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1.  Stabilization of hot-melt extrusion formulations containing solid solutions using polymer blends 
AAPS PharmSciTech  2007;8(2):E152-E161.
This study was aimed at enhancing the physical stability of the drug clotrimazole (CT) and the polymer contained within hot-melt extrusion (HME) films using polymer blends of hydroxypropyl cellulose (HPC) and poly(ethylene oxide) (PEO). The HME films were investigated for solid-state characteristics, moisture sorption, bioadhesivity, mechanical properties, glass transition temperature, release characteristics, and physical and chemical stability of the drug and the polymer within the HME films. The solid-state characterization of the drug and the polymer was performed using differential scanning calorimetry, x-ray diffractometry, and dynamic mechanical analysis. A texture analyzer was used to study the bioadhesive and mechanical properties of the HME films. The physical and chemical stability of the films, stored at 25°C/60% relative humidity or in a desiccator, was studied for up to 12 months. CT was found to be in solid solution within all of the formulations extruded. The physical stability of the drug and PEO in the HME films increased with increasing HPC concentration, but the bioadhesivity and flexibility of the PEO films decreased with increasing HPC concentration. Films containing HPC: PEO∶CT in the ratio of 55∶35∶10 demonstrated optimum physical-mechanical, bioadhesive, and release properties. In conclusion, polymer blends of HPC and PEO were used successfully to tailor the drug release, mechanical and bio-adhesive properties, and stability of the HME films.
doi:10.1208/pt0802050
PMCID: PMC2750365  PMID: 17622123
Solid solution; physical stability; hot-melt extrusion; polymers; physicochemical characterization
2.  Klucel™ EF and ELF polymers for immediate-release oral dosage forms prepared by melt extrusion technology 
AAPS PharmSciTech  2012;13(4):1158-1169.
The objective of this research work was to evaluate Klucel™ hydroxypropylcellulose (HPC) EF and ELF polymers, for solubility enhancement as well as to address some of the disadvantages associated with solid dispersions. Ketoprofen (KPR), a Biopharmaceutics Classification System class II drug with poor solubility, was utilized as a model compound. Preliminary thermal studies were performed to confirm formation of a solid solution/dispersion of KPR in HPC matrix and also to establish processing conditions for hot-melt extrusion. Extrudates pelletized and filled into capsules exhibited a carrier-dependent release with ELF polymer exhibiting a faster release. Tablets compressed from milled extrudates exhibited rapid release owing to the increased surface area of the milled extrudate. Addition of mannitol (MNT) further enhanced the release by forming micro-pores and increasing the porosity of the extrudates. An optimized tablet formulation constituting KPR, MNT, and ELF in a 1:1:1 ratio exhibited 90% release in 15 min similar to a commercial capsule formulation. HPC polymers are non-ionic hydrophilic polymers that undergo polymer-chain-length-dependent solubilization and can be used to enhance solubility or dissolution rate of poorly soluble drugs. Dissolution/release rate could be tailored for rapid-release applications by selecting a suitable HPC polymer and altering the final dosage form. The release obtained from pellets was carrier-dependent and not drug-dependent, and hence, such a system can be effectively utilized to address solubility or precipitation issues with poorly soluble drugs in the gastrointestinal environment.
doi:10.1208/s12249-012-9834-z
PMCID: PMC3513444  PMID: 22961411
hot-melt extrusion; Klucel™ EF/ELF; solid solutions/dispersions; solubility enhancement; thermal miscibility evaluation
3.  The Influence of Sodium Carboxymethylcellulose on Drug Release from Polyethylene Oxide Extended Release Matrices 
AAPS PharmSciTech  2011;12(3):862-871.
Anionic polymer sodium carboxymethylcellulose (CELLOGEN® HP-HS and/or HP-12HS) was investigated for its ability to influence the release of three model drugs propranolol hydrochloride, theophylline and ibuprofen from polyethylene oxide (POLYOX™ WSR 1105 and/or Coagulant) hydrophilic matrices. For anionic ibuprofen and non-ionic theophylline, no unusual/unexpected release profiles were obtained from tablets containing a mixture of two polymers. However, for cationic propranolol HCl, a combination of polyethylene oxide (PEO) with sodium carboxymethylcellulose (NaCMC) produced a significantly slower drug release compared to the matrices with single polymers. The potential use of this synergistic interaction can be a design of new extended release pharmaceutical dosage forms with a more prolonged release (beyond 12 h) using lower polymer amount, which could be particularly beneficial for freely water-soluble drugs, preferably for once daily oral administration. In order to explain changes in the obtained drug release profiles, Fourier transform infrared absorption spectroscopy was performed. A possible explanation for the more prolonged propranolol HCl release from matrices based on both PEO and NaCMC may be due to a chemical bond (i.e. ionic/electrostatic intermolecular interaction) between amine group of the cationic drug and carboxyl group of the anionic polymer, leading to a formation of a new type/form of the active (i.e. salt) with sustained release pattern.
