Intracranial stents being modeled as a porous medium: flow simulation in stented cerebral aneurysms.

Intracranial aneurysms may be treated by flow diverters, alternatively to stents and coils combination. Numerical simulation allows the assessment of the complex nature of aneurismal flow. Endovascular devices present a rather dense and fine strut network, increasing the complexity of the meshing. We propose an alternative strategy, which is based on the modeling of the device as a porous medium. Two patient-specific aneurysm data sets were reconstructed using conventional clinical setups. The aneurysms selection was done so that intra-aneurismal flow was shear driven in one and inertia driven in the other. Stents and their porous medium analog were positioned at the aneurysm neck. Physiological flow and standard boundary conditions were applied. The comparison between both approaches was done by analyzing the velocity, vorticity, and shear rate magnitudes inside the aneurysm as well as the wall shear stress (WSS) at the aneurysm surface. Simulations without device were also computed. The average flow reduction reaches 76 and 41% for the shear and inertia driven flow models, respectively. When comparing the two approaches, results show a remarkable similarity in the flow patterns and magnitude. WSS, iso-velocity surfaces and velocity on a trans-sectional plane are in fairly good agreement. The root mean squared error on the investigated parameters reaches 20% for aneurysm velocity, 30.6% for aneurysm shear rate, and 47.4% for aneurysm vorticity. It reaches 20.6% for WSS computed on the aneurysm surface. The advantages of this approach reside in its facility to implement and in the gain in computational time. Results predicted by the porous medium approach compare well with the real stent geometry model and allow predicting the main effects of the device on intra-aneurismal flow, facilitating thus the analysis.

Methodologies to assess blood flow in cerebral aneurysms: current state of research and perspectives.

With intracranial aneurysms disease bringing a weakened arterial wall segment to initiate, grow and potentially rupture an aneurysm, current understanding of vessel wall biology perceives the disease to follow the path of a dynamic evolution and increasingly recognizes blood flow as being one of the main stakeholders driving the process. Although currently mostly morphological information is used to decide on whether or not to treat a yet unruptured aneurysm, among other factors, knowledge of blood flow parameters may provide an advanced understanding of the mechanisms leading to further aneurismal growth and potential rupture. Flow patterns, velocities, pressure and their derived quantifications, such as shear and vorticity, are today accessible by direct measurements or can be calculated through computation. This paper reviews and puts into perspective current experimental methodologies and numerical approaches available for such purposes. In our view, the combination of current medical imaging standards, numerical simulation methods and endovascular treatment methods allow for thinking that flow conditions govern more than any other factor fate and treatment in cerebral aneurysms. Approaching aneurysms from this perspective improves understanding, and while requiring a personalized aneurysm management by flow assessment and flow correction, if indicated.

Reproducibility of haemodynamical simulations in a subject-specific stented aneurysm model--a report on the Virtual Intracranial Stenting Challenge 2007.

This paper presents the results of the Virtual Intracranial Stenting Challenge (VISC) 2007, an international initiative whose aim was to establish the reproducibility of state-of-the-art haemodynamical simulation techniques in subject-specific stented models of intracranial aneurysms (IAs). IAs are pathological dilatations of the cerebral artery walls, which are associated with high mortality and morbidity rates due to subarachnoid haemorrhage following rupture. The deployment of a stent as flow diverter has recently been indicated as a promising treatment option, which has the potential to protect the aneurysm by reducing the action of haemodynamical forces and facilitating aneurysm thrombosis. The direct assessment of changes in aneurysm haemodynamics after stent deployment is hampered by limitations in existing imaging techniques and currently requires resorting to numerical simulations. Numerical simulations also have the potential to assist in the personalized selection of an optimal stent design prior to intervention. However, from the current literature it is difficult to assess the level of technological advancement and the reproducibility of haemodynamical predictions in stented patient-specific models. The VISC 2007 initiative engaged in the development of a multicentre-controlled benchmark to analyse differences induced by diverse grid generation and computational fluid dynamics (CFD) technologies. The challenge also represented an opportunity to provide a survey of available technologies currently adopted by international teams from both academic and industrial institutions for constructing computational models of stented aneurysms. The results demonstrate the ability of current strategies in consistently quantifying the performance of three commercial intracranial stents, and contribute to reinforce the confidence in haemodynamical simulation, thus taking a step forward towards the introduction of simulation tools to support diagnostics and interventional planning.

