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[Display omitted] During tablet manufacturing an increase in the production temperature can lead to an alteration of tablet characteristics. In the present study, the influence of the initial particle size on the tableting behavior of ductile polymers upon temperature rise was investigated. Different grades of the respective materials were tableted at temperatures ranging from 22 to 70 °C. Alterations in tableting behavior were affected by the initial particle size. Smaller particle sizes led to a more pronounced decrease in yield pressure and net work of compaction during compressibility analysis. The results were confirmed in the tabletability studies. Tablets from binary mixtures with lactose containing smaller polymer particles yielded a stronger increase in tensile strength. Differences in the tensile strength increase of two grades from the same material correlated with the ratio of their median particle sizes. The alteration of compactibility profiles was also particle size dependent. The increase in solid fraction was more prominent for binary mixtures containing polymers with smaller particle sizes. However, the ratio of the median particle sizes of the compared grades showed no systematic effect. The results underline the importance of controlling the structural properties of a material carefully during formulation development and production. If a formulation responds to temperature variations, an increase in particle size might be beneficial to decrease its heat sensitivity. [ABSTRACT FROM AUTHOR]

The present study focuses on the compaction behavior of polymeric excipients during compression in comparison to nonpolymeric excipients and its consequences on commonly used Heckel analysis. Compression analysis at compaction pressures (CPs) from 50 to 500 MPa was performed using a compaction simulator. This study demonstrates that the particle density, measured via helium pycnometer (ρpar), of polymeric excipients (Kollidon®VA64, Soluplus®, AQOAT®AS-MMP, Starch1500®, Avicel®PH101) was already exceeded at low CPs (<200 MPa), whereas the ρpar was either never reached for brittle fillers such as DI-CAFOS®A60 and tricalcium citrate or exceeded at CPs above 350 MPa (FlowLac®100, Pearlitol®100SD). We hypothesized that the threshold for exceeding ρpar is linked with predominantly elastic deformation. This was confirmed by the start of linear increase in elastic recovery in-die (ERin-die) with exceeding particle density, and in addition, by the applicability in calculating the elastic modulus via the equation of the linear increase in ERin-die. Last, the evaluation of "density under pressure" as an alternative to the ρpar for Heckel analysis showed comparable conclusions for compression behavior based on the calculated yield pressures. However, the applicability of Heckel analysis for polymeric excipients was questioned in principle. In conclusion, the knowledge of the threshold provides guidance for the selection of suitable excipients in the formulation development to mitigate the risk of tablet defects related to stored elastic energy, such as capping and lamination. [ABSTRACT FROM AUTHOR]

Despite the ability to characterize the plasticity of powders in a material-sparing and expedited manner, the in-die Heckel analysis has been widely criticized for its sensitivity to several factors, such as particle elastic deformation, tooling size, lubrication, and speed. Using materials exhibiting a wide range of mechanical properties, we show that the in-die Py correlates strongly with three established plasticity parameters obtained from the out-of-die Heckel analysis, Kuentz-Leuenberger analysis, and macroindentation. Thus, the in-die Py is a reliable parameter for quantifying powder plasticity in a material-sparing and expedited manner.

The present study focuses on the compaction behavior of polymeric excipients during compression in comparison to nonpolymeric excipients and its consequences on commonly used Heckel analysis. Compression analysis at compaction pressures (CPs) from 50 to 500 MPa was performed using a compaction simulator. This study demonstrates that the particle density, measured via helium pycnometer (ρpar), of polymeric excipients (Kollidon®VA64, Soluplus®, AQOAT®AS-MMP, Starch1500®, Avicel®PH101) was already exceeded at low CPs (par was either never reached for brittle fillers such as DI-CAFOS®A60 and tricalcium citrate or exceeded at CPs above 350 MPa (FlowLac®100, Pearlitol®100SD). We hypothesized that the threshold for exceeding ρpar is linked with predominantly elastic deformation. This was confirmed by the start of linear increase in elastic recovery in-die (ERin-die) with exceeding particle density, and in addition, by the applicability in calculating the elastic modulus via the equation of the linear increase in ERin-die. Last, the evaluation of “density under pressure” as an alternative to the ρpar for Heckel analysis showed comparable conclusions for compression behavior based on the calculated yield pressures. However, the applicability of Heckel analysis for polymeric excipients was questioned in principle. In conclusion, the knowledge of the threshold provides guidance for the selection of suitable excipients in the formulation development to mitigate the risk of tablet defects related to stored elastic energy, such as capping and lamination.

This study focuses on the impact of initial particle size on the tabletability and the deformation behaviour (i.e. plasticity) of granules produced by twin-screw melt granulation (TSMG). As model substances, three different grades of anhydrous dicalcium phosphate (aDCP) were melt-granulated with polyethylene glycol 6000 (PEG) using a twin-screw granulator. Compaction performance of the granules and the corresponding physical mixtures (PM) was evaluated by in-die and out-of-die compaction analysis. A major impact on granules deformation behaviour was found for the relation of the specific surface area of the filler material to the binder content. A relative yield pressure (YP) was introduced to describe the enhancement in plastic deformation behaviour, defined as the plasticity performance factor (PPF). Furthermore, a modified Kawakita model was used to describe the granulation efficiency, compared to a calculated physical mixture model. Granules under investigation showed an increased plastic deformation, enhanced tabletability and reduced elastic recovery (ER). The binder was shown to be finely distributed and to fill the voids between the aDCP particles (image analysis of the carbon energy dispersive X-ray maps). A small initial particle size of filler material (DI-CAFOS® A7 and A12) was more efficient than a larger particle size (DI-CAFOS® A60). A very low particle size (DI-CAFOS® A7) required the addition of 1% (w /w) colloidal silicon dioxide to enable feeding of the material into the granulator. Moreover, due to the larger surface area of these particles, a higher amount of binder was necessary to achieve a low PPF and a high tensile strength (TS). The graphical abstract illustrates the SEM images of the used materials. Results of the granules containing 5% (w/w) PEG 6000 are shown. The Heckel plots and deviations from the modified Kawakita model are presented. A formula was defined for the calculation of the plasticity performance factor (PPF) based on the yield pressure (YP) of the formulation and neat filler. The PPFs of the granules are shown as bar charts. Unlabelled Image • Melt granulation effectively changed brittle into plastic deformation behaviour. • Efficiency linked to binder distribution quantified by EDX-mapping and filler PSD. • Tabletability correlated with the achieved solid fraction after compression. • For physical mixtures solid fraction followed a modified Kawakita model. • Granules deviation from the model correlated with the plasticity performance factor. [ABSTRACT FROM AUTHOR]

