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1.  Spherical composite particles of rice starch and microcrystalline cellulose: A new coprocessed excipient for direct compression 
AAPS PharmSciTech  2004;5(2):40-49.
Composite particles of rice starch (RS) and microcrystalline cellulose were fabricated by spray-drying technique to be used as a directly compressible excipient. Two size fractions of microcry stalline cellulose, sieved (MCS) and jet milled (MCJ), having volumetric mean diameter (D50) of 13.61 and 40.51 μm, respectively, were used to form composite particles with RS in various mixing ratios. The composite particles produced were evaluated for their powder and compression properties. Although an increase in the microcrystalline cellulose proportion imparted greater compressibility of the composite particles, the shape of the particles was typically less spherical with rougher surface resulting in a decrease in the degree of flowability. Compressibility of composite particles made from different size fractions of microcrystalline cellulose was not different; however, using MCJ, which had a particle size range close to the size of RS (D50=13.57 μm), provided more spherical particles than using MCS. Spherical composite particles between RS and MCJ in the ratio of 7∶3 (RS-MCJ-73) were then evaluated for powder properties and compressibility in comparison with some marketed directly compressible diluents. Compressibility of RS-MCJ-73 was greater than commercial spray-dried RS (Eratab), coprocessed lactose and microcrystalline cellulose (Cellactose), and agglomerated lactose (Tablettose), but, as expected, lower than microcrystalline cellulose (Vivapur 101). Flowability index of RS-MCJ-73 appeared to be slightly lower than Eratab but higher than Vivapur 101, Cellactose, and Tablettose. Tablets of RS-MCJ-73 exhibited low friability and good self-disintegrating property. It was concluded that these developed composite particles could be introduced as a new coprocessed direct compression excipient.
doi:10.1208/pt050230
PMCID: PMC2750465  PMID: 15760088
rice starch; microcrystalline cellulose; spray drying; coprocessed excipient; direct compression
2.  Physical properties and compact analysis of commonly used direct compression binders 
AAPS PharmSciTech  2003;4(4):489-499.
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.
doi:10.1208/pt040462
PMCID: PMC2750655  PMID: 15198557
direct compression; binder; tensile strength; Heckel analysis; Kawakita analysis; Cooper-Eaton analysis
3.  Study of Compressibility Properties of Yogurt Powder in Order to Prepare a Complementary Formulation  
The aim of the present study was to prepare an oral tablet from liquid yogurt by reforming the physical properties for easy transportation, long-term storage and also as a complementary dairy product in case of nutrient deficiency. The liquid fresh yogurt was lyophilized at -40°C and 0.03 mTor pressure. The dry powder was homogenized by a 12 mesh size sieve. Some tests such as Carr’s compressibility index, Hausner ratio and the angle of repose were applied to evaluate the flowability of yogurt powder. Study of the deformation of particles during forcing was done by calculation of the elastic recovery index. Carr’s compressibility index percent and Hausner ratio were calculated 15 and 0.94, respectively. The range of repose angle was measured between19-20°. The elastic recovery was obtained up to 60%. Since the hardness of tablets increased by decreasing compression velocity, therefore yogurt powder might have a plastic deformation. The reduction of powder volume due to compression force was about 20% (p < 0.05). Tablets with low fat yogurt showed very good compressibility with 6-12 Strong-Cab (SC) hardness units. Producing a complementary formulated as a tablet from yogurt powder is possible and also maybe therapeutically effective against lactose-intolerance syndrome and preventing antibiotic-associated diarrhea.We suggest that for more authentic confirmation of the type of deformation, it should go through Heckel’s equation analysis, too.
PMCID: PMC3813281  PMID: 24250628
Yogurt; Compressibility; Plastic deformation; Tablet processing; Dietary supplements; Lyophilization
4.  Physical mechanical and tablet formation properties of hydroxypropylcellulose: In pure form and in mixtures 
AAPS PharmSciTech  2007;8(4):82-90.
The aim of the study was to analyze hydroxypropylcellulose (HPC) in pure form and in excipient mixtures and to relate its physical and chemical properties to tablet binder functionality. The materials used were Klucel hydroxypropylcellulose grades ranging from low to high molecular weight (80–1000 kDa) of regular particle size (250 µm mean size) and fine particle size (80 µm mean size). These were compared with microcrystalline cellulose, spray-dried lactose, and dicalcium phosphate dihydrate. Thermal behavior of HPC was analyzed by modulated temperature differential scanning calorimetry (MTDSC). Tablets of the pure materials and of dry blends with 4% low viscosity, fine particle HPC and 30% high viscosity, fine particle HPC were produced on an instrumented eccentric tableting machine at 3 relative humidities. The 3-dimensional (3-D) model with the parameters time plasticity d, pressure plasticity e, and the twisting angle ω, the inverse of fast elastic decompression was compared with the Heckel method for characterization of compaction. Elastic recovery and compactibility were also studied. The results show that HPC tablet formation is characterized by high plastic deformation. The d, e, and ω values were markedly higher as compared with the reference materials. Plasticity was highest for the fine particle size HPC types. Maximum compactibility was observed for low molecular weight, fine particle size HPC. Tableting of the mixtures showed deformation, which was strongly influenced by HPC. Plasticity and crushing force of formed tablets was increased. In conclusion, HPC is characterized by strong plastic deformation properties, which are molecular weight and particle size dependent.
doi:10.1208/pt0804092
PMCID: PMC2750678
Tableting; hydroxypropylcellulose; DSC; 3-D modeling; mixtures; elastic recovery; plastic deformation
5.  Pre-dispositions and epigenetic inheritance in the Escherichia coli lactose operon bistable switch 
Under conditions of bistable induction of Escherichia coli lac operon, epigenetic patterns of sublineages of ‘on' and ‘off' cells originate from distinguishable ancestors up to two generations before induction.We found two switching pre-disposing factors, namely low repressor levels and slow growth, demonstrating that stochasticity in gene expression and global physiology synergistically determine the single-cell responses.A quantitative model where growth rate acts through simple dilution of intracellular content and repressor level controls the basal activity of the operon demonstrates that both growth rate and repressor concentration influence the cell switching ability.