Effect of elastin degradation on carotid wall mechanics as assessed by a constituent-based biomechanical model.

Arteries display a nonlinear anisotropic behavior dictated by the elastic properties and structural arrangement of its main constituents, elastin, collagen, and vascular smooth muscle. Elastin provides for structural integrity and for the compliance of the vessel at low pressure, whereas collagen gives the tensile resistance required at high pressures. Based on the model of Zulliger et al. (Zulliger MA, Rachev A, Stergiopulos N. Am J Physiol Heart Circ Physiol 287: H1335-H1343, 2004), which considers the contributions of elastin, collagen, and vascular smooth muscle cells (VSM) in an explicit form, we assessed the effects of enzymatic degradation of elastin on biomechanical properties of rabbit carotids. Pressure-diameter curves were obtained for controls and after elastin degradation, from which elastic and structural properties were derived. Data were fitted into the model of Zulliger et al. to assess elastic constants of elastin and collagen as well as the characteristics of the collagen engagement profile. The arterial segments were also prepared for histology to visualize and quantify elastin and collagen. Elastase treatment leads to a diameter enlargement, suggesting the existence of significant compressive prestresses within the wall. The elastic modulus was more ductile in treated arteries at low circumferential stretches and significantly greater at elevated circumferential stretches. Abrupt collagen fiber recruitment in elastase-treated arteries leads to a much stiffer vessel at high extensions. This change in collagen engagement properties results from structural alterations provoked by the degradation of elastin, suggesting a clear interaction between elastin and collagen, often neglected in previous constituent-based models of the arterial wall.

The influence of product brand-to-brand variability on superdisintegrant Performance. A case study with croscarmellose sodium.

The purpose of this study is to investigate factors influencing croscarmellose sodium functionality with special emphasis on developing a discriminating model tablet formulation to evaluate product brand-to-brand variability. The particle size distribution, water uptake, and swelling properties of five brands of croscarmellose sodium in either neutral water or 0.1 N HCl were studied. Differences were observed in all properties between brands. Media with acidic pH had a negative impact, but to different extents, on both the water uptake and swelling of all croscarmellose sodium brands due to the presence of carboxymethyl sodium substituents. A tablet matrix composed of lactose (75% w/w) and dicalcium phosphate (25% wt/wt) was used to compare the functional equivalency of the five brands of croscarmellose sodium. The tablet disintegration times were inversely proportional to the swelling ability of superdisintegrant in the testing medium regardless of medium temperature and disintegrant concentration. In conclusion; the particle size, total degree of substitution, and the ratio of basic to acidic substituents are important factors that should be considered during product optimization. The tablet matrix composed of lactose and dicalcium phosphate at a weight ratio of 3:1 can be used as a model formulation for product lot-to-lot consistency and product brand-to-brand comparison purposes.

Measurement of elastic properties of blood vessels.

This paper is related to the measurements of the modulus of elasticity of an artery by studying the deformations due to the inflation of an angioplasty balloon catheter used for Interventional Radiology (IR) procedures. Various types of balloons are studied in order to characterize and compare their behaviors at the time of inflation. A test bench, consisting of an angioplasty balloon, a Polyvinyl alcohol model and an actuator used to inflate a balloon, is developed for the realization of the experiments. The pressure-volume curve during the inflation of a balloon is observed. Elasticity modulus are derived with an analytical model of the measurement system. The results are then analyzed and compared to existing data from literature.

Measurement of internal constraints during an interventional radiology procedure.