Drug-drug cocrystals (DDC) represent a unique subset of pharmaceutical materials offering distinct advantages in combination therapies, pharmacokinetics, and patient compliance. However, their structure–function relationships are rarely reported despite its central importance in successful medicine. A material-sparing approach consisting of a molecular and structural perspective is reported to evaluate tabletability of a model DDC, metformin:salicylic acid, relative to its components: metformin HCl (MET) and sodium salicylate (SAL). MET alone displayed a very poor tabletability, which could be attributed to its isotropic and stiff interaction topology. SAL displayed a highly anisotropic interaction topology with layers of strongly hydrogen-bonded salicylate molecules promoting deformation and tabletability. This is also confirmed by its low moduli. DDC yielded intermediate stiffness and elastic anisotropy material with an improved plastic flow and overall better tabletability. Overall, DDC is a promising therapeutic class requiring the physical–mechanical evaluation to assure their processability to enjoy their therapeutic advantages. [ABSTRACT FROM AUTHOR]

Tablets are the most commonly used dosage form in the pharmaceutical industry, and their properties such as disintegration, dissolution, and portability are influenced by their strength. However, in industry, the mixing fraction of powders to obtain a tablet compact with sufficient strength is determined based on empirical rules. Therefore, a method for predicting tablet strength based on the properties of a single material is required. The objective of this study was to quantitatively evaluate the relationship between the compression properties and tablet strength of powder mixtures. The compression properties of the powder mixtures with different plasticities were evaluated based on the force-displacement curves obtained from the powder compression tests. Heckel and compression energy analyses were performed to evaluate compression properties. During the compression energy analysis, the ratio of plastic deformation energy to elastic deformation energy (E p /E e ) was assumed to be the plastic deformability of the powder. The quantitative relationship between the compression properties and tensile strength of the tablets was investigated. Based on the obtained relationship and the compression properties of a single material, a prediction equation was put forward for the compression properties of the powder mixture. Subsequently, a correlation equation for tablet strength was proposed by combining the values of K and E p /E e obtained from the Heckel and compression energy analyses, respectively. Finally, by substituting the compression properties of the single material and the mass fraction of the plastic material into the proposed equation, the tablet strength of the powder mixture with different plastic deformabilities was predicted.

Objective: The objective of this study was to evaluate non-crystalline cellulose (NCC) as a novel tablet excipient in solid oral dosage forms in comparison with microcrystalline cellulose (MCC) and silicified microcrystalline cellulose (Prosolv®, SMCC). Significance: MCC, although a widely used tablet excipient, has diasdvantages in terms of its low dilution potential for potent drugs, and sensitivity to lubricant and moisture. SMCC, a modified version of MCC, has improved tablet compression properties. However, SMCC is expensive and also affects the moisture sorption and particle deformation during compression leading to increased tensile strength and tablet hardness. NCC was found to be similar to SMCC in its performance as a tablet excipient and thus can serve as a cheaper alternative to SMCC. Methods: Scanning electron microscopy (SEM), X-ray diffrectometry (XRD), and differential scanning calorimetry (DSC) analyses were performed on NCC, MCC, and SMCC. Further, out-of-the die Heckel, Kawakita compact densification and stress-strain analyses were performed to evaluate their compaction and compressibility properties. Various compendial and non-compendial tests were performed to to determine the flow properties of materials. Dissolution studies were performed using amlodipine besylate as a marker drug. Results: It was found that NCC has similar or even better flow properties and compactibility than MCC due to its porous and amorphous structure whereas it had similar properties as SMCC. Conclusions: Based on the data, it can be concluded that NCC can serve as a cheaper and better alternative to MCC as excipient in solid dosage forms. [ABSTRACT FROM AUTHOR]

[Display omitted] • Pycnometric tablet density can resolve Heckel negative porosity issue. • New approach allows efficient use of full Heckel plot without negative porosity. • New approach can overcome the limitations of modified Heckel equation approach. A parameterization of compaction simulator generated dynamic compression profile with a few grams of powder provides important information about the material deformation and compact elasticity. The Heckel equation is by far the most popular choice among pharmaceutical scientists for such parametrization. A general approach of Heckel analysis uses pycnometric powder density (ρ P 0) for relative density calculation. However, as 'in-die' tablet bulk density at applied compression pressure (ρ BP) becomes greater than or equal to the measured ρ P 0 , the general approach typically poses a negative porosity challenge at high compression pressure regions. It is only theoretically possible to have a tablet with zero or negative porosity. Negative porosity may be detected during 'in-die' compression analysis, but it will not exist after ejection of the tablet in practical aspect. Thus, the present work proposes a new approach to using pycnometric tablet density (ρ PP) in the relative density calculations of Heckel analysis. This ρ PP may be a better representation of actual tablet particle volume, as it is composed of non-accessible intra-particulate pores, which are broken under applied compression pressure. A new approach showed its immunity for Heckel high-pressure negative porosity. It enables the utilization of the compression and decompression phases of dynamic compression profiles to evaluate macroscopic compaction performance. The proposed approach was validated with a reported modified Heckel approach. The Heckel parameters computed with both methodologies for microcrystalline cellulose and lactose were not statistically different. However, a modified Heckel approach was unable to compute Heckel parameters of poorly compacting starch unlike the new approach. A modified Heckel approach became invalid during starch compaction at low compression pressures (below 400 MPa), where starch was forming weaker but still intact tablets. Certainly, a complete Heckel profiling with a new approach could save time and costs in an early development stage for designing and screening scientifically based lead prototype formulations. [ABSTRACT FROM AUTHOR]

