This study evaluated the use of isothermal microcalorimetry (ITMC) to detect macrophage–nanoparticle interactions. Four different nanoparticle (NP) formulations were prepared: uncoated poly(isobutyl cyanoacrylate) (PIBCA), polysorbate-80-coated PIBCA, gelatin, and mannosylated gelatin NPs. Changes in NP formulations were aimed to either enhance or decrease macrophage–NP interactions via phagocytosis. Alveolar macrophages were cultured on glass slabs and inserted in the ITMC instrument. Thermal activities of the macrophages alone and after titration of 100 μL of NP suspensions were compared. The relative interactive coefficients of macrophage–NP interactions were calculated using the heat exchange observed after NP titration. Control experiments were performed using cytochalasin B (Cyto B), a known phagocytosis inhibitor. The results of NP titration showed that the total thermal activity produced by macrophages changed according to the NP formulation. Mannosylated gelatin NPs were associated with the highest heat exchange, 75.4 ± 7.5 J, and thus the highest relative interactive coefficient, 9,269 ± 630 M-1. Polysorbate-80-coated NPs were associated with the lowest heat exchange, 15.2 ± 3.4 J, and the lowest interactive coefficient, 890 ± 120 M-1. Cyto B inhibited macrophage response to NPs, indicating a connection between the thermal activity recorded and NP phagocytosis. These results are in agreement with flow cytometry results. ITMC is a valuable tool to monitor the biological responses to nano-sized dosage forms such as NPs. Since the thermal activity of macrophage–NP interactions differed according to the type of NPs used, ITMC may provide a method to better understand phagocytosis and further the development of colloidal dosage forms.
Electronic supplementary material
The online version of this article (doi:10.1208/s12248-010-9240-y) contains supplementary material, which is available to authorized users.
flow cytometry; isothermal microcalorimetry; macrophages; nanoparticles; phagocytosis
The purpose of this study is to enhance the dissolution rate of prednisone by co-grinding with Neusilin to form a complex that can be incorporated into a mini-tablet formulation for pediatrics. Prednisone–Neusilin complex was co-grinded at various ratios (1:1, 1:3, 1:5, and 1:7). The physicochemical properties of the complex were characterized by various analytical techniques including: differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), scanning electron microscope (SEM), particle size, surface area, solubility, and dissolution rate. The co-grinded prednisone–Neusilin complex (1:7) was blended with other excipients and was formulated into a 2-mm diameter mini-tablet. The mini-tablets were further evaluated for thickness, weight, content uniformity, and dissolution rate. To improve taste masking and stability, mini-tablets were coated by dip coating with Eudragit® EPO solution. DSC and XRPD results showed that prednisone was transformed from crystalline state into amorphous state after co-grinding with Neusilin. Particle size, surface area, and SEM results confirmed that prednisone was adsorbed to Neusilin’s surface. Co-grinded prednisone–Neusilin complex (1:7) had a solubility of 0.24 mg/mL and 90% dissolved within 20 min as compared to crystalline prednisone which had a solubility of 0.117 mg/mL and 30% dissolved within 20 min. The mini-tablets containing co-grinded prednisone–Neusilin complex (1:7) exhibited acceptable physicochemical and mechanical properties including dissolution rate enhancement. These mini-tablets were successfully dip coated in Eudragit® EPO solution to mask the taste of the drug during swallowing. This work illustrates the potential use of co-grinded prednisone–Neusilin to enhance solubility and dissolution rate as well as incorporation into a mini-tablet formulation for pediatric use.