The bacterium Escherichia coli, like many other microorganisms can use different sugars as a carbon source and uses some of these sugars in preference to others. For example, when grown in the presence of both lactose and glucose, the bacteria first consume glucose and use lactose only when glucose is exhausted. To this end, the enzymes necessary for lactose uptake and metabolism, grouped in one transcriptional unit called the lac operon (lacZ, Y, A encoding for the lactose degrading enzyme (β-galactosidase), permease and transacetylase, respectively) are produced only in the absence of glucose and in the presence of lactose or its analogs, such as the non-metabolizable analog thiomethyl-β-galactoside (TMG). In the absence of such inducers, the transcription of the operon is inhibited by the repressor molecule LacI. This inhibition is relieved by the inducers, which bind and inactivate LacI, initiating an amplifying feedback loop through the expression of the permease that ensures a high influx of inducer to maintain the operon's expression in the ‘on' state. This phenomenon of adaptive enzyme production has been widely studied since its discovery by Jacques Monod and François Jacob and is one of the most famous and best characterized examples of transcriptional gene regulation. E. coli lactose operon is also a paradigm of cellular differentiation. Indeed, in the presence of an intermediate concentration of TMG, an isogenic bacterial population is divided in two subpopulations of cells with the operon's genes either turned on or remaining off. The differentiation step is generally hypothesized to depend on fluctuations in expression of the operon's proteins. Nevertheless, it is still poorly characterized. On the basis of experimental and theoretical approaches, we explored the determinants of cell fate in this system.
We designed a microfluidic device allowing the observation of single cells growing within a microcolony under conditions that can be changed at will. We used this setup to study phenotypic variability in the lactose operon induction under conditions leading to a transient bimodality of lac expression in the population. We used an E. coli strain modified to express the yellow fluorescent protein (YFP) and the cyan fluorescent protein (CFP), both under the control of a promoter regulated by LacI (PLlacO1). Therefore, yellow and cyan fluorescence intensities both represent the concentration of active repressor molecules and indirectly, the expression state of the lactose operon. Microcolonies originating from a single cell were grown in the microfluidic device and followed by time-lapse microscopy. During the first generations of growth, cells were grown in the absence (or with a very low concentration) of inducer and after several generations, TMG was introduced at intermediate concenteration into the medium and maintained thereafter. In the absence of TMG, cells exhibit an overall weak fluorescence yet with significant variations between cells that were shown to correspond in part to the variability in the intracellular concentration of active LacI molecules. Upon induction, transient bimodality is observed, as the cells are divided between two subpopulations of bright and dim fluorescence.
We found a strong clustering of induced cells within their genealogical trees, indicating a substantial epigenetic inheritance. This epigenetic inheritance can be traced back up to two generations prior induction, suggesting that some molecular determinants of cell fate are epigenetically inherited with a short-range memory lasting around two divisions.
The promoter used to control fluorescence proteins expression is sensitive to small variations in active LacI concentration. Thus, in the absence of inducer, these variations result into correlated variations of YFP and CFP levels. We used the arithmetical mean of yellow and cyan fluorescence intensities to estimate the concentration of active LacI in the cells. We found that the cells exhibiting a low LacI concentration before induction are more likely to be induced upon TMG introduction. Likewise, the slowly growing cells were found to have a higher switching probability than the fast-growing ones. We used a multivariate analysis based on a generalized linear model to estimate the correlations of pre-induction LacI concentration and growth rate with the switching probability (Figure 5C). This analysis confirms that both LacI concentration and growth rate are correlated with the switching probability and demonstrates that even though LacI concentration and growth rate can be linked, their correlations with the switching probability represent independent effects. Together, these effects can account for 90% of the observed switching events.
To gain a better understanding of the possible influence of LacI expression fluctuations and growth rate on the switching probability of a cell, we used a model consisting in a system of differential equations and describing the dynamics of the lactose utilization network. In this model, LacI concentration controls the basal level of expression of the operon and the growth rate acts through the dilution of intracellular components. According to this model, depending on both LacI concentration and growth rate, a cell can be in a monostable or bistable regime. Therefore, monostable and bistable cells can coexist in the population due to parameters' variability. In addition, for cells in the bistable regime, the size of the minimal LacY burst necessary to trigger induction increases with LacI concentration and growth rate. Thus, in agreement with our experimental results, these two variables control the sensitivity of the cell to permease bursts and therefore influence its switching probability.
We thus found pre-disposing factors governing the lactose operon switching in a regime of transient bimodality. Some factors, such as LacI and LacY concentrations result from stochasticity at the local level of the network. On the contrary, growth rate variability represents variations in the cell global physiology. Therefore, the effects of local stochasticity are coupled with the influence of the global physiology, demonstrating the importance of considering the embedding of a particular genetic network in the whole cellular physiology to understand fully its dynamics.