The effects of PURE- DENT® and SPRESS® starch properties on their compression behavior was characterized using ' SM2' approach (structural properties, macroscopic properties, and multivariate analysis). Moisture sorption rate constants, moisture content, amylose and amylopectin degradation enthalpy, percent crystallinity, amylose-amylopectin ratio, and cross-linking degree were used to profile starch structural properties. Particle density, particle size distribution, and Heckel compression descriptors [yield pressure ( YP) of plastic deformation, and elastic recovery] were used as macroscopic descriptors. The structural and macroscopic properties were correlated qualitatively [principal component analysis ( PCA)] and quantitatively [standard least square regression ( SLSR)] with the tablet mechanical strength ( TMS). These analyses revealed that the differences correlated with amylose-amylopectin content, particle density, compression mechanisms, and TMS between the starch grades. Univariate analysis proved lacking; however, PCA identified the particle size, moisture content, percent crystallinity, amylose-amylopectin ratio, and YP of plastic deformation and elastic recovery as the main factors influencing the starch TMS. SLSR quantified the positive influence of Fourier transform infrared spectra absorbance ratio at 1022-1003 and YP of the immediate elastic recovery, and the negative contribution of amylopectin content on the TMS. Therefore, starch amylose and amylopectin content, crystallinity, and lower elastic recovery are mainly responsible for better TMS. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:3870-3882, 2015 [ABSTRACT FROM AUTHOR]

Purpose: The aim of the present work was to improve rate of dissolution and processing parameters of BCS class II drug, chlorzoxazone using cogrinding technique in the presence of different excipients as a carrier. Materials and Methods: The drug was coground with various carriers like polyethylene glycol (PEG 4000), hydroxypropyl methylcellulose (HPMC) E50LV, polyvinylpyrrolidone (PVP)K30, Kaolin and Neusilin US2 using ball mill, where only PEG 4000 improved dissolution rate of drug by bringing amorphization in 1:3 ratio. The coground mixture after 3 and 6 h was evaluated for various analytical, physicochemical and mechanical parameters. Results: The analysis showed conversion of Chlorzoxazone from its crystalline to amorphization form upon grinding with PEG 4000. Coground mixture as well as its directly compressed tablet showed 2.5-fold increment in the dissolution rate compared with pure drug. Directly compressible tablets prepared from pure drug required a large quantity of microcrystalline cellulose (MCC) during compression. The coground mixture and formulation was found stable in nature even after storage (40°C/75% relative humidity). Conclusions: Cogrinding can be successfully utilized to improve the rate of dissolution of poorly water soluble drugs and hence bioavailability. [ABSTRACT FROM AUTHOR]

The consumption of fibers is associated with many health benefits, such as a reduction of cardiovascular and gastrointestinal diseases, control of body weight, and prevention of diabetes. Despite the widespread use of fiber supplements such as capsules or tablets, there is an almost complete lack of information concerning the technological properties of functional fibers used in nutraceutical formulations. The aim of this work was to characterize the technological properties of citrus fibers necessary for their use as a processing aid in tableting. The results obtained showed that citrus fibers share many properties of other polysaccharides used as tableting excipients, such as thermal behavior and compaction mechanism, together with an appreciable tabletability. However, the most interesting properties resulted from their disintegration power. Citrus fibers behaved in a similar manner to the well-known super disintegrant croscarmellose sodium and resulted to be little susceptible to their concentration, to lubricant type, and lubricant concentration. Thus, this work supports the idea of a potential use of citrus fibers as “active” substances and processing aid in the tableting of nutraceutical products and also as functional excipient in pharmaceutical tablets formulation. [ABSTRACT FROM AUTHOR]

Abstract: The objective behind this study is to ameliorate the flowability, compressibility and tableting properties of aceclofenac by developing a prolonged release microparticulate system using an algino-carbopol polymeric blend. Prepared microspheres were subjected to various physico-chemical studies along with in vitro drug release studies to optimize the concentration of the polymeric blend required to sustain the drug release for 12h. Optimize formulation was further subjected to different flowability and compressibility studies to observe the impact of microspheres on improvements of flow properties. All the microsphere formulations exhibited good entrapment efficiency and showed prolonged drug release. SEM study revealed that the microspheres were almost spherical in shape with rough outer surface containing small pores. The findings of micromeritic studies suggested that the flowability and compressibility properties of the pure drug were significantly improved by the microsphere formulation. Heckel analysis also suggested that the microspheres exhibited better plasticity and die filling behavior as compared to pure drug. The tablets containing optimized microspheric formulation showed better handling properties than pure drug and no significant difference in drug release when compared with the marketed product. So the present study concluded that encapsulation of aceclofenac into microparticulate system not only enhanced its flowability, compressibility and tableting properties but also simultaneously helped to improve the patient compliance by sustaining the drug release for a prolonged period of time to manage pain and its symptoms. [Copyright &y& Elsevier]