mini-tablet; Neusilin; pediatric; prednisone; solubility
The main objective of the present work was to study the effect of mixing order of Cab-O-Sil (CS) and magnesium stearate (MgSt) and microlayers during mixing on blend and tablet properties. A first set of pharmaceutical blend containing Avicel PH200, Pharmatose and micronized acetaminophen was prepared with three mixing orders (mixing order-1: CS added first; mixing order-2: MgSt added first; mixing order-3: CS and MgSt added together). All the blends were subjected to a shear rate of 80 rpm and strain of 40, 160 and 640 revolutions in a controlled shear environment resulting in nine different blends. A second set of nine blends was prepared by replacing Avicel PH200 with Avicel PH102. A total of eighteen blends thus prepared were tested for powder hydrophobicity, powder flow, tablet weight, tablet hardness and tablet dissolution. Results indicated that powder hydrophobicity increased significantly for mixing order-1. Intermediate hydrophobic behavior was found for mixing order-3. Additionally, mixing order 1 resulted in improved powder flow properties, low weight variability, higher average tablet weight and slow drug release rates. Dissolution profiles obtained were found to be strongly dependent not only on the mixing order of flowing agents, but also on the strain and the resulting hydrophobicity.
Mixing order; Shear; Strain; Hydrophobicity; Dissolution; Drug release
The aim of this study was to prepare highly porous carrier particles by emulsion solvent evaporation and compare the loading capacity of these beads with two traditional carriers, sugar beads, and microcrystalline cellulose granules during an interactive mixing process. The porous carrier particles were prepared by an emulsion solvent evaporation process using cellulose propionate as a binder, anhydrous dibasic calcium phosphate, and ion exchange resins as a fillers, and polyethylene glycol as a pore inducer. Micronized furosemide or griseofulvin powder was mixed with the same volume of each carrier in an interactive mixing process. The tableting properties, drug loading per unit volume of carrier, content uniformity of the mixtures, and dissolution of the drugs from the mixtures were measured. The results showed that highly porous microcapsules with desirable hardness equivalent to that of sugar beads and MCC granules were successfully prepared. On average the loading capacity of the new carrier was 310% that of sugar beads and 320% that of MCC granules during an interactive mixing process with very good content uniformity. The tableting properties of the microcapsules were equivalent to that of microcrystalline cellulose granules, and the dissolution of the drugs from interactive mixtures prepared with the new carrier was equivalent to that of drug suspensions. This showed that the prepared microcapsule carrier could be used to improve the loading capacity during an interactive mixing and to prepare tablets by direct compression.
direct compression; emulsion solvent evaporation; interactive mixing; porous carrier
The aim of the current study was to design oral fast-release polymeric tablets of prednisone and to optimize the drug dissolution profile by modifying the carrier concentration. Solid dispersions were prepared by the solvent evaporation method at different drug:polymer ratios (wt/wt). The physical state and drug:carrier interactions were analyzed by X-ray diffraction, infrared spectroscopy, and scanning electron microscopy. The dissolution rate of prednisone from solid dispersions was markedly enhanced by increasing the polymer concentration. The tablets were prepared from solid dispersion systems using polyethylene glycol (PEG) 6000 as a carrier at low and high concentration. The results showed that PEG 6000-based tablets exhibited a significantly higher prednisone dissolution (80% within 30 minutes) than did conventional tablets prepared without PEG 6000 (<25% within 30 minutes). In addition, the good disintegration and very good dissolution performance of the developed tablets without the addition of superdisintegrant highlighted the suitability of these formulated dosage forms. The stability studies performed in normal and accelerated conditions during 12 months showed that prednisone exhibited high stability in PEG 6000 solid dispersion powders and tablets. The X-ray diffraction showed that the degree of crystallinity of prednisone in solid dispersions decreased when the ratio of the polymer increased, suggesting that the drug is present inside the samples in different physical states. The Fourier transform infrared spectroscopic studies showed the stability of prednisone and the absence of well-defined drug:polymer interactions. Scanning electron microscopy images showed a novel morphology of the dispersed systems in comparison with the pure components.
Solid dispersions; PEG 6000; prednisone; dissolution rate; tablets
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.