The lactose operon regulation in Escherichia coli is a primary model of phenotypic switching, reminiscent of cell fate determination in higher organisms. Under conditions of bistability, an isogenic cell population partitions into two subpopulations, with the operon's genes turned on or remaining off. It is generally hypothesized that the final state of a cell depends solely on stochastic fluctuations of the network's protein concentrations, particularly on bursts of lactose permease expression. Nevertheless, the mechanisms underlying the cell switching decision are not fully understood. We designed a microfluidic system to follow the formation of a transiently bimodal population within growing microcolonies. The analysis of genealogy and cell history revealed the existence of pre-disposing factors for switching that are epigenetically inherited. Both the pre-induction expression stochasticity of the lactose operon repressor LacI and the cellular growth rate are predictive factors of the cell's response upon induction, with low LacI concentration and slow growth correlating with higher switching probability. Thus, stochasticity at the local level of the network and global physiology are synergistically involved in cell response determination.
doi:10.1038/msb.2010.12
PMCID: PMC2872608  PMID: 20393577
adaptation; bistability; differentiation; lac operon; stochastic gene expression
6.  Dry granulation and compression of spray-dried plant extracts 
AAPS PharmSciTech  2005;6(3):E359-E366.
The purpose of this research was to evaluate the influence of dry granulation parameters on granule and tablet properties of spray-dried extract (SDE) fromMaytenus ilicifolia, which is widely used in Brazil in the treatment of gastric disorders. The compressional behavior of the SDE and granules of the SDE was characterized by Heckel plots. The tablet properties of powders, granules, and formulations containing a high extract dose were compared. The SDE was blended with 2% magnesium stearate and 1% colloidal silicon dioxide and compacted to produce granules after slugging or roll compaction. The influences of the granulation process and the roll compaction force on the technological properties of the granules were studied. The flowability and density of spray-dried particles were improved after granulation. Tablets produced by direct compression of granules showed lower crushing strength than the ones obtained from nongranulated material. The compressional analysis by Heckel plots revealed that the SDE undergoes plastic deformation with a very low tendency to rearrangement at an early stage of compression. On the other hand, the granules showed an intensive rearrangement as a consequence of fragmentation and rebounding. However, when the compaction pressure was increased, the granules showed plastic deformation. The mean yield pressure values showed that both granulation techniques and the roll compaction force were able to reduce the material's ability to undergo plastic deformation. Finally, the tablet containing a high dose of granules showed a close dependence between crushing strength and the densification degree of the granules (ie, roll compaction force).
doi:10.1208/pt060345
PMCID: PMC2750380  PMID: 16353993
Dry granulation; Maytenus ilicifolia; spraydried extracts; Heckel plot; tableting
7.  Roller Compaction, Granulation and Capsule Product Dissolution of Drug Formulations Containing a Lactose or Mannitol Filler, Starch, and Talc 
AAPS PharmSciTech  2008;9(2):597-604.
This study investigated the influence of excipient composition to the roller compaction and granulation characteristics of pharmaceutical formulations that were comprised of a spray-dried filler (lactose monohydrate or mannitol), pregelatinized starch, talc, magnesium stearate (1% w/w) and a ductile active pharmaceutical ingredient (25% w/w) using a mixed-level factorial design. The main and interaction effects of formulation variables (i.e., filler type, starch content, and talc content) to the response factors (i.e., solid fraction and tensile strength of ribbons, particle size, compressibility and flow of granules) were analyzed using multi-linear stepwise regression analysis. Experimental results indicated that roller compacted ribbons of both lactose and mannitol formulations had similar tensile strength. However, resulting lactose-based granules were finer than the mannitol-based granules because of the brittleness of lactose compared to mannitol. Due to the poor compressiblility of starch, increasing starch content in the formulation from 0% to 20% w/w led to reduction in ribbon solid fraction by 10%, ribbon tensile strength by 60%, and granule size by 30%. Granules containing lactose or more starch showed less cohesive flow than granules containing mannitol and less starch. Increasing talc content from 0% to 5% w/w had little effect to most physical properties of ribbons and granules while the flow of mannitol-based granules was found improved. Finally, it was observed that stored at 40 °C/75% RH over 12 weeks, gelatin capsules containing lactose-based granules had reduced dissolution rates due to pellicle formation inside capsule shells, while capsules containing mannitol-based granules remained immediate dissolution without noticeable pellicle formation.
doi:10.1208/s12249-008-9088-y
PMCID: PMC2976916  PMID: 18459052
compaction; flowability; granulation; particle size; ribbon; starch
8.  Use of First Derivative of Displacement vs. Force Profiles to Determine Deformation Behavior of Compressed Powders 
AAPS PharmSciTech  2013;14(1):398-401.
