Exploring Canine-Human Differences in Product Performance. Part II: Use of Modeling and Simulation to Explore the Impact of Formulation on Ciprofloxacin In Vivo Absorption and Dissolution in Dogs.

This study explored the in vivo performance of three oral ciprofloxacin formulations (oral solution, fast, or slow dissolving tablets) in beagle dogs. The in vivo absorption and dissolution behaviors, estimated with in silico mechanistic models, were compared to the results previously published in human volunteers. Six normal healthy male beagle dogs (five to completion) received three oral formulations and an intravenous infusion in a randomized crossover design. Plasma ciprofloxacin concentrations were estimated by tandem mass spectrometry detection. A mechanistic absorption model was used to predict the in vivo dissolution and absorption characteristics of the oral formulations. Canine ciprofloxacin absorption was constrained to the duodenum/jejunum. This absorption window was far narrower than that seen in humans. Furthermore, while substantial within-individual variability in drug absorption was seen in human subjects, a greater magnitude of variability was observed in dogs. For three sets of data, a lag time in gastric emptying was necessary to improve the accuracy of model-generated in vivo blood level profile predictions. In addition to species-associated dissimilarities in drug solubilization due to human versus canine differences in gastrointestinal fluid compositions, the far more rapid intestinal transit time and potential segmental differences in drug absorption needed to be considered during human-canine extrapolation of oral drug and drug product performance. Through the use of mechanistic models, the data generated in the human and canine studies contributed insights into some aspects of the interspecies differences to be considered when extrapolating oral bioavailability/formulation effect data between dogs and humans.

Characterization of the interactions between polymethacrylate-based aqueous polymeric dispersions and aluminum lakes.

Instability in film coating formulations can arise from interactions between aluminum lake pigments and aqueous polymeric dispersions. The purpose of this study was to characterize the interactions between three polymethacrylate-based aqueous polymeric dispersions (Eudragit RS 30 D, Eudragit L 30 D-55, and Eudragit NE 30 D) and aluminum lakes. Particle size measurements, pH stability profiles, zeta potential measurements, and microscopy were used to study mixed dispersions of the polymeric latices and the lakes. Interactions leading to dispersion instability were related to the surface charge of the components in the formulation. Interactions between the ionic polymers and the lakes arose from instability of the lakes outside a certain pH range resulting in the release of electrolytes, which led to aggregation of the polymeric particles. Interactions between the nonionic polymer and the lakes were related to the polymer modifying the surface charge of the lakes, resulting in aggregation of the pigment particles.

Estimation of capping incidence by indentation fracture tests.

The purpose of this study was to predict the capping tendencies of pharmaceutical powders by creating indentation fracture on compacts. Three sets of binary mixtures containing different concentrations of each ingredient were used in the study. The binary mixtures were chosen to represent plastic-plastic, plastic-brittle, and brittle-brittle combination of materials. The mixtures were tableted at different pressures and speeds on Prester, a tablet press simulator. These mixtures were also compacted on the Instron Universal Testing Machine 4502. Static indentation tests were done on these compacts at different depths until surface cracking and chipping were observed. The extent of surface cracking and chipping was observed from light microscope and scanning electron microscope images. A rank order correlation was observed between lamination susceptibility and the depth at which indentation failure occurred. It was concluded that indentation fracture tests could provide a useful estimate of lamination properties of pharmaceutical powders.

Influence of various drugs on the glass transition temperature of poly(vinylpyrrolidone): a thermodynamic and spectroscopic investigation.

PURPOSE: To determine the influence of hydrogen bonding and solubility parameter on the glass transition temperature (T(g)) of various drug-poly(vinylpyrrolidone) blends. METHODS: The T(g) of PVP films containing either acetaminophen, naproxen, salicylamide, carbamazepine, griseofulvin or propranolol hydrochloride were measured using differential scanning calorimetry. Fourier transform infrared (FTIR) spectroscopy and X-ray diffraction was used to characterize the specific interactions between the drug-PVP blends and the physical state of the films, respectively. The total solubility parameter and its individual components were calculated using the method of Van Krevelen. RESULTS: Salicylamide displayed the greatest plasticizing effect, depressing the T(g) to the minimum. This was consistent with the FTIR data, which indicated the presence of hydrogen bonding with PVP. Griseofulvin showed the least plasticizing effect due to lack of interaction with PVP. All the drugs except griseofulvin were amorphous within the film up to 30% (w/w) drug composition. The correlation between the various components of the solubility parameters and the plasticizing effect of drugs was very poor. CONCLUSIONS: Spectroscopic investigation for the presence of interaction between the drugs and PVP proved to be extremely predictive of the plasticizing effect of various drugs. In contrast, solubility parameters appeared to be far less sensitive indicators of drug-PVP miscibility.