Cellactose®; chitin; direct compression; microcrystalline cellulose; simplex-centroid mixture design; tablets
Magnesium stearate (MS) is the most commonly used lubricant in pharmaceutical industry. During blending, MS particles form a thin layer on the surfaces of the excipient and drug particles prohibiting the bonding from forming between the particles. This hydrophobic layer decreases the tensile strength of tablets and prevents water from penetrating into the tablet restraining the disintegration and dissolution of the tablets. Although overlubrication of the powder mass during MS blending is a well-known problem, the lubricant distribution in tablets has traditionally been challenging to measure. There is currently no adequate analytical method to investigate this phenomenon. In this study, the distribution of MS in microcrystalline cellulose (MCC) tablets was investigated using three different blending scales. The crushing strength of the tablets was used as a secondary response, as its decrease is known to result from the overlubrication. In addition, coating of the MCC particles by MS in intact tablets was detected using Raman microscopic mapping. MS blending was more efficient in larger scales. Raman imaging was successfully applied to characterize MS distribution in MCC tablets despite low concentration of MS. The Raman method can provide highly valuable visual information about the proceeding of the MS blending process. However, the measuring set-up has to be carefully planned to establish reliable and reproducible results.
blending; lubricant; magnesium stearate; Raman spectroscopy; scale-up
The dry-coated tablet with optimal lag time was designed to simulate the dosing time of drug administration according to the physiological needs. Different compositions of ethylcellulose (EC) powder with a coarse particle (167.5 μm) and several fine particles (<6 μm), respectively, were mixed to formulate the whole layer of the outer shell of dry-coated tablets. The formulations containing different weight ratios of coarse/fine particles of EC powders or 167.5 μm EC powder/excipient in the upper layer of the outer shell to influence the release behavior of sodium diclofenac from dry-coated tablet were also explored. The results indicate that sodium diclofenac released from all the dry-coated tablets exhibited an initial lag period, followed by a stage of rapid drug release. When the mixture of the coarse/fine particles of EC powders was incorporated into the whole layer, the lag time was almost the same. The outer shell broke into 2 halves to make a rapid drug release after the lag time, which belonged to the time-controlled disruption of release mechanism. When the lower layer in the outer shell was composed of 167.5 μm EC powder and the upper layer was formulated by mixing different weight ratios of 167.5 μm and 6 μm of EC powders, the drug release also exhibited a time-controlled disruption behavior. Its lag time might be freely modulated, depending on the amount of 6 μm EC powder added. Once different excipients were respectively incorporated into the upper layer of the outer shell, different release mechanisms were observed as follows: time-controlled explosion for Explotab, disruption for Avicel and spray-dried lactose, erosion for dibasic calcium phosphate anhydrate, and sigmoidal profile for hydroxypropyl methylcellulose.
micronized ethylcellulose; dry-coated tablet; outer layer; time-controlled dissolution; lag time
The aim of this study was to apply quality by design (QbD) for pharmaceutical development of felodipine solid mixture (FSM) containing hydrophilic carriers and/or polymeric surfactants, for easier development of controlled-release tablets of felodipine. The material attributes, the process parameters (CPP), and the critical quality attributes of the FSMs were identified. Box–Behnken experimental design was applied to develop space design and determine the control space of FSMs that have maximum solubility, maximum dissolution, and ability to inhibit felodipine crystallization from supersaturated solution. Material attributes and CPP studied were the amount of hydroxypropyl methylcellulose (HPMC; X1), amount of polymeric surfactants Inutec®SP1 (X2), amount of Pluronic®F-127 (X3) and preparation techniques, physical mixture (PM) or solvent evaporation (SE; X4). There is no proposed design space formed if the Pluronic® content was below 45.1 mg and if PM is used as the preparation technique. The operating ranges, for robust development of FSM of desired quality, of Pluronic®, Inutec®SP1, HPMC, and preparation technique, are 49–50, 16–23, 83–100 mg, and SE, respectively. The calculated value of f2 was 56.85, indicating that the release profile of the controlled-release (CR) tablet (CR-6) containing the optimized in situ-formed FSM was similar to that of the target release profile. Not only did the ternary mixture of Pluronic®, HPMC with Inutec®SP1 enhance the dissolution rate and inhibit crystallization of felodipine, but also they aided Carbopol®974 in controlling felodipine release from the tablet matrix. It could be concluded that a promising once-daily CR tablets of felodipine was successfully designed using QbD approach.