Displacement (D) vs. force (F) profiles obtained during compaction of powders have been reported by several researchers. These profiles are usually used to obtain mechanical energies associated with the compaction of powders. In this work, we obtained displacement–force data associated with the compression of six powders; Avicel PH101, Avicel PH301, pregelatinized corn starch, anhydrous lactose, dicalcium phosphate, and mannitol. The first three powders are known to deform predominantly by plastic behavior while the later ones are known to deform predominantly by brittle fracture. Displacement–force data was utilized to perform in-die Heckel analysis and to calculate the first derivative (dD/dF) of displacement–force plots. First derivative results were then plotted against mean force (F′) at each point and against 1/F′ at compression forces between 1 and 20 kN. Results of the in-die Heckle analysis are in very good agreement with the known deformation behavior of the compressed materials. First derivative plots show that materials that deform predominantly by plastic behavior have first derivative values (0.0006–0.0016 mm/ N) larger than those of brittle materials (0.0004 mm/N). Moreover, when dD/dF is plotted against 1/F′ for each powder, a linear correlation can be obtained (R2 = > 0.98). The slopes of the dD/dF vs. 1/F′ plots for plastically deforming materials are relatively larger than those for materials that deform by brittle behavior. It is concluded that first derivative plots of displacement–force profiles can be used to determine deformation behavior of powders.
doi:10.1208/s12249-013-9928-2
PMCID: PMC3581652  PMID: 23341076
compression; deformation; first derivative
9.  Effects of physical properties for starch acetate powders on tableting 
AAPS PharmSciTech  2002;3(4):68-76.
The aim of the study was to investigate particle and powder properties of various starch acetate powders, to study the effect of these properties on direct compression characteristics, and to evaluate the modification opportunity of physical properties for starch acetate powders by using various drying methods. At the end of the production phase of starch acetate, the slurry of starch acetate was dried using various techniques. Particle, powder, and tableting properties of end products were investigated. Particle size, circularity, surface texture, water content and specific surface area varied according to the particular drying method of choice. However, all powders were freely flowing. Bulk and tapped densities of powders varied in the range of 0.29 to 0.44 g/cm3 and 0.39 to 0.56 g/cm3, respectively. Compaction characteristics revealed that all powders were easily deformed under compression, having yield pressure values of less than 66 MPa according to Heckel analysis. All powders possessed a significant interparticulate bond-forming capacity during compaction. The tensile strength values of tablets varied between 10 and 18 MPa. In conclusion, physical properties of starch acetate could be affected by various drying techniques. A large specific surface area and water content above 4% were favorable properties by direct compression, especially for small, irregular, and rough particles.
doi:10.1208/pt030434
PMCID: PMC2751342  PMID: 12916928
starch acetate; drying techniques; powder; tablet; excipient
10.  Studies on Flowability, Compressibility and In-vitro Release of Terminalia Chebula Fruit Powder Tablets 
The dried fruit of Terminalia chebula is widely used for its laxative properties. The objective of the present study was to examine the flowability and compressibility of Terminalia chebula fruit powder, subsequently developing its tablet formulations by utilizing wet granulation and direct compression technology. Initial studies on flowability and compressibility revealed that the fruit powder flows poorly, is poorly compressible and mucilaginous in nature. The consolidation behaviors of the fruit powder and of its tablet formulations were studied using the Kawakita, Heckel and Leuenberger equations. Kawakita analysis revealed reduced cohesiveness hence improved flowability was achieved in formulations prepared by direct compression and the wet granulation technique. The Heckel plot showed that the Terminalia chebula fruit powder when formulated using direct compression showed initial fragmentation followed by plastic deformation and that the granules exhibited plastic deformation without initial fragmentation. The compression susceptibility parameter obtained from the Leuenberger equation for compacts formed by using the direct compression and wet granulation techniques indicated that the maximum crushing strength is reached faster and at lower compression pressures. The Tannin content (with reference to standard tannin) in fruit powder and tablet formulations was determined by UV spectrophotometry at 273 nm. The in-vitro dissolution study in simulated SGF (without enzymes) showed more than a 90% release of tannin from the tablets with in 1 h. The brittle fracture index value revealed that tablets prepared from granules showed less fracture tendency in comparison to those formed by direct compression formulation. From this study, it was concluded that the desired flowability, compressibility and compactibility of Terminalia chebula fruit powder can be obtained by using the direct compression and wet granulation techniques.
PMCID: PMC3813030  PMID: 24250371
Terminalia chebula; Flowability; Compressibility; Dissolution; Tablet
11.  Studies on Flowability, Compressibility and In-vitro Release ofTerminalia chebula Fruit Powder Tablets 
The dried fruit of Terminalia chebula is widely used for its laxative properties. The objective of the present study was to examine the flowability and compressibility of Terminalia chebula fruit powder, subsequently developing its tablet formulations by utilizing wet granulation and direct compression technology. Initial studies on flowability and compressibility revealed that the fruit powder flows poorly, is poorly compressible and mucilaginous in nature. The consolidation behaviors of the fruit powder and of its tablet formulations were studied using the Kawakita, Heckel and Leuenberger equations. Kawakita analysis revealed reduced cohesiveness hence improved flowability was achieved in formulations prepared by direct compression and the wet granulation technique. The Heckel plot showed that the Terminalia chebula fruit powder when formulated using direct compression showed initial fragmentation followed by plastic deformation and that the granules exhibited plastic deformation without initial fragmentation. The compression susceptibility parameter obtained from the Leuenberger equation for compacts formed by using the direct compression and wet granulation techniques indicated that the maximum crushing strength is reached faster and at lower compression pressures. The Tannin content (with reference to standard tannin) in fruit powder and tablet formulations was determined by UV spectrophotometry at 273 nm. The in-vitro dissolution study in simulated SGF (without enzymes) showed more than a 90% release of tannin from the tablets with in 1 h. The brittle fracture index value revealed that tablets prepared from granules showed less fracture tendency in comparison to those formed by direct compression formulation. From this study, it was concluded that the desired flowability, compressibility and compactibility of Terminalia chebula fruit powder can be obtained by using the direct compression and wet granulation techniques.
PMCID: PMC3869578  PMID: 24363675
Terminalia chebula; Flowability; Compressibility; Dissolution.