doi:10.1208/s12249-011-9648-4
PMCID: PMC3167260  PMID: 21710334
extended release; FT-IR; ibuprofen; matrix tablet; polyethylene oxide; polymer combination; propranolol hydrochloride; sodium carboxymethylcellulose; theophylline
4.  Evaluation of Gum of Moringa oleifera as a Binder and Release Retardant in Tablet Formulation 
The present study was undertaken to find out the potential of gum from Moringa oleifera to act as a binder and release retardant in tablet formulations. The effect of calcium sulphate dihydrate (water insoluble) and lactose (water soluble) diluent on the release of propranolol hydrochloride was studied. The DSC thermograms of drug, gum and mixture of gum/drug indicated no chemical interaction. Tablets (F1, F2, F3, and F4) were prepared containing calcium sulphate dihydrate as diluent, propranolol hydrochloride as model drug using 10%, 8%, 6% and 4% w/v of gum solution as binder. Magnesium stearate was used as lubricant. Physical and technological properties of granules and tablets like flow rate, Carr index, Hausner ratio, angle of repose, hardness, friability and disintegration time were determined and found to be satisfactory. Tablets were prepared by wet granulation method containing calcium sulphate dihydrate as excipient, propranolol hydrochloride as model drug using 10%, 20% and 30% of gum as release retardant, magnesium stearate was used as lubricant. Similarly tablets were prepared replacing lactose with calcium sulphate dihydrate. Despite of the widely varying physico-chemical characteristics of the excipients, the drug release profiles were found to be similar. The drug release increased with increasing proportions of the excipient and decreased proportion of the gum irrespective of the solubility characteristics of the excipient. The values of release exponent ‘n’ are between 0.37 and 0.54. This implies that the release mechanism is Fickian. There is no evidence that the dissolution or erosion of the excipient has got any effect on the release of the drug. The t50% values for tablets containing calcium sulphate dihydrate were on an average 10%-15% longer than the tablets containing lactose as excipient. These relatively small differences in t50% values suggest that the nature of excipient used appeared to play a minor role in regulating the release, while the gum content was a major factor.
doi:10.4103/0250-474X.45400
PMCID: PMC3038286  PMID: 21394258
Binder; gum; Moringa oleifera; release retardant; tablet
5.  Validity of a Power Law Approach to Model Tablet Strength as a Function of Compaction Pressure 
AAPS PharmSciTech  2010;11(1):467-471.
Designing quality into dosage forms should not be only based on qualitative or purely heuristic relations. A knowledge space must be generated, in which at least some mechanistic understanding is included. This is of particular interest for critical dosage form parameters like the strength of tablets. In line with this consideration, the scope of the work is to explore the validity range of a theoretically derived power law for the tensile strength of tablets. Different grades of microcrystalline cellulose and lactose, as well as mixtures thereof, were used to compress model tablets. The power law was found to hold true in a low pressure range, which agreed with theoretical expectation. This low pressure range depended on the individual material characteristics, but as a rule of thumb, the tablets having a porosity of more than about 30% or being compressed below 100 MPa were generally well explained by the tensile strength relationship. Tablets at higher densities were less adequately described by the theory that is based on large-scale heterogeneity of the relevant contact points in the compact. Tablets close to the unity density therefore require other theoretical approaches. More research is needed to understand tablet strength in a wider range of compaction pressures.
doi:10.1208/s12249-010-9416-x
PMCID: PMC2850502  PMID: 20300893
compaction; percolation theory; solid dosage form; tensile strength
6.  Large scale production of vesicles by hollow fiber extrusion: a novel method for generating polymersome encapsulated hemoglobin dispersions 
Vesicles, which include both liposomes and polymersomes (polymer vesicles), are being developed as therapeutic drug carriers. In this study, we present a fully scalable low pressure extrusion methodology for preparing vesicles. Vesicles were generated by continuous extrusion through a 200 nm pore diameter hollow fiber (HF) membrane. The first half of this study describes a method for generating empty polymersomes composed of different molecular weight amphiphilic poly(butadiene-b-ethylene oxide) (PBD-b-PEO) diblock copolymers on a large scale (50 -100 ml) using a HF membrane. Monodisperse empty polymersomes were formed with particle diameters slightly less than 200 nm, which were close to the rated 200 nm pore size of the HF membrane. The second half of this study describes the successful encapsulation of hemoglobin (Hb) inside the aqueous core of polymersomes using the HF extrusion methodology. We demonstrate that polymersome encapsulated hemoglobin (PEH) particles formed by this technique had similar oxygen affinity, cooperativity coefficient, and methemoglobin (metHb) level compared to PEHs formed by the 1 ml volume small-scale manual extrusion method. Most notably, Hb encapsulation inside the polymer vesicles formed by the HF extrusion method increased two-fold compared to the manual extrusion method.
This work is important, since it will enable facile scale-up of homogeneous vesicle dispersions that are typically required for preclinical and clinical studies as well as industrial use.
doi:10.1021/la9036343
PMCID: PMC2847677  PMID: 20000689
7.  Development and Evaluation of Buccoadhesive Controlled Release Tablets of Lercanidipine 
AAPS PharmSciTech  2008;9(1):182-190.