The influence of excipients on the stability of the moisture sensitive drugs aspirin and niacinamide: comparison of tablets containing lactose monohydrate with tablets containing anhydrous lactose.

The purpose of this study is to test the hypothesis that in tablet formulations, moisture-sensitive drugs formulated with lactose monohydrate have the same stability as formulations containing anhydrous lactose, and to characterize the kinetics of niacinamide degradation in the solid state. Aspirin and niacinamide decomposition were used as indicators of stability. Aspirin and niacinamide tablets containing either lactose monohydrate or anhydrous lactose were separately investigated at different temperatures and relative humidities; the stability tests were done at 25 degrees C--60% RH, 40 degrees C--80% RH, 60 degrees C--60% RH, 60 degrees C--80% RH, and 80 degrees C--80% RH. Official U.S. Pharmacopeia methods were used for the aspirin and niacinamide assays. Statistical analysis showed that tablets containing lactose monohydrate have the same stability as tablets containing anhydrous lactose, which means that even though water is present in the crystal structure, the bound water does not influence the reaction rate. In addition, niacinamide degradation in the solid-state can be described by a third order rate equation.

Design and validation of an annular shear cell for pharmaceutical powder testing.

An annular shear cell was constructed for powder flow testing, the influence of design and process parameters was characterized, and the results were compared with other flow methods. The shear cell was designed with interchangeable parts to mimic other shear cells. The texture of the powder-metal interface and the gap distance between the lid and side wall of the trough were varied, and the effects of shear rate, powder bed thickness, and consolidation times were tested. Shear parameters, such as cohesion, angles of friction, and flow factors, were measured for microcrystalline cellulose, anhydrous lactose, spray-dried lactose, mannitol, dibasic calcium phosphate dihydrate, anhydrous theophylline, and theophylline monohydrate powder. The results were then compared with the Carr index, mass flow rate, and flowability index. Design parameters such as surface texture and the gap distance significantly affected the shear call results, whereas for the process parameters studied, the shear rate, consolidation time, and powder bed height had a minimal effect on the shear cell results. Of the shear parameters obtained, the angles of friction best represented the known flow properties of powders and were in general agreement with those from other flow tests.

Practical limitations of tableting indices.

The purpose of this study was to utilize tableting indices to distinguish between materials with varying degrees of compactibility by establishing a quantitative relationship between indices and compactibility. Compactibility in this study is restricted to tablet strength and friability alone. Nine mixtures with varying degrees of compactibility were tableted and the tensile strength and friability of the tablets were determined. The tableting indices of these mixtures were determined using an Instron Universal testing machine. An artificial neural network program was used to establish a quantitative relationship between indices and tablet strength and friability. Six new powders were used to validate the models describing the relationship between indices and tablet strength and friability. These powders were compressed into tablets and their strength and friability were determined. Their indices were also determined. The established models were used to predict tablet strength and friability from index values. The predicted values were compared with the experimentally determined values. There was little correlation between the predicted and experimentally determined values for tablet strength and friability. It was also found that materials or mixtures having almost similar indices had remarkably different compactibilities. It was concluded that models created to predict compactibility using one set of materials may not be able to successfully predict the compactibility of a new material. This calls into question the practicality of indices.

Assessment of polymer-polymer interactions in blends of HPMC and film forming polymers by modulated temperature differential scanning calorimetry.