12.  Application of Crustacean Chitin as a Co-diluent in Direct Compression of Tablets 
AAPS PharmSciTech  2010;11(1):409-415.
A “simplex-centroid mixture design” was used to study the direct-compression properties of binary and ternary mixtures of chitin and two cellulosic direct-compression diluents. Native milled and fractioned (125–250 μm) crustacean chitin of lobster origin was blended with microcrystalline cellulose, MCC (Avicel® PH 102) and spray-dried lactose–cellulose, SDLC Cellactose® (composed of a spray-dried mixture of alpha-lactose monohydrate 75% and cellulose powder 25%). An instrumented single-punch tablet machine was used for tablet compactions. The flowability of the powder mixtures composed of a high percentage of chitin and SDLC was clearly improved. The fractioned pure chitin powder was easily compressed into tablets by using a magnesium stearate level of 0.1% (w/w) but, as the die lubricant level was 0.5% (w/w), the tablet strength collapsed dramatically. The tablets compressed from the binary mixtures of MCC and SDLC exhibited elevated mechanical strengths (>100 N) independent of the die lubricant level applied. In conclusion, fractioned chitin of crustacean origin can be used as an abundant direct-compression co-diluent with the established cellulosic excipients to modify the mechanical strength and, consequently, the disintegration of the tablets. Chitin of crustacean origin, however, is a lubrication-sensitive material, and this should be taken into account in formulating direct-compression tablets of it.
doi:10.1208/s12249-010-9398-8
PMCID: PMC2850466  PMID: 20238188
Cellactose®; chitin; direct compression; microcrystalline cellulose; simplex-centroid mixture design; tablets
13.  The 3-D model: Does time plasticity represent the influence of tableting speed? 
AAPS PharmSciTech  2003;4(4):523-530.
The objective of this study is to test the hypothesis that time plasticity (parameterd from 3-D modeling) is influenced by tableting speed. Tablets were produced at different maximum relative densities (ϱrel,max) on an instrumented eccentric tableting machine and on a linear rotary tableting machine replicator. Some 3-D data plots were prepared using pressure, normalized time, and porosity according to Heckel. After fitting of a twisted plane, the resulting parameters were analyzed in a 3-D parameter plot. The materials used were dicalcium phosphate dihydrate (DCPD), spray-dried lactose, microcrystalline cellulose (MCC), hydroxypropyl methylcellulose (HPMC), κ-carrageenan (CAR), and theophylline monohydrate (TheoM). The results show that tableting speed especially influences the parameterd (time plasticity) of the 3-D model for plastically and viscoelastically deforming materials such as MCC, HPMC, CAR, and TheoM. For more plastically deforming materials such as MCC, HPMC, and TheoM, a subtle influence on ω is also visible. The stages of higher densification are affected more than the stages of lower densification. Brittle materials such as DCPD exhibit no influence of tableting speed. The influence of speed on spray-dried lactose is minor. The results are valid for data obtained from an eccentric tableting machine and also for data from a linear rotary tableting machine replicator. Thus, the empirically derived parameter time plasticityd really represents the influence of time.
doi:10.1208/pt040466
PMCID: PMC2750659  PMID: 15198561
rotary tableting machine simulator; eccentric tableting machine; tableting speed; excipients; compression
14.  The Effect of Lubricants on Powder Flowability for Pharmaceutical Application 
AAPS PharmSciTech  2013;14(3):1158-1168.
Pharmaceutical tablets are manufactured through a series of batch steps finishing with compression into a form using a tablet press. Lubricants are added to the powder mixture prior to the tabletting step to ensure that the tablet is ejected properly from the press. The addition of lubricants also affects tablet properties and can affect the behavior of the powder mixture. The objective of this research was to investigate the effect of lubricants on powder flowability as flowability into the tablet press is critical. Four lubricants (magnesium stearate, magnesium silicate, stearic acid, and calcium stearate) were mixed, in varying amounts, with spray-dried lactose. In addition, magnesium stearate was also mixed with placebo granules from a high-shear granulator. Measurements based on avalanche behavior indicated flowability potential and dynamic density and were more sensitive to changes in the mixture and provided a more accurate and reproducible indication of flowability than traditional static measurements. Of the tested lubricants, magnesium stearate provided the best increase in flowability even in the low amounts commonly added in formulations.
doi:10.1208/s12249-013-0007-5
PMCID: PMC3755167  PMID: 23897035
avalanche behavior; flowability; lubricants; magnesium stearate
15.  A Preformulation Study of a New Medicine for Chagas Disease Treatment: Physicochemical Characterization, Thermal Stability, and Compatibility of Benznidazole 
AAPS PharmSciTech  2010;11(3):1391-1396.