Box–Behnken design; dissolution; felodipine; QbD; solid mixture
Blending of powders is a crucial step in the production of pharmaceutical solid dosage forms. The active pharmaceutical ingredient (API) is often a powder that is blended with other powders (excipients) in order to produce tablets. The blending efficiency is influenced by several external factors, such as the desired degree of homogeneity and the required blending time, which mainly depend on the properties of the blended materials and on the geometry of the blender. This experimental study investigates the mixing behavior of acetyl salicylic acid as an API and α-lactose monohydrate as an excipient for different filling orders and filling levels in a blender. A multiple near-infrared probe setup on a laboratory-scale blender is used to observe the powder composition quasi-simultaneously and in-line in up to six different positions of the blender. Partial least squares regression modeling was used for a quantitative analysis of the powder compositions in the different measurement positions. The end point for the investigated mixtures and measurement positions was determined via moving block standard deviation. Observing blending in different positions helped to detect good and poor mixing positions inside the blender that are affected by convective and diffusive mixing.
blender geometry; multiprobe measurement; multivariate analysis; near-infrared spectroscopy; powder mixing dynamics; quantitative continuous monitoring
An ultrasound-assisted powder-coating technique was used to produce a homogeneous powder formulation of a low-dose active pharmaceutical ingredient (API). The powdered particles of microcrystalline cellulose (MCC; Avicel® PH-200) were coated with a 4% m/V aqueous solution of riboflavin sodium phosphate, producing a uniform drug layer on the particle surfaces. It was possible to regulate the amount of API in the treated powder. The thickness of the API layer on the surface of the MCC particles increased near linearly as the number of coating cycles increased, allowing a precise control of the drug content. The tablets (n = 950) prepared from the coated powder showed significantly improved weight and content uniformity in comparison with the reference tablets compressed from a physical binary powder mixture. This was due to the coated formulation remaining uniform during the entire tabletting process, whereas the physical mixture of the powders was subject to segregation. In conclusion, the ultrasound-assisted technique presented here is an effective tool for homogeneous drug coating of powders of irregular particle shape and broad particle size distribution, improving content uniformity of low-dose API in tablets, and consequently, ensuring the safe delivery of a potent active substance to patients.
content uniformity; homogeneity; low-dose API; powder coating; ultrasound
The objective of the present investigation was to design a sustained release floating microcapsules of theophylline using two polymers of different permeability characteristics; Eudragit RL 100 (Eu RL) and cellulose acetate butyrate (CAB) using the oil-in-oil emulsion solvent evaporation method. Polymers were used separately and in combination to prepare different microcapsules. The effect of drug-polymer interaction was studied for each of the polymers and for their combination. Encapsulation efficiency, the yield, particle size, floating capability, morphology of microspheres, powder X-ray diffraction analysis (XRD), and differential scanning calorimetry (DSC) were evaluated. The in vitro release studies were performed in PH 1.2 and 7.4. The optimized drug to polymer ratios was found to be 4:1 (F2) and 0.75:1 (F'2) with Eu RL and CAB, respectively. The best drug to polymer ratio in mix formulation was 4:1:1 (theophylline: Eu RL: CAB ratio). Production yield, loading efficiencies, and particle size of F2 and F’2 were found to be 59.14% and 45.39%, 73.93% and 95.87%, 372 and 273 micron, respectively. Microsphere prepared with CAB showed the best floating ability (80.3 ± 4.02% buoyancy) in 0.1 M HCl for over 12 h. The XRD and DSC showed that theophylline in the drug loaded microspheres was stable and in crystaline form. Microparticles prepared using blend of Eu RL and CAB polymers indicated more sustained pattern than the commercial tablet (P<0.05). Drug loaded floating microballoons prepared of combination of Eu RL and CAB with 1:1 ratio were found to be a suitable delivery system for sustained release delivery of theophylline which contained lower amount of polymer contents in the microspheres.
Theophylline; Eudragit RL100; Cellulose acetate butyrate; Microparticles; Emulsion-solvent evaporation
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.