PURPOSE: To assess the miscibility and phase behavior of binary blends of hydroxypropylmethyl cellulose (HPMC) with hydroxypropyl cellulose (HPC), methylcellulose (MC), and polyvinylpyrrolidone (PVP). METHODS: Polymer-polymer miscibility was assessed by measurement of the glass transition temperature (Tg) and the width of the glass transition temperature (W-Tg), using modulated temperature differential scanning calorimetry (MTDSC). RESULTS: HPMC K4M/PVP and HPMC E5/MC blends were miscible as evidenced by a single, composition dependent, Tg throughout the entire composition range. HPMC/HPC blends were immiscible at all compositions. For the miscible blends, the variation in Tg with blend composition was compared to the values predicted by the Fox and Couchman-Karasz equations. At intermediate blend compositions, HPMC K4M/PVP blends exhibited negative deviations from ideal behavior. The Tg of the HPMC E5/MC blends was found to follow the Fox equation. The W-Tg measurements of the miscible blends gave evidence of phase separation at certain compositions. CONCLUSIONS: MTDSC was shown to be a useful technique in characterizing the interactions between some commonly used pharmaceutical polymers.

Bead compacts. II. Evaluation of rapidly disintegrating nonsegregating compressed bead formulations.

In this study, three techniques for the prevention or mitigation of polymer coat fracture on compaction of sustained-release beads into tablets were investigated. All techniques in this paper were evaluated without the addition of any cushioning excipients, but rather by spray coating these excipients to avoid segregation during product manufacturing. First, it was shown that use of swellable polymers such as polyethylene oxide (PEO) serves a unique and effective role in preventing polymer coat rupture. PEO was spray coated between the ethylcellulose (EC) and microcrystalline cellulose (MCC) coats to evaluate its cushioning effect. The compacted PEO layered beads, on dissolution, disintegrated into individual beads with sustained drug release of up to 8 hr. It is postulated that the PEO was hydrated and formed a gel that acts as a sealant for the cracks formed in the ruptured polymer coating (sealant-effect compacts). Second, EC-coated drug-layered beads were also overcoated with cushioning excipients such as polyethylene glycol (PEG) and MCC with an additional coating of a disintegrant. These beads were compressed at pressures of 125, 500, and 1000 pounds into caplets and, on dissolution testing, disintegrated into individual beads when the dissolution medium was switched from simulated gastric to intestinal fluid. The dissolution profiles show that the polymer coat was partly disrupted on compaction, leading to a total drug release in 8-10 hr. Third, EC-coated beads were also granulated with cushioning excipient and compressed.

Powder densification. 2. Viscoelastic material properties in modeling the uniaxial compaction of powders.

A micromechanical model for predicting the densification of particulate matter under hydrostatic loading was developed to account for the time-dependent response of materials to applied loads. Viscoelastic material response used in the analysis was based upon a standard three-parameter rheological model. Compaction data under closed die conditions were collected using an Instron analyzer for different rates of applied load. Densification during the loading phase of PMMA/coMMA powder, a pharmaceutical polymeric coating material, was well predicted by the proposed algorithm, which contrasts with the prediction implied through a static indentation model. Secondary factors which affect compaction such as die-wall friction are also briefly discussed.

Bead compacts. I. Effect of compression on maintenance of polymer coat integrity in multilayered bead formulations.

Little information is available on the compactability of beads for oral sustained-release dosage forms. It is known that polymer-coated beads may fuse together to produce a non-disintegrating controlled-release matrix tablet when compressed. This study evaluates the effect of compression on beads with multiple layers of polymer and drug coat, and the effect of cushioning excipients and compaction pressure on drug release from compressed bead formulations. The multilayered beads consist of several alternating layers of acetaminophen (APAP) and polymer coats (Aquacoat) with an outer layer of mannitol as a cushioning excipient. Percent drug release versus time profiles showed that the release of drug decreases from noncompacted beads as the amount and number of coatings increases, with only 43% of drug released in 24 hr for coated beads with 10 layers. It was shown that the compacted multilayered beads will disintegrate in gastrointestinal fluids, providing a useful drug release pattern. It was shown that beads of drug prepared by any method can be spray-layered with excipients such as Avicel and mannitol. Spray-layering of the cushioning excipient onto beads can provide an effective way to circumvent segregation issues associated with mixing of the polymer-coated beads and powdered or spherical/nonspherical cushioning excipients. Spray layering of the cushioning excipient can also provide excellent flow properties of the final formulation as visually observed in our experiments. Triple-layered caplets (TLC) were also prepared with outer layers of Avicel PH-101 or polyethylene oxide (PEO), and a center layer of polymer-coated beads. For TLC, the polymer coating on the beads fractured, and nondisintegrating matrix formulations were obtained with both caplet formulations.

Theory of force transducer design optimization for die wall stress measurement during tablet compaction: optimization and validation of split-web die using finite element analysis.