This work aimed the studies of physicochemical characterization, thermal stability, and compatibility of benznidazole (BNZ) drug by spectroscopy (NMR, IR), thermoanalytical (differential thermal analysis, differential scanning calorimetry, and thermogravimetry), and chromatographic (HPLC) techniques, beyond the analytical tools of Van’t Hoff equation and Ozawa model. The compatibility study was conducted by binary mixtures (1:1, w/w) of the drug with microcrystalline cellulose 102 and 250, anhydrous lactose, and sodium starch glycolate. The physicochemical characterization confirmed data reported in scientific literature, guaranteeing authenticity of the analyzed raw material. The drug melts at 191.68°C (∆H, 119.71 J g−1), characteristic of a non-polymorphic raw material, and a main stage decomposition at 233.76–319.35°C (∆m, 43.32%) occurred, ending the study with almost all mass volatilized. The quantification of drug purity demonstrated a correlation of 99.63% between the data obtained by chromatographic (99.20%) and thermoanalytical technique (99.56%). The Arrhenius equation and Ozawa model showed a zero-order kinetic behavior for the drug decomposition, and a calculated provisional validity time was 2.37 years at 25°C. The compatibility study evidenced two possible chemical incompatibilities between BNZ and the tested excipients, both associated by the authors to the reaction of the BNZ’s amine and a polymer carbohydrate’s carbonile, being maillard reactions. The BNZ reaction with anhydrous lactose is more pronounced than with the sodium starch glycolate because the lactose has more free hydroxyl groups to undergo reduction by the drug. In this sense, this work guides the development of a new solid pharmaceutical product for Chagas disease treatment, with defined quality control parameters and physicochemical stability.
doi:10.1208/s12249-010-9495-8
PMCID: PMC2974147  PMID: 20824514
binary mixtures; Chagas disease; drug stability; excipients; preformulation
16.  The suitability of disintegrating force kinetics for studying the effect of manufacturing parameters on spironolactone tablet properties 
AAPS PharmSciTech  2003;4(2):50-56.
The aim of this paper was to study the effect of the granulate properties and tablet compression force on disintegrating force behavior in order to investigate the capability of the disintegrating force to characterize tablets that have the same composition but were manufactured in different conditions. Several tablets containing spironolactone in the external or internal granulated mixture of calcium carbonate and maize starch differing in particle size distribution, were prepared at 3 compression levels. The force developed by tablets during water uptake and disintegration was measured and plotted versus time. The curves obtained were analyzed by the Weibull equation in order to calculate the parameters characterizing the tablet disintegration kinetics. The disintegrating force time parameter, the maximum force developed, and the area under the curve were determined. In general, the reduction of time parameter value and/or the increase in maximum force developed corresponded to an acceleration in tablet disintegration. In addition, the area under the force curve increased in stronger tablets, monitoring in a sensitive way the tablet structural changes introduced by compression force. The results showed that the disintegrating force measurement can detect small changes in the structure of the tablet that cannot be discriminated by pharmacopoeia tests. The effect of manufacturing, in particular compression force, on tablet properties was quantified by the parameters of disintegrating force kinetics.
doi:10.1208/pt040217
PMCID: PMC2750595  PMID: 12916899
disintegrating force; spironolactone; tablet; granulation; compression force
17.  Modification of flow and compressibility of corn starch using quasi-emulsion solvent diffusion method 
Objective(s):
The aim of this study was to improve flowability and compressibility characteristics of starch to use as a suitable excipient in direct compression tabletting. Quasi-emulsion solvent diffusion was used as a crystal modification method.
Materials and Methods:
Corn starch was dissolved in hydrochloric acid at 80°C and then ethanol as a non-solvent was added with lowering temperature until the formation of a precipitate of modified starch. Flow parameters, particle size and thermal behavior of the treated powders were compared with the native starch. Finally, the 1:1 mixture of naproxen and each excipient was tabletted, and hardness and friability of different tablets were evaluated.
Results:
Larger and well shaped agglomerates were formed which showed different thermal behavior. Treated starch exhibited suitable flow properties and tablets made by the treated powder had relatively high hardness.
Conclusion:
It was found that recrystallization of corn starch by quasi emulsion solvent diffusion method could improve its flowability and compressibility characteristics.
PMCID: PMC4240787  PMID: 25422746
Direct compression; Excipient; Flow; Starch
18.  Regulation of Lactose Utilization Genes in Staphylococcus xylosus 
Journal of Bacteriology  1998;180(9):2273-2279.
The lactose utilization genes of Staphylococcus xylosus have been isolated and characterized. The system is comprised of two structural genes, lacP and lacH, encoding the lactose permease and the β-galactosidase proteins, respectively, and a regulatory gene, lacR, coding for an activator of the AraC/XylS family. The lactose utilization genes are divergently arranged, the lacPH genes being opposite to lacR. The lacPH genes are cotranscribed from one promoter in front of lacP, whereas lacR is transcribed from two promoters of different strengths. Lactose transport as well as β-galactosidase activity are inducible by the addition of lactose to the growth medium. Primer extension experiments demonstrated that regulation is achieved at the level of lacPH transcription initiation. Inducibility and efficient lacPH transcription are dependent on a functional lacR gene. Inactivation of lacR resulted in low and constitutive lacPH expression. Expression of lacR itself is practically constitutive, since transcription initiated at the major lacR promoter does not respond to the availability of lactose. Only the minor lacR promoter is lactose inducible. Apart from lactose-specific, LacR-dependent control, the lacPH promoter is also subject to carbon catabolite repression mediated by the catabolite control protein CcpA. When glucose is present in the growth medium, lacPH transcription initiation is reduced. Upon ccpA inactivation, repression at the lacPH promoter is relieved. Despite this loss of transcriptional regulation in the ccpA mutant strain, β-galactosidase activity is still reduced by glucose, suggesting another level of control.
PMCID: PMC107164  PMID: 9573174
19.  Direct Compression Behavior of Low- and High-Methoxylated Pectins 
AAPS PharmSciTech  2009;11(1):18-26.