Abstract: The water-induced ionic charge transport in compacted microcrystalline cellulose (MCC) has been reported to be governed by the densification behaviour. Hence, mechanical properties were expected to correlate with conductivity behaviour of MCC compacts. Both in-die and out-of-die compaction behaviour of MCC powder was investigated using a fully instrumented rotary tablet press. The dielectric measurements were carried out using a Novocontrol Concept 40 broadband dielectric spectrometer and dc conductivity (σ dc) was extracted from the low frequency conductivity data at room temperature. As postulated, compaction pressure corresponding to maximum conductivity (σ dc max) was observed to correlate with yield strength of MCC, determined using in-die and out-of-die Heckel analysis. Although Heckel transformation is most commonly used in pharmaceutical technology, its general use to characterise the mechanical properties of organic pharmaceutical materials has been criticized. The present study has provided experimental evidence that Heckel equation is practically useful to describe plastic deformation of organic pharmaceutical powders. [Copyright &y& Elsevier]

Ammonio methacrylate copolymers Eudragit® RS PO and Eudragit® RL PO have found widespread use as key components in various types of extended release solid dosage forms. The deformation behavior of neat polymers and binary mixes was evaluated using Heckel Analysis, strain rate sensitivity, work of compaction and elastic recovery index. Additionally, the compact forming ability of neat materials and binary mixes were evaluated by analyzing their tabletability, compressibility and compactibility profiles. The Heckel analysis of both polymers exhibited a speed-sensitive deformation behavior typical to plastic materials. The yield values of the binary mixes of the polymers with microcrystalline cellulose revealed a linear relationship with the weight fractions of individual components. The yield values of binary mixes of both the polymers with dibasic calcium phosphate exhibited slight negative deviations from linearity. Both polymers exhibited axial relaxation after ejection typical of viscoelastic materials, as measured by the elastic recovery index values. The work of compaction and the elastic recovery index values of the binary mixtures were found to be linearly related to the weight fractions of the individual components thus, confirming ideal mixing behavior based on the composition. Addition of microcrystalline cellulose to both polymers significantly improved their tabletability and compactibility. The tensile strengths of the compacts prepared with neat materials and binary mixes with microcrystalline cellulose, dibasic calcium phosphate and lactose were the function of their solid fraction and independent of the tableting speeds tested; thus, validating compactibility as a reliable parameter in predicting acceptable tablet properties. [ABSTRACT FROM AUTHOR]

Abstract: Scale-up of tableting process is particularly difficult due to specific concerns related exclusively to the process itself and that cannot be determined on a smaller scale, which are the effect of compression speed and the build-up of heat due to the length of the compaction operations. In this work, it has been simulated the rise of temperature observed during the tablets manufacturing in a full production scale by means of an appropriate modification of a R&D rotary tablet machine. Four common pharmaceutical excipients, characterized by different chemical nature, consolidation behaviour and temperature sensitiveness have been analysed in terms of compaction mechanism (Heckel and energy analysis) and tabletability, in order to verify any effect of the increase of temperature. The results showed a relevance of the temperature on mechanical tablets properties only on materials characterized by low temperature thermal transitions (melting or glass transition), while, for compounds which do not exhibit thermal events at low temperature, it becomes less important for ductile materials and irrelevant for brittle materials. Heckel analysis highlighted a noticeable increase of ductility only in those materials whose tablets mechanical properties depended on the temperature. On the other hand, energy analysis showed low sensitivity failing to identify any temperature effect on compaction materials properties. This work showed how to simulate the process of temperature rise on a small scale and the influence of temperature on materials compaction properties. The use of a modified tableting machine, able to control the temperature and moisture levels and also capable of monitoring the punch movements, resulted in identifying the effect of temperature both on mechanical and compaction properties on materials. Thus, it represents a valuable tool in order to provide useful information at an early stage during the development of tablets formulations. [Copyright &y& Elsevier]

Abstract: Understanding how a material''s response to stress changes as the stress is applied at different rates is important in predicting performance of pharmaceutical powders during tablet compression. Widely used methods for determining strain rate sensitivity (SRS) are empirically based and can often provide inconsistent or misleading results. Indentation creep data, collected during hardness tests on compacts formed from several common tableting excipients, were used to predict each material''s relative sensitivity to changes in strain rate. Linear relationships between Ln(indentation hardness) and Ln(strain rate) were observed for all materials tested. The slope values taken from these relationships were compared to traditional strain rate sensitivity estimates based on in-die Heckel analysis. Overall, the results from the two methods were quite similar, but several advantages were evident in the creep data. The most notable advantage was the ability to characterize strain rate sensitivity derived from plastic behavior with little influence of elastic deformation. For example, two grades of corn starch had very similar creep behavior, but their yield pressures were affected very differently when the compaction rate was increased. This inconsistency was related to the difference in the viscoelastic recovery exhibited by these two materials. This new method promises to allow a better understanding of strain rate effects observed during tablet manufacturing. [Copyright &y& Elsevier]