PURPOSE: 1) To illustrate how computer aided engineering stress analysis can be used to improve the transducer design process for tablet press instrumentation; 2) to use these optimal design procedures for the geometric optimization of a cylindrical, segmented, and a novel split-web die design. Discussion includes the selection of optimal die wall thickness, segment cutting angle, strain gage placement, Wheatstone bridge configuration, and the influence of tablet height and position within the die on signal output. METHODS: Stress analysis was done with a finite element analysis (FEA) software package running on a personal computer. RESULTS: For the segmented die, the admissible range of die wall thicknesses depends upon cutting angle; the signal output is non-linear because the stress distribution in the die wall is influenced by tablet height and position within the die. For the split-web die, the optimal configuration consists of a 1/8 in. sensing web with a strain gage located at the peak of the sensing-web arch. This prototype had a linear calibration curve (r2 = 0.999) with no hysteresis. Radial versus axial stress transmission curves for: starch and sodium chloride were consistent with literature data. CONCLUSIONS: Finite element analysis (FEA) is a useful numerical tool for the systematic optimization of tablet press instrumentation. By enclosing the sensing web of a three layered die design in a cylinder, the split-web design can be directly mounted without modification of the die table.

Failure of prescription prenatal vitamin products to meet USP standards for folic acid dissolution.

OBJECTIVE: To determine whether prescription prenatal vitamins meet United States Pharmacopeial Convention (USP) standards for folic acid dissolution. METHODS: Dissolution was measured using USP Apparatus II and test conditions specified in the 23rd revision of the United States Pharmacopeia (USP 23). Folic acid was assayed by a chromatographic method modified from that specified in the official monographs, for oil- and water-soluble vitamins with minerals tablets, in USP 23. RESULTS: Only three out of nine multivitamin products met USP specifications for folic acid release. Most missed by a wide margin; folic acid dissolution from two products was less than 25%. CONCLUSIONS: Because a wide variety of brand-name and generic prescription prenatal multivitamin products were tested, these results are likely to be representative of the multivitamin products on the market. Given the significance of folic acid to public health, the authors believe that this subject should be studied further and that prompt action should be taken to ensure that folic-acid-containing products are of the highest quality possible.

Deformation of the Stokes B2 rotary tablet press: quantitation and influence on tablet compaction.

Deformations that affect the vertical punch displacement of a Stokes B2 rotary tablet press were characterized with a cathetometer. The press deformation was found to be elastic for both the upper and lower compression roller assemblies. However, the upper and lower compression roller assemblies have different Hookian spring constants: 8.58 x 10(4) and 5.18 x 10(4) kN/m for the upper and lower assemblies, respectively. Using two-way analysis of variance, the Hookian spring constants were shown to be independent of compaction phases and lower punch penetration setting. To study the influence of press deformation on tablet compaction, the Hookian spring constants were factored into the caculation of the incremental work of compaction for dibasic calcium phosphate dihydrate and microcrystalline cellulose. As the peak compression pressure increases, the force-displacement work done on the tablet during the loading phase decreases relative to calculations that neglect press deformation. This decrease in force-displacement work was attributed to elastic press deformation, which absorbs energy during the loading phase and then releases this energy later in the compaction cycle, altering the punch-displacement profile. The rate at which the press stores and releases elastic energy depends in part upon the viscoelastic properties of the tablet. Based upon these results, the coupling between press elasticity and a tablet's viscoelastic properties should be accounted for when analyzing tablet compaction or trying to simulate the punch-displacement profile of a tablet press that deforms during compaction.

Thermodynamic analysis of energy dissipation by pharmaceutical tablets during stress unloading.

A thermodynamic analysis of the energy transformations occurring within pharmaceutical tablets during the unloading phase of compaction was performed on Avicel, calcium phosphate, acetaminophen, and calcium oxalate. This analysis was based on viscoelastic stress data collected using an instrumented rotary press and was conducted for the purpose of determining the extent and nature of energy release, beyond that of force displacement, during this phase of compaction. The four materials investigated were selected to reflect a range of compaction properties, and the viscous vs force-displacement energy distributions were seen to be consistent with their brittle vs plastic character. Magnesium stearate, added in various concentrations up to 4% w/w, was found to act both as an internal lubricant for particle-particle slipping and as a moderator of interparticulate bonding.