Effervescent tablet; Ranitidine HCl; Fusion method; Direct compression method
The purpose of this research was to evaluate β-cyclodextrin (β-CD) as a vehicle, either singly or in blends with lactose (spray-dried or monohydrate), for preparing a meloxicam tablet. Aqueous solubility of meloxicam in presence of β-CD was investigated. The tablets were prepared by direct compression and wet granulation techniques. The powder blends and 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, disintegration time, and in vitro dissolution studies. The effect of β-CD on the bioavailability of meloxicam was also investigated in human volunteers using a balanced 2-way crossover study. Phase-solubility studies indicated an AL-type diagram with inclusion complex of 1∶1 molar ratio. The powder blends and granules of all formulations showed satisfactory flow properties, compressibility, and drug content. All tablet formations prepared by direct compression or wet granulation showed acceptable mechanical properties. The dissolution rate of meloxicam was significantly enhanced by inclusion of β-CD in the formulations up to 30%. The mean pharmacokinetic parameters (Cmax, Ke, and area under the curve [AUC]0−∞) were significantly increased in presence of β-CD. These results suggest that β-CD would facilitate the preparation of meloxicam tablets with acceptable mechanical properties using the direct compression technique as there is no important difference between tablets prepared by direct compression and those prepared by wet granulation. Also, β-CD is particularly useful for improving the oral bioavailablity of meloxicam.
meloxicam; β-CD; tablet; solubility; bioavailability
The purpose of this study was to investigate the effect of mechanical shear on hydrophobicity of pharmaceutical powder blends as a function of composition and particle size, and to determine the impact on drug release from tablets.
Four powder formulations were subjected to three different shear strain conditions (40 rev, 160 rev, and 640 rev) in a controlled shear environment operating at a shear rate of 80 rpm. A total of 12 blends were tested for hydrophobicity. Subsequently, sheared blends were compressed into tablets at 8 kN and 12 kN in a rotary tablet press. During tablet compression, powder samples were collected after the feed frame and their hydrophobicity was again measured.
Results indicated that increase in shear strain could significantly increase hydrophobicity, predominantly as an interacting function of blend composition. Blends with both colloidal silica and magnesium stearate (MgSt) were found to show higher hydrophobicity with shear than other blends. Additional shear applied by the tablet press feed frame was found to change the powder hydrophobicity only in the absence of MgSt.
Studies showed that the drug release rates dropped with shear more for the blends with both colloidal silica and MgSt than the other blends. Furthermore, the rate of drug release dropped with a decrease in particle size of the main excipient. Surprisingly, the relationship between the relative increase in hydrophobicity and a corresponding drop in the drug release rate was not found when either MgSt or colloidal silica was mixed alone in the blends.
Colloidal silica; drug release; dissolution; hydrophobicity; shear
Oral bioavailability of atorvastatin calcium (ATC) is very low (only 14%) due to instability and incomplete intestinal absorption and/or extensive gut wall extraction. When ATC is packed in the form of tablets, powders, etc., it gets destabilized as it is exposed to the oxidative environment, which is usually present during the production process, the storage of the substance, and the pharmaceutical formulation. Therefore, stabilized gastro-retentive floating tablets of ATC were prepared to enhance bioavailability. Water sorption and viscosity measurement studies are performed to get the best polymer matrix for gastro-retention. A 32 factorial design used to prepare optimized formulation of ATC. The selected excipients such as docusate sodium enhanced the stability and solubility of ATC in gastric media and tablet dosage form. The best formulation (F4) consisting of hypromellose, sodium bicarbonate, polyethylene oxide, docusate sodium, mannitol, crosscarmellose sodium, and magnesium stearate, gave floating lag time of 56 ± 4.16 s and good matrix integrity with in vitro dissolution of 98.2% in 12 h. After stability studies, no significant change was observed in stability, solubility, floating lag time, total floating duration, matrix integrity, and sustained drug release rates, as confirmed by DSC and powder X-ray diffraction studies. In vivo pharmacokinetic study performed in rabbits revealed enhanced bioavailability of F4 floating tablets, about 1.6 times compared with that of the conventional tablet (Storvas® 80 mg tablet). These results suggest that the gastric resident formulation is a promising approach for the oral delivery of ATC for improving bioavailability.