This paper presents a novel method for measurements of internal constraints during an Interventional Radiology procedure. Fiber-optic strain gauge, operating as a Fabry-Perot interferometer, is inserted and navigated inside a polyvinyl alcohol (PVA) model. The information obtained from deformation of the Fabry-Perot cavity is analyzed and the results are then rescaled through a calibration procedure for catheters. The measures help to locate the maximum interaction forces between catheter and blood vessel wall at approximately 1.3 N and to observe the shape of dynamic interaction during manipulation.

Production of inert cushioning beads: effect of excipients on the physicomechanical properties of freeze-dried beads containing microcrystalline cellulose produced by extrusion-spheronization.

Conventional highly compactible fillers such as microcrystalline cellulose (MCC) can be mixed with drug-loaded membrane-coated beads and compressed to form a tablet. However, due to particle size differences, there is substantial risk of segregation leading to weight variation and content uniformity problems. Furthermore, whenever modified release beads are included in a tablet matrix, care must be taken to assure the integrity of the coated beads. This paper describes the development of placebo beads containing MCC whose properties make them uniquely suitable for tableting modified release beads. These placebo beads have high compactibility and the ability to rapidly disintegrate. They deform readily and may provide a high degree of protection to drug-loaded membrane-coated beads during compression ('cushioning effect'). They can be produced in size ranges that provide minimal segregation propensity. Beads containing different MCC/lactose ratios and different types and levels of superdisintegrants were produced by extrusion-spheronization followed by freeze drying. The presence of high levels of MCC and different superdisintegrants, especially croscarmellose sodium, increased the granulation liquid requirement, thus producing freeze-dried beads with higher porosities and compactibility. Athy-Heckel analysis studies revealed that beads rich in MCC exhibited lower mean yield pressures than those containing high levels of lactose. The freeze-dried beads exhibited both plastic deformation and brittle fracture characteristics.

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.

Study of crystallization of endogenous surfactant in Eudragit NE30D-free films and its influence on drug-release properties of controlled-release diphenhydramine HCl pellets coated with Eudragit NE30D.

This study investigates the crystallization of the endogenous surfactant nonoxynol 100 in Eudragit NE30D-free films during storage and the influences of nonoxynol 100 on the dissolution of diphenhydramine hydrochloric acid (HCl) pellets coated with Eudragit NE30D before and after aging at ambient conditions. Polarizing light microscopy showed that when Eudragit NE30D-free films were stored at ambient conditions, off-white, flower-shaped crystals formed and increased in the polymer film as storage time increased. Also, x-ray diffraction showed polymer crystals in the aged free film. Thermogravimetric analysis showed no evidence of combined volatile molecules with the polymer molecules, and Fourier transformed infrared spectroscopy (FTIR) data suggested the same chemical composition of the polymer before and after phase separation. Further, from normal light microscopy, the appearance of the melting droplets in the polymer film indicated that the polymer molecules did not form the crystals. After the extraction of nonoxynol 100 by water, the free film formed by the water-extracted Eudragit NE30D was found free of the crystals after aging at the same conditions. The combination of the thermogravimetric analysis, FTIR, and microscopy showed that the origin of the crystals in dry Eudragit NE30D-free films came from nonoxynol 100, and not from the polymer molecules themselves. Monitoring by differential scanning calorimeter, it was found that the rates of crystallization of nonoxynol 100 were faster when the films were stored at 30 degrees C and 40 degrees C than when stored at ambient conditions and 45 degrees C. When stored at -5 degrees C, the crystallization rate was nearly zero. As the temperature got closer to melting temperature, the crystallization rate was very low because the system was in a thermodynamically disfavored state. The rate gradually increased and finally passed through a maximum as the crystallization temperature decreased. As the temperature kept decreasing, the crystallization rate became small again and eventually stopped because the system turned into a kinetically disfavored state. Because the phase transition of nonoxynol 100 in Eudragit NE30D occurred at ambient conditions, its influence on the dissolution of diphenhydramine HCl pellets coated with Eudragit NE30D was studied. Three different levels of nonoxynol 100 were used in Eudragit NE30D dispersions to make 3 different batches of Eudragit NE30D film-coated, controlled-release diphenhydramine HCl pellets. The results showed the dissolution rate increased as the level of nonoxynol 100 increased in the coating formula. Compared to the commonly used water-soluble additive human peripheral mononuclear cell, nonoxynol 100 was more effective in enhancing the dissolution of diphenhydramine HCl from pellets coated with Eudragit NE30D. Further study showed that the phase separation of the surfactant during aging tends to stabilize or slightly increase dissolution rates at higher surfactant levels.