The purpose of this research was to develop and evaluate buccal mucoadhesive controlled release tablets of lercanidipine hydrochloride using polyethylene oxide and different viscosity grades of hydroxypropyl methylcellulose individually and in combination. Effect of polymer type, proportion and combination was studied on the drug release rate, release mechanism and mucoadhesive strength of the prepared formulations. Buccal mucoadhesive tablets were made by direct compression and were characterized for content uniformity, weight variation, friability, surface pH, thickness and mechanism of release. In order to estimate the relative enhancement in bioavailability one optimized formulation was evaluated in rabbits. Further, placebo tablets were also evaluated for acceptability in human subjects. Results indicated acceptable physical characteristics of designed tablets with good content uniformity and minimum weight variation. Drug release and mucoadhesive strength were found to depend upon polymer type, proportion and viscosity. The formulations prepared using poly ethylene oxide gave maximum mucoadhesion. The release mechanism of most formulations was found to be of anomalous non-Fickian type. In vivo studies of selected formulation in rabbits demonstrated significant enhancement in bioavailability of lercanidipine hydrochloride relative to orally administered drug. Moreover, in human acceptability studies of placebo formulations, the designed tablets adhered well to the buccal mucosa for more than 4 h without causing any discomfort. It may be concluded that the designed buccoadhesive controlled release tablets have the potential to overcome the disadvantage of poor and erratic oral bioavailability associated with the presently marketed formulations of lercanidipine hydrochloride.
doi:10.1208/s12249-007-9031-7
PMCID: PMC2976881  PMID: 18446480
buccal; hydroxypropyl methylcellulose; lercanidipine; mucoadhesive; poly ethylene oxide
8.  Improvement of Dissolution Behavior for Poorly Water-Soluble Drug by Application of Cyclodextrin in Extrusion Process: Comparison between Melt Extrusion and Wet Extrusion 
AAPS PharmSciTech  2010;11(2):885-893.
The purpose of this study was to improve dissolution behavior of poorly water-soluble drugs by application of cyclodextrin in extrusion processes, which were melt extrusion process and wet extrusion process. Indomethacin (IM) was employed as a model drug. Extrudates containing IM and 2-hydroxypropyl-β-cyclodextrin (HP-β-CyD) in 1:1 w/w ratio were manufactured by both melt extrusion process and wet extrusion process. In vitro drug release properties of IM from extrudates and physiochemical properties of extrudates were investigated. The dissolution rates of IM from extrudates manufactured by melt extrusion and wet extrusion with HP-β-CyD were significantly higher than that of the physical mixture of IM and HP-β-CyD. In extrudate manufactured by melt extrusion, γ-form of IM changed to amorphous completely during melt extrusion due to heating above melting point of IM. On the other hand, in extrudate manufactured by wet extrusion, γ-form of IM changed to amorphous partially due to interaction between IM and HP-β-CyD and mechanical agitating force during process. Application of HP-β-CyD in extrusion process is useful for the enhancement of dissolution rate for poorly water-soluble drugs.
doi:10.1208/s12249-010-9448-2
PMCID: PMC2902314  PMID: 20496019
2-hydroxypropyl-β-cyclodextrin; dissolution; extrusion; indomethacin; poor water-soluble drug
9.  Use of Propranolol-Magnesium Aluminium Silicate Intercalated Complexes as Drug Reservoirs in Polymeric Matrix Tablets 
The objective of the present study was to investigate the use of propranolol–magnesium aluminium silicate intercalated complexes as drug reservoirs in hydroxypropylmethylcellulose tablets. The matrix tablets containing the complexes were prepared and characterised with respect to propranolol release and were subsequently compared with those loading propranolol or a propranolol–magnesium aluminium silicate physical mixture. Additionally, the effects of varying viscosity grades of hydroxypropyl methylcellulose, compression pressures and calcium acetate incorporation on the drug release characteristics of the complex-loaded tablets were also examined. The results showed that the complex-loaded tablets have higher tablet hardness than those containing propranolol or a physical mixture. The drug release from the complex-loaded tablets followed a zero-order release kinetic, whereas an anomalous transport was found in the propranolol or physical mixture tablets. The drug release rate of the complex tablet significantly decreased with increasing hydroxypropylmethylcellulose viscosity grade. Increase in the compression pressure caused a decrease in the drug release rate of the tablets. Furthermore, the incorporation of calcium ions could accelerate propranolol release, particularly in acidic medium, because calcium ions could be exchanged with propranolol molecules intercalated in the silicate layers of magnesium aluminium silicate. These findings suggest that propranolol-magnesium aluminium silicate intercalated complexes show strong potential for use as drug reservoirs in matrix tablets intended for modifying drug release.
doi:10.4103/0250-474X.107048
PMCID: PMC3630724  PMID: 23626384
Complexes; drug release; hydroxypropylmethylcellulose; propranolol; magnesium aluminium silicate; matrix tablets
10.  Formulation, Characterization and Physicochemical Evaluation of Ranitidine Effervescent Tablets 
Advanced Pharmaceutical Bulletin  2013;3(2):315-322.