atorvastatin calcium; bioavailibility; floating tablets; gastro-retention; stabilization
Lacidipine (LCDP) is a very low soluble and highly biovariable calcium channel blocker used in the treatment of hypertension. To increase its apparent solubility and to reduce its biovariability, solid dispersion fluid bed processing technology was explored, as it produces highly dispersible granules with a characteristic porous structure that enhances dispersibility, wettability, blend uniformity (by dissolving and spraying a solution of actives), flow ability and compressibility of granules for tableting and reducing variability by uniform drug-binder solution distribution on carrier molecules.
Materials and Methods:
Main object of this quality risk management (QRM) study is to provide a sophisticated “robust and rugged” Fluidized Bed Process (FBP) for the preparation of LCDP tablets with desired quality (stability) and performance (dissolution) by quality by design (QbD) concept.
Results and Conclusion:
This study is principally focusing on thorough mechanistic understanding of the FBP by which it is developed and scaled up with a knowledge of the critical risks involved in manufacturing process analyzed by risk assessment tools like: Qualitative Initial Risk-based Matrix Analysis (IRMA) and Quantitative Failure Mode Effective Analysis (FMEA) to identify and rank parameters with potential to have an impact on In Process/Finished Product Critical Quality Attributes (IP/FP CQAs). These Critical Process Parameters (CPPs) were further refined by DoE and MVDA to develop design space with Real Time Release Testing (RTRT) that leads to implementation of a control strategy to achieve consistent finished product quality at lab scale itself to prevent possible product failure at larger manufacturing scale.
Critical process parameter; critical quality attribute; failure mode effective analysis; fluidized bed process; quality by design; quality risk management; scale-up
The aim of this investigation was to develop fast dissolving tablet of cinnarizine. A combination of super disintegrants, i.e., sodium starch glycolate (SSG) and crosscarmellose sodium (CCS) were used along with camphor as a subliming material. An optimized concentration of camphor was added to aid the porosity of the tablet. A 32 full factorial design was applied to investigate the combined effect of two formulation variables: Amount of SSG and CCS. Infrared (IR) spectroscopy was performed to identify the physicochemical interaction between drug and polymer. IR spectroscopy showed that there is no interaction of drug with polymer. In the present study, direct compression was used to prepare the tablets. The powder mixtures were compressed into tablet using flat face multi punch tablet machine. Camphor was sublimed from the tablet by exposing the tablet to vacuum drier at 60°C for 12 hours. All the formulations were evaluated for their characteristics such as average weight, hardness, wetting time, friability, content uniformity, dispersion time (DT), and dissolution rate. An optimized tablet formulation (F 9) was found to have good hardness of 3.30 ± 0.10 kg/cm2, wetting time of 42.33 ± 4.04 seconds, DT of 34.67 ± 1.53 seconds, and cumulative drug release of not less than 99% in 16 minutes.
Cinnarizine; contour plot; factorial design; orally disintegrating tablet; wetting time; water absorption ratio
A novel high-throughput methodology for the simultaneous optimization of many cell culture media components is presented. The method is based on the media blending approach which has several advantages as it works with ready-to-use media. In particular it allows precise pH and osmolarity adjustments and eliminates the need of concentrated stock solutions, a frequent source of serious solubility issues. In addition, media blending easily generates a large number of new compositions providing a remarkable screening tool. However, media blending designs usually do not provide information on distinct factors or components that are causing the desired improvements. This paper addresses this last point by considering the concentration of individual medium components to fix the experimental design and for the interpretation of the results. The extended blending strategy was used to reshuffle the 20 amino acids in one round of experiments. A small set of 10 media was specifically designed to generate a large number of mixtures. 192 mixtures were then prepared by media blending and tested on a recombinant CHO cell line expressing a monoclonal antibody. A wide range of performances (titers and viable cell density) was achieved from the different mixtures with top titers significantly above our previous results seen with this cell line. In addition, information about major effects of key amino acids on cell densities and titers could be extracted from the experimental results. This demonstrates that the extended blending approach is a powerful experimental tool which allows systematic and simultaneous reshuffling of multiple medium components.
