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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.  Development of Orodispersible Tizanidine HCl Tablets Using Spray Dried Coprocessed Exipient Bases 
Tizanidine HCl is a centrally acting α-2 adrenergic agonist muscle relaxant with a slightly bitter taste having short half-life of 2.5 h. In the present study effect of co-processed excipient bases in formulation of orodispersible tizanidine HCl tablets by direct compression method was investigated. Co-processed excipient of microcrystalline cellulose with SSL-hydroxypropylcellulose was prepared using spray drier in 1:1, 1:2 and 1:3 ratio. Formulated tablets were evaluated for hardness, friability, in vitro disintegration time and in vitro drug release. Formulation F-3 prepared by addition of co-processed excipient base in ratio of 1:3 showed minimum disintegration time of 9.15±0.04 s and higher amount of drug release of 93.75% at the end of 15 min. Granules obtained by spray drying technique were found to be more spherical which improved its flow property and was supported by scanning electron microscope studies. Thermal studies indicated change in amorphous state, compatibility of drug in formulation was confirmed by fourier transform infrared studies. Analyses of drug release data indicated formulation followed first order kinetics. Inclusion of co-processed excipient base in formulation of orodispersible tablets enhanced disintegration significantly.
doi:10.4103/0250-474X.95616
PMCID: PMC3374554  PMID: 22707822
Co-processed excipient; enhanced disintegration; orodispersible tablet; spray drying
3.  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
4.  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
5.  Improving the tablet characteristics and dissolution profile of ibuprofen by using a novel coprocessed superdisintegrant: A technical note 
AAPS PharmSciTech  2007;8(1):E94-E99.
Summary and Conclusion
The coprocessed superdisintegrant proved to be superior to the physical blend in terms of flow due to size enlargement. Furthermore, the coprocessed superdisintegrant displayed superiority in terms of crushing strength, disintegration time, and drug dissolution. The advantages of the proposed method are easy adaptability in industry and the possibility of bypassing the existing patents in the ereas of quick disintegration and dissolution.
doi:10.1208/pt0801013
PMCID: PMC2750448  PMID: 17408213
Croscarmellose sodium; crospovidone; coprocessing by dry granulation; dissolution enhancement; ibuprofen
6.  Preparation and assessment of novel coprocessed superdisintegrant consisting of crospovidone and sodium starch glycolate: A technical note 
AAPS PharmSciTech  2007;8(1):E63-E69.
Summary and Conclusion
Coprocessed superdisintegrant consisting of crospovidone and SSG exhibited good flow and compression characteristics. Cefixime trihydrate and ibuprofen tablets containing coprocessed superdisintegrant exhibited quick disintegration and improved drug dissolution.
doi:10.1208/pt0801009
PMCID: PMC2750444  PMID: 17915813
Crospovidone; sodium starch glycolate; coprocessing; disintegration; dissolution
7.  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
8.  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
9.  Terminalia Gum as a Directly Compressible Excipient for Controlled Drug Delivery 
AAPS PharmSciTech  2011;13(1):16-23.
ABSTRACT
The exudates from the incised trunk of Terminalia randii has been evaluated as controlled release excipient in comparison with xanthan gum and hydroxypropylmethylcellulose (HPMC) using carvedilol (water insoluble) and theophylline (water soluble) as model drugs. Matrix tablets were prepared by direct compression and the effects of polymer concentration and excipients—spray dried lactose, microcrystalline cellulose and dicalcium phosphate dihydrate on the mechanical (crushing strength (CS) friability (F) and crushing strength–friability ratio (CSFR)) and drug release properties of the matrix tablets were evaluated. The drug release data were fitted into different release kinetics equations to determine the drug release mechanism(s) from the matrix tablets. The results showed that the CS and CSFR increased with increase in polymer concentration while F decreased. The ranking of CS and CSFR was HPMC > terminalia > xanthan while the ranking was reverse for F. The ranking for t25 (i.e. time for 25% drug release) at a polymer concentration of 60% was xanthan > terminalia = HPMC. The dissolution time, t25, of theophylline matrices was significantly lower (p < 0.001) than those of carvedilol matrix tablets. Drug release from the matrices was by swelling, diffusion and erosion. The mechanical and drug release properties of the tablets were significantly (p < 0.05) dependent on the type and concentration of polymer and excipients used with the release mechanisms varying from Fickian to anomalous. Terminalia gum compared favourably with standard polymers when used in controlled release matrices and could serve as a suitable alternative to the standard polymers in drug delivery.
doi:10.1208/s12249-011-9712-0
PMCID: PMC3299455  PMID: 22068290
excipients; hydroxypropylmethylcellulose; matrix tablets; terminalia gum; xanthan gum
10.  Excipient selection can significantly affect solid-state phase transformation in formulation during wet granulation 
AAPS PharmSciTech  2005;6(2):E311-E322.