Purpose: The aim of this study was to design, formulate and physicochemically evaluate effervescent ranitidine hydrochloride (HCl) tablets since they are easily administered while the elderly and children sometimes have difficulties in swallowing oral dosage forms. Methods: Effervescent ranitidine HCl tablets were prepared in a dosage of 300 mg by fusion and direct compression methods. The powder blend and granule mixture were evaluated for various pre-compression characteristics, such as angle of repose, compressibility index, mean particle size and Hausner's ratio. The tablets were evaluated for post-compression features including weight variation, hardness, friability, drug content, dissolution time, carbon dioxide content, effervescence time, pH, content uniformity and water content. Effervescent systems with appropriate pre and post-compression qualities dissolved rapidly in water were selected as the best formulations. Results: The results showed that the flowability of fusion method is more than that of direct compression and the F5 and F6 formulations of 300 mg tablets were selected as the best formulations because of their physicochemical characteristics. Conclusion: In this study, citric acid, sodium bicarbonate and sweeteners (including mannitol, sucrose and aspartame) were selected. Aspartame, mint and orange flavors were more effective for masking the bitter taste of ranitidine. The fusion method is the best alternative in terms of physicochemical and physical properties.
doi:10.5681/apb.2013.051
PMCID: PMC3848210  PMID: 24312854
Effervescent tablet; Ranitidine HCl; Fusion method; Direct compression method
11.  Comparative evaluation of tableting compression behaviors by methods of internal and external lubricant addition: Inhibition of enzymatic activity of trypsin preparation by using external lubricant addition during the tableting compression process 
AAPS PharmSci  2001;3(3):32-42.
This study evaluated tableting compression by using internal and external lubricant addition. The effect of lubricant addition on the enzymatic activity of trypsin, which was used as a model drug during the tableting compression process, was also investigated. The powder mixture (2% crystalline trypsin, 58% crystalline lactose, and 40% microcrystalline cellulose) was kneaded with 5% hydroxypropyl cellulose aqueous solution and then granulated using an extruding granulator equipped with a 0.5-mm mesh screen at 20 rpm. After drying, the sample granules were passed through a 10-mesh screen (1680 μm). A 200-mg sample was compressed by using 8-mm punches and dies at 49, 98, 196, or 388 MPa (Mega Pascal) at a speed of 25 mm/min. The external lubricant compression was performed using granules without lubricant in the punches and dies. The granules were already dry coated by the lubricant. In contrast, the internal lubricant compression was performed using sample granules (without dry coating) containing 0.5% lubricant. At 98 MPa, for example, the compression level using the external lubricant addition method was about 13% higher than that for internal addition. The significantly higher compressing energy was also observed at other MPas. By comparison, the friction energy for the external addition method calculated based on upper and lower compression forces was only slightly larger. The hardness of tablets prepared using the internal addition method was 34% to 48% lower than that for the external addition method. The total pore volume of the tablet prepared using the external addition method was significantly higher. The maximum ejection pressure using the no-addition method (ie, the tablet was prepared using neither dry-coated granules nor added lubricant) was significantly higher than that of other addition methods. The order was as follows: no addition, external addition, and then internal addition. The ejection energy (EE) for internal addition was the lowest; for no addition, EE was the highest. In the dissolution test, the tablets obtained using external addition immediately disintegrated and showed faster drug release than those prepared using internal addition. This result occurred because the water penetration rate of the tablet using the external addition was much higher. The trypsin activity in tablets prepared using the external addition method was significantly higher than that produced using the internal addition method at the same pressure. All these results suggest that the external addition method might produce a fast-dissolution tablet. Because the drug will be compressed using low pressure only, an unstable bulk drug may be tableted without losing potency.
doi:10.1208/ps030320
PMCID: PMC2751015  PMID: 11741271
Tableting; Trypsin; Preparation; Compression; Dissolution
12.  Water Dynamics and Interactions in Water-Polyether Binary Mixtures 
Poly(ethylene) oxide (PEO) is a technologically important polymer with a wide range of applications including ion-exchange membranes, protein crystallization, and medical devices. PEO’s versatility arises from its special interactions with water. Water molecules may form hydrogen bond bridges between the ether oxygens of the backbone. While steady-state measurements and theoretical studies of PEO’s interactions with water abound, experiments measuring dynamic observables are quite sparse. A major question is the nature of the interactions of water with the ether oxygens as opposed to the highly hydrophilic PEO terminal hydroxyls. Here, we examine a wide range of mixtures of water and tetraethylene glycol dimethyl ether (TEGDE), a methyl-terminated derivative of PEO with 4 repeat units (5 ether oxygens) using ultrafast infrared polarization selective pump-probe measurements on water’s hydroxyl stretching mode to determine vibrational relaxation and orientational relaxation dynamics. The experiments focus on the dynamical interactions of water with the ether backbone because TEGDE does not have the PEO terminal hydroxyls. The experiments observe two distinct subensembles of water molecules: those that are hydrogen bonded to other waters and those that are associated with TEGDE molecules. The water orientational relaxation has a fast component of a few ps (water-like) followed by much slower decay of ∼20 ps (TEGDE associated). The two decay times vary only mildly with the water concentration. The two subensembles are evident even in very low water content samples, indicating pooling of water molecules. Structural change as water content is lowered either through conformational changes in the backbone or increasing hydrophobic interactions is discussed.
doi:10.1021/ja809261d
PMCID: PMC2889155  PMID: 19323522
13.  Effect of Drug Solubility on Polymer Hydration and Drug Dissolution from Polyethylene Oxide (PEO) Matrix Tablets 
AAPS PharmSciTech  2008;9(2):437-443.