Medium optimization; Screening; CHO cells; Mixture design; Media blending; Amino acids
Purpose: Rosuvastatin is a poorly water soluble drug and the rate of its oral absorption is often controlled by the dissolution rate in the gastrointestinal tract. Hence it is necessary to increase the solubility of the Rosuvastatin.
Methods: Several liquisolid tablets formulations containing various drug concentrations in liquid medication (ranging from 15% to 25% w/w) were prepared. The ratio of Avicel PH 102 (carrier) to Aerosil 200 (coating powder material) was kept 10, 20, 30. The prepared liquisolid systems were evaluated for their flow properties and possible drug-excipient interactions by Infrared spectra (IR) analysis, differential scanning calorimetry (DSC) and X- ray powder diffraction (XRPD).
Results: The liquisolid system showed acceptable flow properties. The IR and DSC studies demonstrated that there is no significant interaction between the drug and excipients. The XRPD analysis confirmed formation of a solid solution inside the compact matrix. The tabletting properties of the liquisolid compacts were within the acceptable limits. Liquisolid compacts demonstrated significantly higher drug release rates than those of conventional and marketed tablet due to increasing wetting properties and surface area of the drug.
Conclusion: This study shows that liquisolid technique is a promising alternative for improvement of the dissolution rate of water insoluble drug.
Rosuvastatin calcium; Liquisolid compacts; Liquid load factor; Excipient ratio; Tablets; Dissolution rate
The present studies entail formulation development of novel solid self-nanoemulsifying drug delivery systems (S-SNEDDS) of valsartan with improved oral bioavailability, and evaluation of their in vitro and in vivo performance. Preliminary solubility studies were carried out and pseudoternary phase diagrams were constructed using blends of oil (Capmul MCM), surfactant (Labrasol), and cosurfactant (Tween 20). The SNEDDS were systematically optimized by response surface methodology employing 33-Box–Behnken design. The prepared SNEDDS were characterized for viscocity, refractive index, globule size, zeta potential, and TEM. Optimized liquid SNEDDS were formulated into free flowing granules by adsorption on the porous carriers like Aerosil 200, Sylysia (350, 550, and 730) and Neusilin US2, and compressed into tablets. In vitro dissolution studies of S-SNEDDS revealed 3–3.5-fold increased in dissolution rate of the drug due to enhanced solubility. In vivo pharmacodynamic studies in Wistar rats showed significant reduction in mean systolic BP by S-SNEDDS vis-à-vis oral suspension (p < 0.05) owing to the drug absorption through lymphatic pathways. Solid-state characterization of S-SNEDDS using FT-IR and powder XRD studies confirmed lack of any significant interaction of drug with lipidic excipients and porous carriers. Further, the accelerated stability studies for 6 months revealed that S-SNEDDS are found to be stable without any change in physiochemical properties. Thus, the present studies demonstrated the bioavailability enhancement potential of porous carriers based S-SNEDDS for a BCS class II drug, valsartan.
BCS; bioavailability; in vitro dissolution; porous carriers; XRD
The objectives of this study were to investigate the effects of manufacturing parameters on the moisture sorption isotherms of some tablet formulations and to predict the moisture isotherms of the final formulations using polynomial equations. Three tablet formulations including a placebo and 2 drug products were prepared through wet granulation, drying, compression, and coating processes. Equilibrium moisture content of excipients and granules at 25°C with different relative humidities were determined using a dynamic moisture sorption microbalance, while such data for tablets were determined using desiccators. Moisture sorption isotherms were expressed in polynomial equations. Excipient isotherms were used to predict the moisture sorption isotherms of the 3 tablet products. Results showed that different physical properties of granules and tablets, such as particle size distribution, density, and porosity resulting from different granulation and compression conditions did not have significant effect on the moisture isotherms of the materials. Changing coating materials from a powder mixture to a film also did not change the moisture sorption characteristics significantly. The predicted moisture sorption isotherms of the formulations agreed well with the experimental results. These results show that moisture isotherms of solid pharmaceutical products manufactured with conventional processes may be predicted using the isotherms of excipients, and polynomial equations may be used as a tool for the prediction of moisture isotherms.