Abstract: The objectives of the present study were to address the issues of poor flow and inadequate compressibility of metformin HCl by adopting particle engineering technique. Metformin HCl was crystallized in the presence of polyvinylpyrrolidone (PVP K30). A 32 full factorial design (FFD) was employed for optimization of the processing parameters. Percentage PVP K30 in solution (X 1) and crystallization time (X 2) were chosen as the independent variables. Percentage yield (Y 1), Carr’s index (Y 2) and tensile strength of compacts (Y 3) were selected as dependent variables. Mathematical models were evolved and contour plots were drawn. Metformin HCl particles crystallized in the presence of 2% PVP K30 with crystallization time of four hours (CryMet), showed impressive improvement in flow property, compressibility as well as compactibility as compared to untreated metformin HCl (XMet). The derived compaction parameters ‘a’, ‘1/b’ and ‘Py ’, obtained using Kawakita and Heckel equations were 0.369, 15.34 and 198.54MPa for XMet; and 0.249, 11.05 and 143.33MPa for CryMet respectively. Compressibility evaluation of the samples revealed poor compressibility of XMet while CryMet was directly compressible. DSC and FTIR experiments showed that CryMet particles did not undergo chemical modifications during crystallization. [Copyright &y& Elsevier]

Abstract: A comparison study was made on the powder flow characteristics, tableting properties of experimental Assam Bora rice starch, obtained from the variety Aghuni Bora of Oryza sativa and the mechanical properties of tablets made up of it with those of official Starch 1500®. The influences of physical and geometrical properties of both the starch were evaluated with regards to their compression properties. It has been found that Assam Bora rice starch reflects better physical characteristics such as higher bulk and tap densities, less porosity, better powder packing ability, minimum lubricant sensitivity, large surface area and improved flowability. Apart from that the mechanical properties, such as toughness and Young''s modulus of Assam Bora rice starch were also compared with that of Starch 1500®. It has been also brought into result that compactibility of Assam Bora rice starch was not affected by the blending time. Further compaction properties of the experimental starch were evaluated by using Kawakita and Heckel equations and compared well with those of Starch 1500®. The result obtained shows that it mainly deforms by plastic deformation. Their onset of plastic deformation and strain rate sensitivity as compared to that of Starch 1500® demonstrates its potential use as a direct compression filler-binders. [Copyright &y& Elsevier]

Purpose: To study the mechanical and dynamic swelling properties of grewia gum, evaluate its compression behaviour and determine the effect of drying methods on its properties. Methods: Compacts (500 mg) of both freeze-dried and air-dried grewia gum were separately prepared by compression on a potassium bromide (KBr) press at different pressures and subjected to Heckel analysis. Swelling studies were performed using 200 mg compacts of the gum (freeze-dried or air-dried) compressed on a KBr press. The mechanical properties of the films of the gum prepared by casting 1 % dispersions of the gum were evaluated using Hounsfield tensiometer. The mechanical properties of grewia gum films were compared with films of pullulan and guar gum which were similarly prepared. The effect of temperature on the water uptake of the compacts was studied and the data subjected to Schott's analysis. Results: Drying conditions had no effect on the yield pressure of the gum compacts as both air-dried and freeze-dried fractions had a yield pressure of 322.6 MPa. The plots based on Schott's equation for the grewia gum samples showed that both samples (freeze-dried and air-dried) exhibited long swelling times. Grewia gum film had a tensile strength of 19.22±3.61 MPa which was similar to that of pullulan films (p > 0.05). It had an elastic modulus of 2.13±0.12 N/mm2 which was significantly lower (p < 0.05) than those of pullulan and guar gum with elastic moduli of 3.33±0.00 and 2.86±0.00 N/mm2, respectively. Conclusion: The type of drying method used does not have any effect on the degree of plasticity of grewia gum compacts. Grewia gum obtained by either drying method exhibited extended swelling duration. Matrix tablet formulations of the gum will likely swell slowly and promote sustained release of drug. [ABSTRACT FROM AUTHOR]

Background: The mechanical properties of extrusion-spheronized beads as part of multiparticulate systems has not been adequately studied. Aim: The purpose was to study the mechanical properties of such drug beads and blends of drug beads and glycerol monostearate (GMS)-placebo beads. Method: Heckel analysis (mean yield pressure, Py), strain rate sensitivity (SRS), elastic recovery (ER), and total work of compression (TWC) studies were conducted using a PressterTM linear rotary tablet machine simulator operating at several combinations of speed and force. Results: The GMS-placebo beads exhibited the lowest Py values (9.1 ± 1.6 MPa) and TWC (1.9 ± 0.3 J) overall and these values steadily increased with increases in both applied speed and force. Although the placebo beads had the lowest ER values of 3.8 ± 0.7%, these beads showed significant time-dependent deformation behavior based on their SRS value of 70.2%. Heckel analysis showed that uncoated theophylline beads containing 58% ethylcellulose were more compressible than control beads containing 58% dicalcium phosphate dihydrate, the latter having the highest overall Py of 79.3 ± 3.8 MPa for the low speed/low force condition. Heckel plots also showed that 50:50 ratios of blends containing drug beads coated with either Surelease® or Eudragit® NE30D behaved similarly under increasing force and speed. Surelease®-coated cimetidine beads gave the highest Py, TWC, and ER values and these values were higher than Eudragit® NE30D-coated beads. The 50:50 blend ratios containing coated cimetidine beads showed higher Py, TWC, and ER values than the 60:40 ratios. Conclusion: Variation in the compressibility of different beads and blends can be attributed to excipients used in their formulation as well as to the drug bead-to-placebo bead ratio. [ABSTRACT FROM AUTHOR]

The aim of this study was to compare the densification of powder mixtures on eccentric and rotary tablet presses and to establish relationships with the halving properties of the resulting scored tablets. This is an important problem because the recent guidelines of EU require verification of the equal masses of tablet halves. The models of Walker, Heckel, and Kawakita were used to describe the powder densification on the two machines. The calculated parameters revealed that the shorter compression cycle of rotary machines results in poorer densification and lower tablet hardness at a given compression force. This is manifested in poorer halving properties, which are influenced mainly by the hardness. Better densification improves the halving even at lower tablet hardness. This demonstrates that these parameters can be good predictors of tablet halving properties. [ABSTRACT FROM AUTHOR]