The purpose of the study was to investigate the effect of drug solubility on polymer hydration and drug dissolution from modified release matrix tablets of polyethylene oxide (PEO). Different PEO matrix tablets were prepared using acetaminophen (ACE) and ibuprofen (IBU) as study compounds and Polyox® WSR301 (PEO) as primary hydrophilic matrix polymer. Tablet dissolution was tested using the USP Apparatus II, and the hydration of PEO polymer during dissolution was recorded using a texture analyzer. Drug dissolution from the preparations was dependent upon drug solubility, hydrogel formation and polymer proportion in the preparation. Delayed drug release was attributed to the formation of hydrogel layer on the surface of the tablet and the penetration of water into matrix core through drug dissolution and diffusion. A multiple linear regression model could be used to describe the relationship among drug dissolution, polymer ratio, hydrogel formation and drug solubility; the mathematical correlation was also proven to be valid and adaptable to a series of study compounds. The developed methodology would be beneficial to formulation scientists in dosage form design and optimization.
doi:10.1208/s12249-008-9060-x
PMCID: PMC2976924  PMID: 18431663
drug dissolution; modified release; polymer hydration; texture analyzer
14.  Buccal Drug Delivery of Pravastatin Sodium 
AAPS PharmSciTech  2010;11(1):416-424.
The purpose of this study was to develop and optimize formulations of mucoadhesive bilayered buccal tablets of pravastatin sodium using carrageenan gum as the base matrix. The tablets were prepared by direct compression method. Polyvinyl pyrrolidone (PVP) K 30, Pluronic® F 127, and magnesium oxide were used to improve tablet properties. Magnesium stearate, talc, and lactose were used to aid the compression of tablets. The tablets were found to have good appearance, uniform thickness, diameter, weight, pH, and drug content. A 23 full factorial design was employed to study the effect of independent variables viz. levels of carrageenan gum, Pluronic F 127 and PVP K30, which significantly influenced characteristics like in vitro mucoadhesive strength, in vitro drug release, swelling index, and in vitro residence time. The tablet was coated with an impermeable backing layer of ethyl cellulose to ensure unidirectional drug release. Different penetration enhancers were tried to improve the permeation of pravastatin sodium through buccal mucosa. Formulation containing 1% sodium lauryl sulfate showed good permeation of pravastatin sodium through mucosa. Histopathological studies revealed no buccal mucosal damage. It can be concluded that buccal route can be one of the alternatives available for the administration of pravastatin sodium.
doi:10.1208/s12249-010-9381-4
PMCID: PMC2850451  PMID: 20300898
bilayered buccal tablets; carrageenan; mucoadhesive; pravastatin sodium; 23 factorial design
15.  Formulation and design of sustained release matrix tablets of metformin hydrochloride: Influence of hypromellose and polyacrylate polymers 
Aim:
The current paper was an attempt to design a sustained release dosage form using various grades of hydrophilic polymers, Hypromellose (hydroxyl-propyl methylcellulose [HPMC] K15M, HPMC K100M and HPMC K200M) and Polyacrylate polymers, Eudragit RL100 and Eudragit RS100 with or without incorporating ethyl cellulose on a matrix-controlled drug delivery system of Metformin hydrochloride.
Materials and Methods:
Laboratory scale batches of nine tablet formulations were prepared by wet granulation technique (Low shear). Micromeritic properties of the granules were evaluated prior to compression. Tablets were characterized as crushing strength, friability, weight variation, thickness, drug content or assay and evaluated for in-vitro release pattern for 12 h using Phosphate buffer of pH 6.8 at 37 ± 0.5°C. The in-vitro release mechanism was evaluated by kinetic modeling.
Results and Discussion:
The results obtained revealed that HPMC K200M at a concentration of 26% in formulation (F6) was able to sustain the drug release for 12 h and followed the Higuchi pattern quasi-Fickian diffusion. With that, combined effect of HPMC K15M as an extragranular section and Eudragit RS100 displayed a significant role in drug release. Dissolution data were compared with innovator for similarity factor (f2), and exhibited an acceptable value of ≥50 Three production validation scale batches were designed based on lab scale best batch and charged for stability testing, parameters were within the limit of acceptance. There was no chemical interaction found between the drug and excipients during Fourier Transform Infrared Spectroscopy (FTIR) and Differential scanning calorimetry study.
Conclusion:
Hence, combinely HPMC K200M and Eudragit RS100 at a suitable concentration can effectively be used to sustain drug release.
doi:10.4103/2229-516X.112242
PMCID: PMC3678683  PMID: 23776841
Hydrophilic polymer; innovator; Metformin hydrochloride; micromeritic properties; sustained release tablet matrix
16.  Floating Matrix Tablets of Domperidone Formulation and Optimization Using Simplex Lattice Design 
The purpose of this research was to prepare a floating matrix tablet containing domperidone as a model drug. Polyethylene oxide (PEO) and hydroxypropyl methylcellulose (HPMC) were evaluated for matrix-forming properties. A simplex lattice design was applied to systemically optimize the drug release profile. The amounts of PEO WSR 303, HPMC K15M and sodium bicarbonate were selected as independent variables and floating lag time, time required to release 50% of drug (t50) and 80% of drug (t80), diffusion coefficient (n) and release rate (k) as dependent variables. The amount of PEO and HPMC both had significant influence on the dependent variables. It was found that the content of PEO had dominating role as drug release controlling factor, but using suitable concentration of sodium bicarbonate, one can tailor the desired drug release from hydrophilic matrixes. The linear regression analysis and model fitting showed that all these formulations followed Korsmeyer and Peppas model, which had a higher value of correlation coefficient (r). The tablets of promising formulation were found to be stable for 3 months under accelerated (40°C / 75% RH) stability testing.