The objective of this study was to evaluate possible usefulness of pectins for direct compression of tablets. The deformation behavior of pectin grades of different degree of methoxylation (DM), namely, 5%, 10%, 25%, 35%, 40%, 50%, and 60% were, examined in terms of yield pressures (YP) derived from Heckel profiles for both compression and decompression and measurements of elastic recovery after ejection. All pectin grades showed a high degree of elastic recovery. DM 60% exhibited most plastic deformation (YP 70.4 MPa) whereas DM 5% (104.6 MPa) and DM 10% (114.7 MPa) least. However, DM 60% gave no coherent tablets, whereas tablet tensile strengths for DM 5% and DM 10% were comparable to Starch 1500®. Also, Heckel profiles were similar to Starch 1500®. For sieved fractions (180–250 and 90–125 μm) of DM 25% and DM 40% originating from the very same batch, YPs were alike, indicating minor effects of particle size. These facts indicate that DM is important for the compaction behavior, and batch-to-batch variability should also be considered. Therefore, pectins of low degree of methoxylation may have a potential as direct compression excipients.
doi:10.1208/s12249-009-9349-4
PMCID: PMC2850496  PMID: 20013080
deformation behavior; degree of methoxylation; direct compression; pectin; tensile strength
20.  Direct Compression Behavior of Low- and High-Methoxylated Pectins 
AAPS PharmSciTech  2009;11(1):18-26.
The objective of this study was to evaluate possible usefulness of pectins for direct compression of tablets. The deformation behavior of pectin grades of different degree of methoxylation (DM), namely, 5%, 10%, 25%, 35%, 40%, 50%, and 60% were, examined in terms of yield pressures (YP) derived from Heckel profiles for both compression and decompression and measurements of elastic recovery after ejection. All pectin grades showed a high degree of elastic recovery. DM 60% exhibited most plastic deformation (YP 70.4 MPa) whereas DM 5% (104.6 MPa) and DM 10% (114.7 MPa) least. However, DM 60% gave no coherent tablets, whereas tablet tensile strengths for DM 5% and DM 10% were comparable to Starch 1500®. Also, Heckel profiles were similar to Starch 1500®. For sieved fractions (180–250 and 90–125 μm) of DM 25% and DM 40% originating from the very same batch, YPs were alike, indicating minor effects of particle size. These facts indicate that DM is important for the compaction behavior, and batch-to-batch variability should also be considered. Therefore, pectins of low degree of methoxylation may have a potential as direct compression excipients.
doi:10.1208/s12249-009-9349-4
PMCID: PMC2850496  PMID: 20013080
deformation behavior; degree of methoxylation; direct compression; pectin; tensile strength
21.  The 3-D model: Comparison of parameters obtained from and by simulating different tableting machines 
AAPS PharmSciTech  2003;4(3):55-61.
The aim of this study is to apply 3-D modeling to data obtained from different tableting machines and for different compression wheels on a linear rotary tableting machine replicator. A new analysis technique to interpret these data by 3-D parameter plots is presented. Tablets were produced on an instrumented eccentric tableting machine and on a linear rotary tableting machine replicator. The materials used were dicalcium phosphate dihydrate (DCPD), spray-dried lactose, microcrystalline cellulose (MCC), hydroxypropyl methylcellulose (HPMC), and theophylline monohydrate. Tableting was performed to different maximum relative densities (ρ rel, max). Force, time and displacement were recorded during compaction. The 3-D data plots were prepared using pressure, normalized time, and porosity according to Heckel. A twisted plane was fitted to these data according to the 3-D modeling technique. The resulting parameters were analyzed in a 3-D parameter plot. The results show that the 3-D modeling technique can be applied to compaction cycles from different tableting machines as different as eccentric and rotary tableting machines (simulated). The relation of the data to each other is the same even when the absolute values are different. This is also true for different compression wheels used on the linear rotary tableting machine replicator. By using compression wheels of different sizes on this simulator, mainly time plasticity changes. By using bigger compression wheels for simulation, the materials deform slower at lower densification and they deform faster at higher densification. For brittle materials, the stages of higher densification are influenced; for plastically deforming materials, the stages of lower and higher densification can be influenced.
doi:10.1208/pt040335
PMCID: PMC2750628  PMID: 14621967
rotary tableting machine simulator; eccentric tableting machine; compression wheels; excipients; compression
22.  Barley callus: a model system for bioengineering of starch in cereals 
Plant Methods  2012;8:36.
Background
Starch is the most important source of calories for human nutrition and the majority of it is produced by cereal farming. Starch is also used as a renewable raw material in a range of industrial sectors. It can be chemically modified to introduce new physicochemical properties. In this way starch is adapted to a variety of specific end-uses. Recombinant DNA technologies offers an alternative to starch industrial processing. The plant biosynthetic pathway can be manipulated to design starches with novel structure and improved technological properties. In the future this may reduce or eliminate the economical and environmental costs of industrial modification. Recently, many advances have been achieved to clarify the genetic mechanism that controls starch biosynthesis. Several genes involved in the synthesis and modification of complex carbohydrates in many organisms have been identified and cloned. This knowledge suggests a number of strategies and a series of candidate genes for genetic transformation of crops to generate new types of starch-based polymers. However transformation of cereals is a slow process and there is no easy model system available to test the efficiency of candidate genes in planta.
Results
We explored the possibility to use transgenic barley callus generated from immature embryo for a fast test of transgenic modification strategies of starch biosynthesis. We found that this callus contains 4% (w/w dw) starch granules, which we could modify by generating fully transgenic calli by Agrobacterium-transformation. A Green Fluorescent Protein reporter protein tag was used to identify and propagate only fully transgenic callus explants. Around 1 – 1.5 g dry weight of fully transgenic callus could be produced in 9 weeks. Callus starch granules were smaller than endosperm starch granules and contained less amylose. Similarly the expression profile of starch biosynthesis genes were slightly different in callus compared with developing endosperm.