Evaluation of the functional equivalence of crospovidone NF from different sources. I. Physical characterization.

In the past two decades, three categories of newer disintegrants have come into widespread use. These substances are a synthetic polymer (crospovidone), chemically modified starch (sodium starch glycolate) and cellulose (croscarmellose sodium). Multiple suppliers are now available for each category. Current NF monographs do not provide tests which reflect on their functionality and one cannot assume reliable performance of disintegrants from different sources meeting NF standards. The objective of this study was to identify differences in physical properties thought to be related to functionality among crospovidones from multiple sources. Physical properties examined included particle size and distribution, surface area, porosity and surface morphology. Disintegration and dissolution were performed on a model tablet formulation using either an insoluble or a soluble filler. Substantial differences in particle size and distribution, surface area, porosity and surface morphology were observed which correlated with differences in disintegration time and dissolution rate of the model drug from an insoluble tablet core. None of the differences in physical properties resulted in any differences in the disintegration or dissolution of the model drug from a soluble tablet core.

Selected physical and chemical properties of commercial Hypericum perforatum extracts relevant for formulated product quality and performance.

OBJECTIVE: The complex composition-activity relationship of botanicals such as St John's Wort (SJW) presents a major challenge to product development, manufacture, and establishment of appropriate quality and performance standards for the formulated products. As part of a larger study aimed at addressing that challenge, the goals of the present study are to (1) determine and compare the phytochemical profiles of 3 commercial SJW extracts; (2) assess the possible impact of humidity, temperature, and light on their stability; and (3) evaluate several physical properties important to the development of solid dosage forms for these extracts. METHODS: An adapted analytical method was developed and validated to determine phytochemical profiles and assess their stability. The extract physical properties measured were particle size (Malvern Mastersizer), flow (Carr's compressibility index; minimum orifice diameter), hygroscopicity (method of Callahan et al), and low-pressure compression physics (method of Heda et al). RESULTS: The phytochemical properties differed greatly among the extracts and were extremely sensitive to changes in storage conditions, with marked instability under conditions of elevated humidity. All extracts exhibited moderate to free-flow properties and were very hygroscopic. Compression properties varied among the extracts and differed from a common use excipient, microcrystalline cellulose. CONCLUSIONS: Three commercial sources of SJW extracts exhibited different physical and chemical properties. Standardization to 1 or 2 marker compounds does not ensure chemical equivalence nor necessarily equivalent pharmacological activity. Flow and compression properties appear suitable for automatic capsule-filling machines, but hygroscopicity and the moisture sensitivity of the phytochemical profile are concerns.

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.

Evaluation of "external" predictability of an in vitro-in vivo correlation for an extended-release formulation containing metoprolol tartrate.

The purpose of this study was to examine the external predictability of an in vitro-in vivo correlation (IVIVC) for a metoprolol hydrophilic matrix extended-release formulation, with an acceptable internal predictability, in the presence of a range of formulation/manufacturing changes. In addition, this report evaluated the predictability of the IVIVC for another formulation of metoprolol tartrate differing in its release mechanism. Study 1 examined the scale up of a matrix extended-release tablet from a 3-kg small batch (I) to a 50-kg large batch (II). The second study examined the influence of scale and processing changes [3-kg small batch with fluid bed granulation and drying (III); 80-kg large batch with high shear granulation and microwave drying (IV), and a formulation with an alternate release mechanism formulated as a multiparticulate capsule (V)]. In vitro dissolution of all formulations (I-V) was conducted with a USP apparatus I at pH 6.8 and 150 rpm. Subjects received the metoprolol formulations, and serial blood samples were collected over 48 h and analyzed by a validated HPLC assay using fluorescence detection. A previously developed IVIVC was used to predict plasma profiles. Prediction errors (PE) were <10% for C(max) and area under the curve (AUC) of concentration versus time for I, II, and IV. The C(max) for III was slightly underestimated (11.7%); however, the PE of the AUC was <10%. Formulation V displayed a PE for C(max) > 20% and an AUC within 5% of observed values. The low PEs for C(max) and AUC observed for I-IV strongly suggest that the metoprolol IVIVC is externally valid, predictive of alternate processing methods (IV), scale-up (II, III), and allows the in vitro dissolution data to be used as a surrogate for validation studies. However, the lack of predictability for V supports the contention that IVIVCs are formulation specific.