Phase transformations in formulations can lead to instability in physicochemical, biopharmaceutical, and processing properties of products. The influences of formulation design on the optimal dosage forms should be specified. The aim here was to investigate whether excipients with different water sorption behavior affect hydrate formation of nitrofurantoin in wet masses. Nitrofurantoin anhydrate was used as a hydrate-forming model drug, and 4 excipients with different water-absorbing potential (amorphous low-substituted hydroxypropylcellulose, modified maize starch, partially amorphous silicified microcrystalline cellulose, and crystalline α-lactose monohydrate) were granulated with varying amounts of purified water. Off-line evaluation of wet masses containing nitrofurantoin anhydrate and excipient (1∶1) was performed using an X-ray powder diffractometer (XRPD) and near-infrared spectroscopy, and drying phase was evaluated by variable temperature XRPD. Only amorphous excipient in the formulation retarded hydrate formation of an active pharmaceutical ingredient (API) at high water contents. Hygroscopic partially crystalline excipient hindered hydrate formation of API at low water contents. Crystalline excipient was unable to control hydrate formation of API. The character of excipient affects the stability of formulation. Thus, correct selection of excipients for the formulation can control processing-induced phase transitions and improve the storage stability of the final dosage form.
doi:10.1208/pt060241
PMCID: PMC2750544  PMID: 16353990
nitrofurantoin; near-infrared spectroscopy; sorption; X-ray powder diffraction
11.  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
12.  Optimization of fast disintegration tablets using pullulan as diluent by central composite experimental design 
Journal of Pharmacy & Bioallied Sciences  2012;4(Suppl 1):S86-S87.
The objective of this work was to apply central composite experimental design to investigate main and interaction effect of formulation parameters in optimizing novel fast disintegration tablets formulation using pullulan as diluents. Face centered central composite experimental design was employed to optimize fast disintegration tablet formulation. The variables studied were concentration of diluents (pullulan, X1), superdisintigrant (sodium starch glycolate, X2), and direct compression aid (spray dried lactose, X3). Tablets were characterized for weight variation, thickness, disintegration time (Y1) and hardness (Y2). Good correlation between the predicted values and experimental data of the optimized formulation methodology in optimizing fast disintegrating tablets using pullulan as a diluent.
doi:10.4103/0975-7406.94150
PMCID: PMC3467825  PMID: 23066220
Pullulan; central composite experimental design
13.  Comparative determination of polymorphs of indomethacin in powders and tablets by chemometrical near-infrared spectroscopy and X-ray powder diffractometry 
AAPS PharmSciTech  2003;4(2):58-69.
The purpose of this research was to develop a rapid chemometrical method based on near-infrared (NIR) spectroscopy to determine indomethacin (IMC) polymorphic content in mixed pharmaceutical powder and tablets. Mixed powder samples with known polymorphic contents of forms α and γ were obtained from physical mixing of 50% of IMC standard polymorphic sample and 50% of excipient mixed powder sample consisting of lactose, corn starch, and hydroxypropyl-cellulose. The tablets were obtained by compressing the mixed powder at 245 MPa. X-ray powder diffraction profiles and NIR spectra were recorded for 6 kinds of standard materials with various polymorphic contents. The principal component regression analysis was performed based on normalized NIR spectra sets of mixed powder standard samples and tablets. The relationships between the actual and predicted polymorphic contents of form g in the mixed powder measured using x-ray powder diffraction and NIR spectroscopy show a straight line with a slope of 0.960 and 0.995, and correlation coefficient constants of 0.970 and 0.993, respectively. The predicted content values of unknown samples by x-ray powder diffraction and NIR spectroscopy were reproducible and in close agreement, but those by NIR spectroscopy had smaller SDs than those by x-ray powder diffraction. The results suggest that NIR spectroscopy provides a more accurate quantitative analysis of polymorphic content in pharmaceutical mixed powder and tablets than does conventional x-ray powder diffractometry.
doi:10.1208/pt040219
PMCID: PMC2750597  PMID: 12916901
near-infrared spectroscopy; chemometrics; polymorph; indomethacin; x-ray powder diffractometry
14.  Hydrophilic excipients modulate the time lag of time-controlled disintegrating press-coated tablets 
AAPS PharmSciTech  2004;5(4):25-29.