Conclusions
In this study we have developed an easy and rapid in planta model system for starch bioengineering in cereals. We suggest that this method can be used as a time-efficient model system for fast screening of candidate genes for the generation of modified starch or new types of carbohydrate polymers.
doi:10.1186/1746-4811-8-36
PMCID: PMC3479045  PMID: 22958600
23.  Characterisation and Deposition Studies of Recrystallised Lactose from Binary Mixtures of Ethanol/Butanol for Improved Drug Delivery from Dry Powder Inhalers 
The AAPS Journal  2010;13(1):30-43.
Dry powder inhaler formulations comprising commercial lactose–drug blends can show restricted detachment of drug from lactose during aerosolisation, which can lead to poor fine particle fractions (FPFs) which are suboptimal. The aim of the present study was to investigate whether the crystallisation of lactose from different ethanol/butanol co-solvent mixtures could be employed as a method of altering the FPF of salbutamol sulphate from powder blends. Lactose particles were prepared by an anti-solvent recrystallisation process using various ratios of the two solvents. Crystallised lactose or commercial lactose was mixed with salbutamol sulphate and in vitro deposition studies were performed using a multistage liquid impinger. Solid-state characterisation results showed that commercial lactose was primarily composed of the α-anomer whilst the crystallised lactose samples comprised a α/β mixture containing a lower number of moles of water per mole of lactose compared to the commercial lactose. The crystallised lactose particles were also less elongated and more irregular in shape with rougher surfaces. Formulation blends containing crystallised lactose showed better aerosolisation performance and dose uniformity when compared to commercial lactose. The highest FPF of salbutamol sulphate (38.0 ± 2.5%) was obtained for the lactose samples that were crystallised from a mixture of ethanol/butanol (20:60) compared to a FPF of 19.7 ± 1.9% obtained for commercial lactose. Engineered lactose carriers with modified anomer content and physicochemical properties, when compared to the commercial grade, produced formulations which generated a high FPF.
Electronic supplementary material
The online version of this article (doi:10.1208/s12248-010-9241-x) contains supplementary material, which is available to authorized users.
doi:10.1208/s12248-010-9241-x
PMCID: PMC3032097  PMID: 21057906
deposition study; dry powder inhaler; lactose; particle engineering; salbutamol sulphate
24.  Interactions among lactose, β-lactoglobulin and starch in co-lyophilized mixtures as determined by Fourier Transform Infrared Spectroscopy 
Journal of Food Science and Technology  2012;51(11):3376-3382.
Processing and storage change food powders containing a large quantity of lactose due to lactose crystallization and interactions among components. Model food systems were prepared by co-lyophilization of lactose, β-lactoglobulin (BLG), and gelatinized starch. A mixture design was used to define the percentage of each mixture component to simulate a wide range of food powders. Interactions among lactose, BLG and starch were studied using Fourier Transform Infrared (FT-IR) at different relative humidities (RH), before and after 3 months storage. Results showed the presence of hydrogen bonds among these components. Moreover, interactions or formation of hydrogen bonds among lactose, starch and BLG preserved BLG against freezing and freeze-drying shocks. Lactose crystallization could be identified by comparing infrared spectra of amorphous and crystallized lactose at O − H and C − H stretching vibration bands.
doi:10.1007/s13197-012-0843-4
PMCID: PMC4571200  PMID: 26396334
Solid state interaction; Crystallization; Lactose; Spectroscopy; Storage
25.  Evaluation of Granulated Lactose as a Carrier for DPI Formulations 1: Effect of Granule Size 
AAPS PharmSciTech  2014;15(6):1417-1428.
The objective of this study was to investigate the effect of large granulated lactose carrier particle systems on aerosol performance of dry powder inhaler formulations. Granulated lactose carriers with average sizes ranging from 200 to 1,000 μm were prepared and subsequently fractionated into separate narrow size powders. The fractionated granulated lactose (GL) samples were characterized in terms of size, specific surface area, surface roughness, morphology, density, flowability, and solid-state. The in vitro aerosolization performance was performed on the different size fractions of GL samples from a commercial inhaler device (Aerolizer®) with a model formulation (2% w/w salbutamol sulfate). The cascade impaction parameters employed were 60 or 90 L/min with standard (aperture size, 0.6 mm) or modified piercing holes (aperture size, 1.2 mm) of the inhaler loaded capsules. It was shown that the largest size fraction formulation (850–1000 μm) had a slight improvement in the fine particle fraction (FPF) compared to immediately preceding size fractions, explained by a smaller adhesive force between drug and carrier. Compared to commercial piercing holes, enlarged piercing holes generated a slight decreasing trend of FPF as the lactose powder sizes increased from 200–250 μm to 600–850 μm, perhaps due to the reduced detachment force by flow forces. The size, surface roughness, density, and flowability of lactose carrier as well as device design all contributed to the aerosol dispersion performance of granulated lactose-based adhesive mixtures. It was concluded that poorer or enhanced redispersion performance is not an inherent property to the significantly large size of granulated lactose carriers as previously contended.
doi:10.1208/s12249-014-0166-z
PMCID: PMC4245420  PMID: 24962007
adhesive force; carrier roughness; carrier size; DPI formulations; granulated lactose

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