Abstract: Nowadays, graft copolymers are being used as an interesting option when developing a direct compression excipient for controlled release matrix tablets. New graft copolymers of ethyl methacrylate (EMA) on waxy maize starch (MS) and hydroxypropylstarch (MHS) were synthesised by free radical polymerization and alternatively dried in a vacuum oven (OD) or freeze-dried (FD). This paper evaluates the performance of these new macromolecules and discusses the effect of the carbohydrate nature and drying process on their physicochemical and technological properties. Grafting of EMA on the carbohydrate backbone was confirmed by IR and NMR spectroscopy, and the grafting yields revealed that graft copolymers present mainly a hydrophobic character. The graft copolymerization also leads to more amorphous materials with larger particle size and lower apparent density and water content than carbohydrates (MS, MHS). All the products show a lack of flow, except MHSEMA derivatives. MSEMA copolymers underwent much plastic flow and less elastic recovery than MHSEMA copolymers. Concerning the effect of drying method, FD derivatives were characterised by higher plastic deformation and less elasticity than OD derivatives. Tablets obtained from graft copolymers showed higher crushing strength and disintegration time than tablets obtained from raw starches. This behaviour suggests that these copolymers could be used as excipients in matrix tablets obtained by direct compression and with a potential use in controlled release. [Copyright &y& Elsevier]

Abstract: The effect of roller compaction pressure on the bulk compaction of roller compacted ibuprofen was investigated using instrumented rotary tablet press. Three different roller pressures were utilized to prepare granules and Heckel analysis, Walker analysis, compressibility, and tabletability were performed to derive densification, deformation, course of volume reduction and bonding phenomenon of different pressure roller compacted granules. Nominal single granule fracture strength was obtained by micro tensile testing. Heckel analysis indicated that granules prepared using lower pressure during roller compaction showed lower yield strength. The reduction in tabletability was observed for higher pressure roller compacted granules. The reduction in tabletability supports the results of granule size enlargement theory. Apart from the granule size enlargement theory, the available fines and relative fragmentation during compaction is responsible for higher bonding strength and provide larger areas for true particle contact at constant porosity for lower pressure roller compacted granules. Overall bulk compaction parameters indicated that granules prepared by lower roller compaction pressure were advantageous in terms of tabletability and densification. Overall results suggested that densification during roller compaction affects the particle level properties of specific surface area, nominal fracture strength, and compaction behavior. [Copyright &y& Elsevier]

Heckel analysis, tablet tensile strength, and indentation hardness were determined for a series of sieved and roller compacted microcrystalline cellulose mixtures under both unlubricated and lubricated conditions with magnesium stearate. These results have been used to evaluate the loss of reworkability following roller compaction for microcrystalline cellulose and show the extent of impact on tableting properties when magnesium stearate is added intragranularly prior to roller compaction. While results consistent with traditional work-hardening are observed as shown by a modest increase in dynamic hardness and mean yield pressure for unlubricated, roller compacted microcrystalline cellulose, it is overshadowed by the overlubrication effect seen during roller compaction and in particular, the subsequent milling step. The common practice of lubricating the feedstock with magnesium stearate to avoid sticking of the material to the compaction rolls appears to be the major cause of decreased mechanical strength of the final compressed tablets. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 1342–1355, 2007 [ABSTRACT FROM AUTHOR]

Abstract: The water vapour sorption–desorption behaviour of graft copolymers (hydroxypropylstarch–methyl methacrylate -HSMMA- and carboxymethylstarch–methyl methacrylate -CSMMA-) synthetised by free-radical polymerisation and alternatively dried by oven (OD) or freeze-drying (FD) techniques was investigated in a previous paper. The aim of the present study was to analyse the influence of the amount and distribution of water molecules on the flow and compaction characteristics of this family of methyl methacrylate–starch copolymers. Products were stored at constant temperature (25°C) and different relative humidity conditions (RH). Flow properties of the powdered materials were evaluated using glass and stainless-steel funnels and the densification behaviour was studied in detail by means of Heckel treatment and compression parameters. Results revealed that the storage at 25–50% RH was the optimum condition relating flowability for HSMMA and OD-CSMMA copolymers. At higher RH values, the flow characteristics worsened, due to an increment in cohesive forces. Compaction experiments showed that the 25–50% RH range improved also the compression performance of the copolymers, due to increasing powder compressibility and reduced compact relaxation. Under these circumstances, absorbed water might act as plasticiser and adsorbed water as lubricant. [Copyright &y& Elsevier]

This study evaluates the effect of variation in the ambient moisture on the compaction behavior of microcrystalline cellulose (MCC) powder. The study was conducted by comparing the physico-mechanical properties of, and the near infrared (NIR) spectra collected on, compacts prepared by roller compaction with those collected on simulated ribbons, that is, compacts prepared under uni-axial compression. Relative density, moisture content, tensile strength (TS), and Young modulus were used as key sample attributes for comparison. Samples prepared at constant roller compactor settings and feed mass showed constant density and a decrease in TS with increasing moisture content. Compacts prepared under uni-axial compression at constant pressure and compact mass showed the opposite effect, that is, density increased while TS remained almost constant with increasing moisture content. This suggests difference in the influence of moisture on the material under roller compaction, in which the roll gap (i.e., thickness and therefore density) remains almost constant, vs. under uni-axial compression, in which the thickness is free to change in response to the applied pressure. Key sample attributes were also related to the NIR spectra using multivariate data analysis by the partial least squares projection to latent structures (PLS). Good agreement was observed between the measured and the NIR-PLS predicted values for all key attributes for both, the roller compacted samples as well as the simulated ribbons. © 2005 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:2301–2313, 2005 [ABSTRACT FROM AUTHOR]