An oral press-coated tablet was developed by means of direct compression to achieve the time-controlled disintegrating or rupturing function with a distinct predetermined lag time. This press-coated tablet containing sodium diclofenac in the inner core was formulated with an outer shell by different weight ratios of hydrophobic polymer of micronized ethylcellulose (EC) powder and hydrophilic excipients such as spray-dried lactose (SDL) or hydroxypropyl methylcellulose (HPMC). The effect of the formulation of an outer shell comprising both hydrophobic polymer and hydrophilic excipients on the time lag of drug release was investigated. The release profile of the press-coated tablet exhibited a time period without drug release (time lag) followed by a rapid and complete release phase, in which the outer shell ruptured or broke into 2 halves. The lag phase was markedly dependent on the weight ratios of EC/SDL or EC/HPMC in the outer shell. Different time lags of the press-coated tablets from 1.0 to 16.3 hours could be modulated by changing the type and amount of the excipients. A semilogarithmic plot of the time lag of the tablet against the weight ratios of EC/SDL or EC/HPMC in the outer shell demonstrated a good linear relationship, withr=0.976 andr=0.982, respectively. The predetermined time lag prior to the drug release from a press-coated tablet prepared by using a micronized EC as a retarding coating shell can be adequately scheduled with the addition of hydrophilic excipients according to the time or site requirements.
doi:10.1208/pt050454
PMCID: PMC2750479  PMID: 15760051
micronized ethylcellulose; press-coated tablet; time lag; spray-dried lactose; HPMC; time-controlled disintegration; weight ratio
15.  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
16.  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.
17.  Microscale Investigation of Arsenic Distribution and Species in Cement Product from Cement Kiln Coprocessing Wastes 
The Scientific World Journal  2013;2013:518676.
To improve the understanding of the immobilization mechanism and the leaching risk of Arsenic (As) in the cement product from coprocessing wastes using cement kiln, distribution and species of As in cement product were determined by microscale investigation methods, including electron probe microanalysis (EPMA) and X-ray absorption spectroscopy. In this study, sodium arsenate crystals (Na3AsO412H2O) were mixed with cement production raw materials and calcined to produce cement clinker. Then, clinker was mixed water to prepare cement paste. EPMA results showed that As was generally distributed throughout the cement paste. As content in calcium silicate hydrates gel (C-S-H) was in low level, but higher than that in other cement mineral phases. This means that most of As is expected to form some compounds that disperse on the surfaces of cement mineral phases. Linear combination fitting (LCF) of the X-ray absorption near edge structure spectra revealed that As in the cement paste was predominantly As(V) and mainly existed as Mg3(AsO4)2, Ca3(AsO4)2, and Na2HAsO4.
doi:10.1155/2013/518676
PMCID: PMC3816081  PMID: 24223030
18.  New Direct Compression Excipient from Tigernut Starch: Physicochemical and Functional Properties 
AAPS PharmSciTech  2013;14(2):818-827.