PMCID: PMC3813035  PMID: 24250376
Domperidone; Floating matrix tablets; Simplex lattice design; Release kinetics; Polyethylene oxide; Hydroxypropyl methylcellulose; Floating lag time; Total floating time.
17.  Design of naltrexone-loaded hydrolyzable crosslinked nanoparticles 
A hydrolyzable crosslinker (N,O-dimethacryloylhydroxylamine (MANHOMA)) was synthesized by a modified method and was characterized using 1H-NMR, FTIR, and melting point determination. Naltrexone-loaded nanoparticles were prepared by copolymerization of poly(ethylene glycol)1000 monomethyl ether mono methacrylate (PEO-MA), methyl methacrylate (MMA) and N,O-dimethacryloylhydroxylamine (MANHOMA) in 0.4% poly(vinyl alcohol) aqueous solution. The nanoparticles were characterized by FTIR, particle size determination and transmission electron microscope (TEM). The TEM photomicrographs of the nanoparticles show a crosslinked core surrounded by a ring formed by the polyethylene glycol tail of PEO-MA. The loading efficiency of the nanoparticles and in vitro drug availability from the nanoparticles were investigated. The naltrexone-loaded hydrolyzable crosslinked nanoparticles were able to sustain the release of naltrexone for different periods of time, depending on the monomer feed composition.
PMCID: PMC2925203  PMID: 12204561
Hydrolyzable crosslinked copolymer; Nanoparticles; Drug delivery system; Naltrexone
18.  Once-daily sustained-release matrix tablets of nicorandil: Formulation and in vitro evaluation 
AAPS PharmSciTech  2003;4(4):480-488.
The objective of the present study was to develop once-daily sustained-release matrix tablets of nicorandil, a novel potassium channel opener used in cardiovascular diseases. The tablets were prepared by the wet granulation method. Ethanolic solutions of ethylcellulose (EC), Eudragit RL-100, Eudragit RS-100, and polyvinylpyrrolidone were used as granulating agents along with hydrophilic matrix materials like hydroxypropyl methylcellulose (HPMC), sodium carboxymethylcellulose, and sodium alginate. The granules were evaluated for angle of repose, bulk density, compressibility index, total porosity, and drug content. The tablets were subjected to thickness, diameter, weight variation test, drug content, hardness, friability, and in vitro release studies. The granules showed satisfactory flow properties, compressibility, and drug content. All the tablet formulations showed acceptable pharmacotechnical properties and complied with in-house specifications for tested parameters. According to the theoretical release profile calculation, a oncedaily sustained-release formulation should release 5.92 mg of nicorandil in 1 hour, like conventional tablets, and 3.21 mg per hour up to 24 hours. The results of dissolution studies indicated that formulation F-I (drug-to-HPMC, 1∶4; ethanol as granulating agent) could extend the drug release up to 24 hours. In the further formulation development process, F-IX (drug-to-HPMC, 1∶4; EC 4% wt/vol as granulating agent), the most successful formulation of the study, exhibited satisfactory drug release in the initial hours, and the total release pattern was very close to the theoretical release profile. All the formulations (except F-IX) exhibited diffusion-dominated drug release. The mechanism of drug release from F-IX was diffusion coupled with erosion.
doi:10.1208/pt040461
PMCID: PMC2750654  PMID: 15198556
nicorandil; hydroxypropyl methylcellulose; ethylcellulose; sustained release; matrix tablets
19.  Mucoadhesive Microparticles in a Rapidly Dissolving Tablet for Sustained Drug Delivery to the Eye 
Topical drug delivery to the eye is subject to low bioavailability because of the rapid clearance of drug from the ocular surface. In this study, the authors prepared mucoadhesive microparticles formulated in a rapidly dissolving tablet to achieve sustained drug delivery to the eye.
Purpose.
To test the hypothesis that mucoadhesive microparticles formulated in a rapidly dissolving tablet can achieve sustained drug delivery to the eye.
Methods.
Mucoadhesive microparticles, smaller than 5 μm were fabricated with poly(lactic-co-glycolic acid) and poly(ethylene glycol) as a core material and mucoadhesion promoter, respectively, and encapsulated pilocarpine as a model drug. These microparticles were embedded in a poly(vinyl alcohol) matrix to form a dry tablet designed to reduce rapid clearance of the microparticles on initial application to the eye.
Results.
This in vitro drug release study exhibited that for all formulations, approximately 90% of pilocarpine was released during the first 10 minutes, and the remaining 10% was released slowly for 3 hours. In vivo mucoadhesion test on the rabbit eye indicated that mucoadhesive microparticles adhered significantly better to the preocular surface than other formulations. To assess the pharmacodynamics, the most prolonged pilocarpine-induced pupil constriction was observed in rabbit eyes in vivo using a tablet with mucoadhesive microparticles; it lasted up to 330 minutes.
Conclusions.