Abstract: The characterisation of mechanical properties of particulate solids (e.g. yield pressure and failure strength) is often done by an analysis of bulk compression. However, the relationship between bulk compression behaviour and the physical and mechanical parameters of single particles is not well understood. In this paper the deformation and failure behaviour of soft synthetic detergent granules is investigated experimentally using single granule and bulk compression analyses. Furthermore, the bulk compression of soft spheres, with the properties, which are the same as those of single granules used here, is simulated by distinct element method (DEM) and the predictions are compared with the experimental results. Both the experimental and simulation analyses are for a range of low pressures, less than 30kPa, with the aim of characterising the yield pressure (limiting contact pressure) of the individual granules using the bulk compression models of Heckel, Kawakita and Lüdde and Adams and co-workers. It is shown that the ratio of the yield pressure of single granules to the Heckel parameter for this type of granules is less than one, and is about 0.5. Furthermore, a relationship is developed among the above three models of bulk compression, in which the above ratio is related to parameters such as the inter-particle and particle wall friction coefficients, initial porosity of the bed and lateral to axial pressure ratio of the particles in the bed. Therefore the use of bulk compression method to infer single particle properties should be made with great caution. [Copyright &y& Elsevier]

The volume reduction behaviour of powders has been quantified by means of the ‘in-die’ yield pressure (YP) using Heckel analysis. However, because different YPs are reported for the same material, the experimental conditions influencing this material-constant were investigated. Silicified microcrystalline cellulose was compressed into flat-faced and convex tablets using a compaction simulator instrumented with load and displacement transducers. During compression, upper and lower punch force and displacement data were recorded and corrected for punch deformation. A symmetrical triangle wave compression profile was used and the instantaneous punch velocity was kept constant (5 mm/s). Individual tablet height and weight were used for Heckel analysis. The influence of the ‘effective compression pressure’ (PEFF) (ranging from 10 to 350 MPa), punch diameter (PD) (4, 9.5 and 12 mm) and filling depth (FD) (4.5, 7.5 and 10.5 mm) on YP was statistically evaluated using Response Surface Modelling software. A quadratic surface response equation, describing the relationship between PEFF, PD, FD and YP, was proposed for concave (Adj R2: 0.8424; S.D.: 14.60 MPa) and flat-faced (Adj R2: 0.8409; S.D.: 4.49 MPa) punches. YP and tensile strength were mainly determined by PEFF, irrespective of punch curvature. FD and PD had only a minor influence on the YP, although more pronounced for the concave punches. The method used resulted in reproducible PEFF and tensile strength values and the flat-faced tablets showed less weight variation. Flat-faced punches are preferred over punches with a concave surface when investigating the volume reduction behaviour of a powder by means of Heckel analysis and the experimental parameters should be reported. [Copyright &y& Elsevier]

In a number of powder processing operations such as dosing, compaction and tabletting, the behaviour of bulk powders subjected to compression is of great interest. Single particle mechanical properties obviously affect the bulk behaviour and there have been a number of attempts to establish relationships between the two scales of single particle and bulk deformation. A widely used approach, particularly in the pharmaceutical industries, is the Heckel analysis where the applied load and bulk deformation are used to infer the yield stress of individual particles. However, it is difficult to analyse this process rigorously and to ascribe any significance to the parameters quantified in the Heckel analysis because the individual particles are not loaded uniformly in the bed. It is therefore of great interest to elucidate what exactly the Heckel analysis does provide. The most appropriate approach for this purpose is the use of the Distinct Element Method (DEM) to simulate the bulk deformation based on single particle properties. Our analysis shows that there is a critical ratio of Young''s modulus to the yield stress of individual particles (E/σy)c, above which the Heckel analysis does reflect the effect of the yield stress, but below which it in fact reflects the effect of Young''s modulus. Heckel''s parameter is numerically equal to the yield stress of particles only for a certain value of E/σy. For ratios higher than this value, Heckel''s parameter can even exceed the yield stress of the individual particles. Therefore the Heckel analysis does not have general validity and should be used with caution. [Copyright &y& Elsevier]

This study investigated the basic physico-chemical property and binding functionality of commonly used commercial direct compression binders/fillers. The compressibility of these materials was also analyzed using compression parameters derived from the Heckel, Kawakita, and Cooper-Eaton equations. Five classes of excipients were evaluated, including microcrystalline cellulose (MCC), starch, lactose, dicalcium phosphate (DCP), and sugar. In general, the starch category exhibited the highest moisture content followed by MCC, DCP, lactose, and finally sugars; DCP displayed the highest density, followed by sugar, lactose, starch, and MCC; the material particle size is highly processing dependent. The data also demonstrated that MCC had moderate flowability, excellent compressibility, and extremely good compact hardness; with some exceptions, starch, lactose, and sugar generally exhibited moderate flowability, compressibility, and hardness; DCP had excellent flowability, but poor compressibility and hardness. This research additionally confirmed the binding mechanism that had been well documented: MCC performs as binder because of its plastic deformation under pressure; fragmentation is the predominant mechanism in the case of lactose and DCP; starch and sugar perform by both mechanism. [ABSTRACT FROM AUTHOR]