Tigernut starch has been isolated and modified by forced retrogradation of the acidic gel by freezing and thawing processes. Relevant physicochemical and functional properties of the new excipient (tigernut starch modified by acid gelation and accelerated (forced) retrogradation (STAM)) were evaluated as a direct compression excipient in relation to the native tigernut starch (STNA), intermediate product (tigernut starch modified by acid gelation (STA)), and microcrystalline cellulose (MCC). The particle morphology, swelling capacity, moisture sorption, differential scanning calorimeter (DSC) thermographs and X-ray powder diffraction (XRD) patterns, flow, dilution capacity, and tablet disintegration efficiency were evaluated. The particles of STNA were either round or oval in shape, STA were smooth with thick round edges and hollowed center while STAM were long, smooth, and irregularly shaped typically resembling MCC. The DSC thermographs of STNA and MCC showed two endothermic transitions as compared with STA and STAM which showed an endothermic and an exothermic. The moisture uptake, swelling, flow, and dilution capacity of STAM were higher than those of MCC, STA, and STNA. The XRD pattern and moisture sorption profile of STAM showed similarities and differences with STNA, STA, and MCC that relate the modification. Acetylsalicylic acid (ASA) tablets containing STAM disintegrated at 3 ± 0.5 min as compared with the tablets containing STNA, STA, and MCC which disintegrated at 8.5 ± 0.5, 10 ± 0.5, and 58 ± 0.8 min, respectively. The study shows the physicochemical properties of tigernut starch modified by forced retrogradation as well as its potential as an efficient direct compression excipient with enhanced flow and disintegration abilities for tablets production.
doi:10.1208/s12249-013-9968-7
PMCID: PMC3666000  PMID: 23649994
direct compression excipient; forced retrogradation; functional properties; physicochemical properties; tigernut starch
19.  High-Amylose Sodium Carboxymethyl Starch Matrices: Development and Characterization of Tramadol Hydrochloride Sustained-Release Tablets for Oral Administration 
ISRN Pharmaceutics  2014;2014:391523.
Substituted amylose (SA) polymers were produced from high-amylose corn starch by etherification of its hydroxyl groups with chloroacetate. Amorphous high-amylose sodium carboxymethyl starch (HASCA), the resulting SA polymer, was spray-dried to obtain an excipient (SD HASCA) with optimal binding and sustained-release (SR) properties. Tablets containing different percentages of SD HASCA and tramadol hydrochloride were produced by direct compression and evaluated for dissolution. Once-daily and twice-daily SD HASCA tablets containing two common dosages of tramadol hydrochloride (100 mg and 200 mg), a freely water-soluble drug, were successfully developed. These SR formulations presented high crushing forces, which facilitate further tablet processing and handling. When exposed to both a pH gradient simulating the pH variations through the gastrointestinal tract and a 40% ethanol medium, a very rigid gel formed progressively at the surface of the tablets providing controlled drug-release properties. These properties indicated that SD HASCA was a promising and robust excipient for oral, sustained drug-release, which may possibly minimize the likelihood of dose dumping and consequent adverse effects, even in the case of coadministration with alcohol.
doi:10.1155/2014/391523
PMCID: PMC4004023
20.  Preparation and Characterization of a Novel Co-processed Excipient of Chitin and Crystalline Mannitol 
AAPS PharmSciTech  2010;11(4):1558-1571.
A co-processed excipient was prepared from commercially available crystalline mannitol and α-chitin using direct compression as well as spray, wet, and dry granulation. The effect of the ratio of the two components, percentage of lubricant and particle size, on the properties of the prepared co-processed excipient has been investigated. α-Chitin forms non-hygroscopic, highly compactable, disintegrable compacts when co-processed with crystalline mannitol. The compaction properties of the co-processed mannitol–chitin mixture were found to be dependent upon the quantity of mannitol added to chitin, in addition to the granulation procedure used. Optimal physicochemical properties of the excipient, from a manufacturing perspective, were obtained using a co-processed mannitol–chitin (2:8, w/w) mixture prepared by wet granulation (Cop-MC). Disintegration time, crushing strength, and friability of tablets, produced from Cop-MC using magnesium stearate as a lubricant, were found to be independent of the particle size of the prepared granules. The inherent binding and disintegration properties of the compressed Cop-MC are useful for the formulation of poorly compressible, high-strength, and low-strength active pharmaceutical ingredients. The ability to co-process α-chitin with crystalline mannitol allows chitin to be used as a valuable industrial pharmaceutical excipient.
doi:10.1208/s12249-010-9523-8
PMCID: PMC3011072  PMID: 21052880
binder; chitin; co-processing; disintegrant; mannitol
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.  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
23.  Formulation development and rheological studies of palatable cefetamet pivoxil hydrochloride dry powder suspension 
Background and the purpose of the study
Because of its intense bitter taste and susceptibility to moisture Cefetamet Pivoxil (CPH) is presently available only in the form of tablet. The aim of this study was to develop taste masked CPH dry powder suspension.