The authors conclude that mucoadhesive microparticles formulated into a dry dosage form is a promising system for sustained drug delivery to the eye.
doi:10.1167/iovs.10-6465
PMCID: PMC3088554  PMID: 21245405
20.  Effect of Hydrophilic Diluents on the Release Profile of Griseofulvin from Tablet Formulations 
Studies have shown that when compressing drugs with low aqueous solubility, the solubility of diluents selected is very crucial as it influences the disintegration, dissolution and bioavailability of such drugs. Based on these reports, the present study was undertaken to investigate the effect of some commonly used hydrophilic tablet diluents (lactose, sucrose, mannitol and dextrose) on the in vitro release properties of griseofulvin from compressed tablets. Griseofulvin granules and tablets were prepared using the wet granulation method. Tablet properties evaluated as a function of the diluents used include, hardness, friability, dissolution profile and dissolution efficiency at 60 min. Results obtained indicated variability in griseofulvin release in the presence of the diluents. The relative enhanced dissolution effects of the four hydrophilic diluents is in the order of dextrose>sucrose>lactose>mannitol. All the griseofulvin tablet batches produced exhibited a better drug release (in terms of rate and extent of release) than a commercially available tablet sample of griseofulvin (Fulcin®). The results of the dissolution efficiency (DE60min) are 91.7, 83.5, 48.7, 35.3 and 15.6% for dextrose, sucrose, lactose, mannitol and fulcin®, respectively. The overall results indicated that dextrose or sucrose can be utilised to improve the in vitro release profile and hence in vivo bioavailability of griseofulvin from compressed tablets.
PMCID: PMC3928738  PMID: 24591749
Griseofulvin; hydrophilic diluent; lactose; sucrose; mannitol; dextrose; dissolution efficiency
21.  The Application of Modified Flow-Through Cell Apparatus for the Assessment of Chlorhexidine Dihydrochloride Release from Lozenges Containing Sorbitol 
AAPS PharmSciTech  2009;10(3):1048-1057.
The objective of this work was to apply a new apparatus for the assay of the drug release from lozenge tablet with a potential use in the treatment of oral candidosis and another conditions connected to microbial etiopathology in the oral cavity or as an antiplaque factor. Also, an approach to comparison of the applied method with the classical paddle apparatus method was performed. Tablets containing chlorhexidine dihydrochloride were formulated with granulated sorbitol of different grades (diameter of 110, 180, 480, and 650 μm, respectively), lactose, and magnesium stearate as excipients. Tablets were obtained through direct compression, and uniformity of weight, friability, breaking strength, disintegration, and release rate were evaluated. The disintegration times ranged between 10 and 21 min. In the next stage of the study, the release of chlorhexidine from lozenges prepared with granulated sorbitol grade 110 μm and different amounts of lactose and magnesium stearate was assessed. Two stages were observed during the release of chlorhexidine dihydrochloride from the lozenges, assayed by the classical paddle apparatus method II USP. In the first stage, release rates were between 2.6 × 10−2 and 4.7 × 10−2 min−1, in the second stage between 1.7 × 10−3 and 7.7 × 10−3 min−1. In the case of the in-house method, the release was near to first-order kinetics through the entire release experiment, with rate constants between 3.6 × 10−2 and 6.6 × 10−2 min−1. The sorbitol granulate of granules with diameter 110 μm was found to be most suitable for the lozenges with chlorhexidine dihydrochloride and lactose. The in-house release method, proposed in this work, seems to be more realistic for the preliminary assessment of predicted drug concentrations in the oral cavity after the intake of a lozenge.
doi:10.1208/s12249-009-9298-y
PMCID: PMC2802162  PMID: 19669894
chlorhexidine; lactose; lozenges; magnesium stearate; release rate; sorbitol
22.  Formulation and in vitro evaluation of floating tablets of hydroxypropyl methylcellulose and polyethylene oxide using ranitidine hydrochloride as a model drug 
The present study was carried out with an objective of preparation and in vitro evaluation of floating tablets of hydroxypropyl methyl cellulose (HPMC) and polyethylene oxide (PEO) using ranitidine hydrochloride as a model drug. The floating tablets were based on effervescent approach using sodium bicarbonate a gas generating agent. The tablets were prepared by dry granulation method. The effect of polymers concentration and viscosity grades of HPMC on drug release profile was evaluated. The effect of sodium bicarbonate and stearic acid on drug release profile and floating properties were also investigated. The result of in vitro dissolution study showed that the drug release profile could be sustained by increasing the concentration of HPMC K15MCR and Polyox WSR303. The formulation containing HPMC K15MCR and Polyox WSR303 at the concentration of 13.88% showed 91.2% drug release at the end of 24 hours. Changing the viscosity grade of HPMC from K15MCR to K100MCR had no significant effect on drug release profile. Sodium bicarbonate and stearic acid in combination showed no significant effect on drug release profile. The formulations containing sodium bicarbonate 20 mg per tablet showed desired buoyancy (floating lag time of about 2 minutes and total floating time of >24 hours). The present study shows that polymers like HPMC K15MCR and Polyox WSR303 in combination with sodium bicarbonate as a gas generating agent can be used to develop sustained release floating tablets of ranitidine hydrochloride.