Methyl methacrylate (MMA) copolymers have recently been proposed as an alternative in controlled-release matrix tablets. The aims of this study were to assess the potential value of these copolymers as direct compression excipients and to investigate relationships between the physical and structural properties of the polymers and the compression behaviour of the powders and the microstructural properties of the tablets. Copolymers were synthesised by free radical copolymerisation of MMA with starch or cellulose derivatives and were alternatively dried by oven or freeze-drying techniques. Thus, the present study focuses on the influence of the carbohydrate nature and the drying process on the mechanical and compaction properties of MMA copolymers. Particle size, shape and surface texture of the copolymers have been studied in detail and Heckel treatment has been chosen for discriminating the densification behaviour of powdered materials. Total pore volume and pore size distribution of MMA copolymer tablets were investigated with mercury porosimetry. Oven drying gave less porous particles with more homogenous surfaces than those freeze-dried. Differences in morphology between the MMA copolymers were demonstrated by increasing apparent particle densities, smaller flow rates and higher binding capacities for freeze-dried products. The porousness and mean pore radius of the tablets obtained from freeze-dried copolymers were higher than those of tablets obtained from oven-dried ones. [Copyright &y& Elsevier]

The Heckel equation is one of the most useful equations for describing the compaction properties of pharmaceutical powders. Important material properties (e.g., yield strength) of powders can be derived using Heckel analysis. Two types of Heckel analysis are in common use. One is the “out-of-die,” or “zero-pressure” method, the other is the “in-die” or “at-pressure” method. Because particles undergo elastic deformation under pressure, which tends to lower the porosity of the powder bed, the “out-of-die” method describes powder consolidation and compaction more accurately than the “in-die” method. However, “in-die” Heckel analysis has been widely used because of the speed and ease of data collection. Using L-lysine monohydrochloride dihydrate as a model compound, this work analyzes quantitatively the effects of elastic deformation on the calculation of porosity of a tablet, and therefore on the Heckel analysis. The effects of a small change in porosity, ε, on Heckel analysis are presented mathematically. It is found that a decrease in porosity of 0.001, when the porosity is lower than 0.05, causes a significant increase in the value of -ln ε. Therefore, data at ε < 0.05 should be interpreted with caution when using Heckel analysis. Elastic deformation causes positive deviations in the Heckel plot, and therefore leads to a yield strength that is lower than the true value. The lower the elastic modulus of the powder, the greater is the deviation from the true value. Therefore, the “in-die” method gives values of yield strength that are significantly lower than the true values for most pharmaceutical powders. [ABSTRACT FROM AUTHOR]

[Display omitted] • Rheology parameters allowed the prediction of compactibility problems. • Continuous compaction of powder mixtures was impossible due to jamming. • High shear granulation improved flowability and tabletability of powder mixtures. • Energy of the blade decreased with the increasing of the granule distribution span. • Tablet tensile strength correlated with conditioned bulk density measured by FT4. The aim of this systematic study was to analyze the granulometric and rheological behavior of tableting mixtures in relation to tabletability by single tablet and lab-scale batch compression with an eccentric tablet machine. Three mixtures containing 33, 50, and 66% of the cohesive drug paracetamol were prepared. The high compressibility of the powder mixtures caused problems with overcompaction or lamination in the single tablet compression method; due to jamming of the material during the filling of the die, the lab-scale batch compression was impossible. Using high shear granulation, the flow properties and tabletability were adjusted. A linear relationship between the span of granules and the specific energy measured by FT4 powder rheometer was detected. In parallel, a linear relationship between conditioned bulk density and the tensile strength of the tablets at lab-scale batch tableting was noted. The combination of dynamic image analysis and powder rheometry was useful for predicting the tabletability of pharmaceutical mixtures during the single tablet (design) compression and the lab-scale batch compression. [ABSTRACT FROM AUTHOR]

Despite the ability to characterize the plasticity of powders in a material-sparing and expedited manner, the in-die Heckel analysis has been widely criticized for its sensitivity to several factors, such as particle elastic deformation, tooling size, lubrication, and speed. Using materials exhibiting a wide range of mechanical properties, we show that the in-die P correlates strongly with three established plasticity parameters obtained from the out-of-die Heckel analysis, Kuentz-Leuenberger analysis, and macroindentation. Thus, the in-die y correlates strongly with three established plasticity parameters obtained from the out-of-die Heckel analysis, Kuentz-Leuenberger analysis, and macroindentation. Thus, the in-die P y is a reliable parameter for quantifying powder plasticity in a material-sparing and expedited manner., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

The effects of PURE-DENT® and SPRESS® starch properties on their compression behavior was characterized using "SM(2) " approach (structural properties, macroscopic properties, and multivariate analysis). Moisture sorption rate constants, moisture content, amylose and amylopectin degradation enthalpy, percent crystallinity, amylose-amylopectin ratio, and cross-linking degree were used to profile starch structural properties. Particle density, particle size distribution, and Heckel compression descriptors [yield pressure (YP) of plastic deformation, and elastic recovery] were used as macroscopic descriptors. The structural and macroscopic properties were correlated qualitatively [principal component analysis (PCA)] and quantitatively [standard least square regression (SLSR)] with the tablet mechanical strength (TMS). These analyses revealed that the differences correlated with amylose-amylopectin content, particle density, compression mechanisms, and TMS between the starch grades. Univariate analysis proved lacking; however, PCA identified the particle size, moisture content, percent crystallinity, amylose-amylopectin ratio, and YP of plastic deformation and elastic recovery as the main factors influencing the starch TMS. SLSR quantified the positive influence of Fourier transform infrared spectra absorbance ratio at 1022-1003 and YP of the immediate elastic recovery, and the negative contribution of amylopectin content on the TMS. Therefore, starch amylose and amylopectin content, crystallinity, and lower elastic recovery are mainly responsible for better TMS., (© 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.)