prediction; moisture sorption isotherm; excipients; formulations
To implement Quality by Design (QbD) in drug development, scientists need tools that link drug products properties to in vivo performance. Physiologically based absorption models are potentially useful tools; yet, their utility of QbD implementation has not been discussed or explored much in the literature. We simulated pharmacokinetics (PK) of carbamazepine (CBZ) after administration of four oral formulations, immediate-release (IR) suspension, IR tablet, extended-release (XR) tablet and capsule, under fasted and fed conditions and presented a general diagram of a modeling and simulation strategy integrated with pharmaceutical development. We obtained PK parameters and absorption scale factors (ASFs) by deconvolution of the PK data for IR suspension under fasted condition. The model was validated for other PK profiles of IR formulations and used to predict PK for XR formulations. We explored three key areas where a modeling and simulation approach impacts QbD. First, the model was used to help identify optimal in vitro dissolution conditions for XR formulations. Second, identification of critical formulations variables was illustrated by a parameter sensitivity analysis of mean particle radius for the IR tablet that showed a PK shift with decreased particle radius, Cmax was increased and Tmax was decreased. Finally, virtual trial simulations allowed incorporation of inter-subject variability in the model. Virtual bioequivalence studies performed for two test formulations suggested that an in vitro dissolution test may be a more sensitive discriminative method than in vivo PK studies. In summary, a well-validated predictive model is a potentially useful tool for QbD implementation in drug development.
Electronic supplementary material
The online version of this article (doi:10.1208/s12248-010-9250-9) contains supplementary material, which is available to authorized users.
advanced compartmental absorption and transit (ACAT) model; gastroplus™; modified release (MR); quality by design (QbD)
This study investigated the effect of phase transformations of amorphous and deliquescent ingredients on catechin stability in green tea powder formulations. Blends of amorphous green tea and crystalline sucrose, citric acid, and/or ascorbic acid were analyzed by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), dynamic water vapor sorption, water activity measurements, and high-performance liquid chromatography (HPLC) after storage for up to 12 weeks at 0–75% relative humidity (RH) and 22 °C. The glass transition temperature (Tg) of green tea was reduced to below room temperature (<22 °C) at 68% RH. Dissolution of deliquescent ingredients commenced at RH values below deliquescence points in blends with amorphous green tea, and these blends had greater water uptake than predicted by an additive model of individual ingredient moisture sorption. Catechin degradation was affected by Tg of green tea powder and both dissolution and deliquescence of citric and ascorbic acids.
Catechins; water vapor sorption; phase behavior; chemical stability; deliquescence
The effectiveness of Okra gum in sustaining the release of propranolol hydrochloride in a tablet was studied. Okra gum was extracted from the pods of Hibiscus esculentus using acetone as a drying agent. Dried Okra gum was made into powder form and its physical and chemical characteristics such as solubility, pH, moisture content, viscosity, morphology study using SEM, infrared study using FTIR, crystallinity study using XRD, and thermal study using DSC and TGA were carried out. The powder was used in the preparation of tablet using granulation and compression methods. Propranolol hydrochloride was used as a model drug and the activity of Okra gum as a binder was compared by preparing tablets using a synthetic and a semisynthetic binder which are hydroxylmethylpropyl cellulose (HPMC) and sodium alginate, respectively. Evaluation of drug release kinetics that was attained from dissolution studies showed that Okra gum retarded the release up to 24 hours and exhibited the longest release as compared to HPMC and sodium alginate. The tensile and crushing strength of tablets was also evaluated by conducting hardness and friability tests. Okra gum was observed to produce tablets with the highest hardness value and lowest friability. Hence, Okra gum was testified as an effective adjuvant to produce favourable sustained release tablets with strong tensile and crushing strength.