doi:10.4103/0975-1483.104363
PMCID: PMC3573371  PMID: 23493037
Floating drug delivery system; gastroretentive drug delivery system; HPMC; PEO; ranitidine hydrochloride; sustained release
23.  Design and Development of Polyethylene Oxide Based Matrix Tablets for Verapamil Hydrochloride 
In the present investigation an attempt has been made to increase therapeutic efficacy, reduced frequency of administration and improved patient compliance by developing controlled release matrix tablets of verapamil hydrochloride. Verapamil hydrochloride was formulated as oral controlled release matrix tablets by using the polyethylene oxides (Polyox WSR 303). The aim of this study was to investigate the influence of polymer level and type of fillers namely lactose (soluble filler), swellable filler (starch 1500), microcrystalline cellulose and dibasic calcium phosphate (insoluble fillers) on the release rate and mechanism of release for verapamil hydrochloride from matrix tablets prepared by direct compression process. Higher polymeric content in the matrix decreased the release rate of drug. On the other hand, replacement of lactose with anhydrous dibasic calcium phosphate and microcrystalline cellulose has significantly retarded the release rate of verapamil hydrochloride. Biopharmaceutical evaluation of satisfactory formulations were also carried out on New Zealand rabbits and parameters such as maximum plasma concentration, time to reach peak plasma concentration, area under the plasma concentration time curve(0-t) and area under first moment curve(0-t) were determined. In vivo pharmacokinetic study proves that the verapamil hydrochloride from matrix tablets showed prolonged release and were be able to sustain the therapeutic effect up to 24 h.
PMCID: PMC3757857  PMID: 24019567
In vivo studies; matrix tablets; polyethylene oxides; verapamil hydrochloride
24.  Formulation and optimization of orodispersible tablets of flutamide 
The present study aimed to formulate orodispersible tablets of flutamide (FTM) to increase its bioavailability. Orodispersible tablets were prepared by direct compression technique using three different approaches namely; super-disintegration, effervescence and sublimation. Different combined approaches were proposed and evaluated to optimize tablet characteristics. Sodium starch glycolate (SSG) was used as the superdisintegrant. The prepared powder mixtures were subjected to both pre and post compression evaluation parameters including; IR spectroscopy, micromeritics properties, tablet hardness, friability, wetting time, disintegration time and in-vitro drug release. IR studies indicated that there was no interaction between the drug and the excipients used except Ludipress. The results of micromeritics studies revealed that all formulations were of acceptable to good flowability. Tablet hardness and friability indicated good mechanical strength. Wetting and dispersion times decreased from 46 to 38 s by increasing the SSG concentration from 3.33 to 6.66% w/w in tablets prepared by superdisintegration method. The F8 formulation which was prepared by combined approaches of effervescence and superdisintegrant addition gave promising results for tablet disintegration and wetting times but failed to give faster dissolution rate. The incorporation of 1:5 solid dispersion of FTM: PEG 6000 instead of the pure drug in the same formulation increased the drug release rate from 73.12 to 96.99% after 15 min. This increase in the dissolution rate may be due to the amorphization of the drug during the solid dispersion preparation. The presence of the amorphous form of the drug was shown in the IR spectra.
doi:10.1016/j.jsps.2013.01.009
PMCID: PMC3909754  PMID: 24493974
Flutamide; Orodispersible tablets; Superdisintegrant-addition; Sublimation; Effervescence
25.  Development of a Melting Tablet Containing Promethazine HCl Against Motion Sickness 
AAPS PharmSciTech  2008;9(3):1006-1015.
The purpose of this study was to design a ‘Traveller Friendly Drug Delivery System’ for PM-HCl. Conventional promethazine (PM-HCl) tablets are bitter, need to be taken 1 h before symptoms and water is also needed. Taste-masked granules were produced with Eudragit® E100 by extrusion, and analyzed with FTIR, DSC, and XRD. Tablets formulated from granules by direct compression using Ac-Di-Sol, Polyplasdone®-XL, Primojel® and ion-exchanger Tulsion®339 and evaluated for mass uniformity, friability, tensile strength, drug content uniformity, water absorption ratio, in-vitro and in-vivo disintegration time and in-vitro dissolution studies. The observed drug-polymer interactions and reduced crystallinity may be reasons for increased dissolution rates. The formulated tablets were disintegrated within 15 s. Tablets (25 mg PM-HCl) with Ac-Di-Sol (4%) showed complete release within 1 min, while marketed conventional tablets (Phenergan®; Rhone-Poulec) release 25% during the same period. A preliminary stability studies for the prepared tablets carried at 30 ± 2°C/60 ± 5% RH, and 40 ± 2°C/75 ± 5%RH for 3 months showed no significant changes in the tablets quality at 30 ± 2°C/60 ± 5% RH. However, at 40 ± 2°C/75 ± 5%RH marked increase in in-vitro disintegration time, tensile strength and decrease in friability and water absorption ratio was found. The present studies indicate the abilities of Eudragit® E 100 for taste masking and improving the dissolution profile of PM-HCl after complexation. In addition, by employing cost effective direct compression method, fast-dissolving tablets of 400 mg total weight with an acceptable quality could be prepared.
doi:10.1208/s12249-008-9133-x
PMCID: PMC2977014  PMID: 18770049
Eudragit® E 100; Eudragit® RD 100; promethazine hydrochloride; rapidly disintegrating tablet; stability study; superdisintegrants

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