely increased in the initial 5-hour milling process and decreased with further milling. A rather long-time ball milling could result in the generation of microdefects in coating, which had an adverse effect on the oxidation resistance of coating. Both the thickness and the roughness of the coating increased with the raise of rotational speed. The low rotational speed would lead to the formation of discontinuous coating. The rotational speed had a limited effect on the coating oxidation behavior. Dense, continuous and high-temperature protective Al–Si coatings could be obtained by mechanical alloying with Al–33.3?wt.%Si powder at the rotational speed ranging from 250 to 350?rpm for 5?h.