Methods
Methods employed for formulations were: a) Film coating of CPH using Eudragit E100 and subsequent adsorption on different carriers such as spray-dried lactose, sodium starch glycolate and spray-dried mannitol and b) Complexation of CPH with three different ion exchange resins indion 234 amberlite IRP64 and amberlite IRP69.
Results
Taste viz evaluation as recognized by volunteers revealed that coating with Eudragit E100 and subsequent adsorption on different carriers do not mask the bitter taste of the drug. Suspensions prepared using amberlite IRP64 and amberlite IRP69 were extremely palatable with no bitter after taste. They showed pseudoplastic flow behavior and were too viscous even after shearing for sufficient duration of time and exhibited poor pourability. The suspension made with indion 234 was palatable with slight or no bitter after taste. It demonstrated plastic flow with negligible thixotropy. It had moderate viscosity at rest and could be poured after a reasonable amount of shaking. CPH dry powder suspensions were very unstable under different conditions except under refrigeration. A 5% degradation of drug was occurred in reconstituted suspension in 4 days period when stored at room temperature.
Conclusion
Dry powder suspension prepared with indion 234 having 5% overages was stable even after 4th day of reconstitution and palatable with slight or no bitter after taste.
PMCID: PMC3232094  PMID: 22615648
Complexation; Indion 239; Thixotropy; Eudragit E100
24.  Influence of Drying Procedure and of Low Degree of Substitution on the Structural and Drug Release Properties of Carboxymethyl Starch 
AAPS PharmSciTech  2010;11(2):775-785.
The aim of this study was to investigate the influence of drying methods and low range of degrees of substitution (DS) on the structural, physicochemical, and drug-release properties of carboxymethyl high-amylose starch (CMS). CMS with three DS of 0.03, 0.14, and 0.25 was synthesized and dried by either solvent precipitation (SP), spray drying (SD), or lyophilization (Ly). DS had an influence on the crystalline structure of CMS. It was found that a DS of 0.14 or higher induced a modification of polymorphism. The drying method and the DS had both an impact on the physical properties of the CMS powder which can further influence the formulation characteristics and drug-release properties from monolithic tablets. The CMS with DS of 0.14 and 0.25 dried by SP or SD presented good excipient properties in terms of compressibility. With acetaminophen (20%) as tracer, the monolithic CMS tablets showed controlled drug release over 17 h for DS of 0.14 and 10 h for DS of 0.25, almost independent of pH, suggesting interesting properties for sustained release applications.
doi:10.1208/s12249-010-9437-5
PMCID: PMC2902335  PMID: 20443088
carboxymethyl starch; controlled delivery; lyophilisation; solvent precipitation; spray drying
25.  Response Surface Methodology to Optimize Novel Fast Disintegrating Tablets Using β Cyclodextrin as Diluent 
AAPS PharmSciTech  2010;11(4):1627-1635.
The objective of this work was to apply response surface approach to investigate main and interaction effects of formulation parameters in optimizing novel fast disintegrating tablet formulation using β cyclodextrin as a diluent. The variables studied were diluent (β cyclodextrin, X1), superdisintegrant (Croscarmellose sodium, X2), and direct compression aid (Spray dried lactose, X3). Tablets were prepared by direct compression method on B2 rotary tablet press using flat plain-face punches and characterized for weight variation, thickness, disintegration time (Y1), and hardness (Y2). Disintegration time was strongly affected by quadratic terms of β cyclodextrin, croscarmellose sodium, and spray-dried lactose. The positive value of regression coefficient for β cyclodextrin suggested that hardness increased with increased amount of β cyclodextrin. In general, disintegration of tablets has been reported to slow down with increase in hardness. However in the present study, higher concentration of β cyclodextrin was found to improve tablet hardness without increasing the disintegration time. Thus, β cyclodextrin is proposed as a suitable diluent to achieve fast disintegrating tablets with sufficient hardness. Good correlation between the predicted values and experimental data of the optimized formulation validated prognostic ability of response surface methodology in optimizing fast disintegrating tablets using β cyclodextrin as a diluent.
doi:10.1208/s12249-010-9541-6
PMCID: PMC3011066  PMID: 21086083
β cyclodextrin; central composite design; fast disintegrating tablets; granisetron hydrochloride; response surface

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