Scale-up effects on dissolution and bioavailability of propranolol hydrochloride and metoprolol tartrate tablet formulations.

This study evaluated the effects of batch size on the in vitro dissolution and the in vivo bioavailability of immediate release formulations of propranolol hydrochloride and metoprolol tartrate. The formulations were manufactured as small and large batches (6 kg and 60 kg for propranolol; 14 kg and 66 kg for metoprolol), and dissolution was performed using USP Apparatus I at 100 rpm and pH 1.2. Two panels of 14 subjects each were randomly assigned to receive the small and large batches of either propranolol or metoprolol in an open, randomized single-dose study. Blood samples were collected over a 24-hour (propranolol) or 18-hour (metoprolol) period and analyzed by validated methods. As determined by the f2 metric (similarity factor), the dissolution of the small and large batches of propranolol and metoprolol was similar. The mean Cmax and AUC(inf) for the small batch of propranolol were 79.0 microg/L and 536 microg/L/hr, and for the large batch they were 83.5 microg/L and 575 microg/L/hr. Cmax and AUC(inf) for the small batch of metoprolol were found to be 95.5 microg/L and 507 microg/L/hr and for the large batch, 95.1 microg/L and 495 microg/L/hr. The 90% confidence intervals for the small and large batches were within the 80% to 120% range for lnCmax, and lnAUC(inf) for both the propranolol and metoprolol formulations. These results suggest that the scale-up process does not significantly affect the bioavailability of highly soluble, highly permeable drugs and in vitro dissolution tests may be useful in predicting in vivo behavior.

Identification of critical formulation and processing variables for metoprolol tartrate extended-release (ER) matrix tablets.

The objective of this study, was to examine the influence of critical formulation and processing variables as described in the AAPS/FDA Workshop II report on scale-up of oral extended-release dosage forms, using a hydrophilic polymer hydroxypropyl methylcellulose (Methocel K100LV). A face-centered central composite design (26 runs+3 center points) was selected and the variables studied were: filler ratio (lactose:dicalcium phosphate (50:50)), polymer level (15/32.5/50%), magnesium stearate level (1/1.5/2%), lubricant blend time (2/6/10 min) and compression force (400/600/800 kg). Granulations (1.5 kg, 3000 units) were manufactured using a fluid-bed process, lubricated and tablets (100 mg metoprolol tartrate) were compressed on an instrumented Manesty D3B rotary tablet press. Dissolution tests were performed using USP apparatus 2, at 50 rpm in 900 ml phosphate buffer (pH 6.8). Responses studied included percent drug released at Q1 (1 h), Q4, Q6, Q12. Analysis of variance indicated that change in polymer level was the most significant factor affecting drug release. Increase in dicalcium phosphate level and compression force were found to affect the percent released at the later dissolution time points. Some interaction effects between the variables studied were also found to be statistically significant. The drug release mechanism was predominantly found to be Fickian diffusion controlled (n=0.46-0.59). Response surface plots and regression models were developed which adequately described the experimental space. Three formulations having slow-, medium- and fast-releasing dissolution profiles were identified for a future bioavailability/bioequivalency study. The results of this study provided the framework for further work involving both in vivo studies and scale-up.

Capsule filling machine simulation. I. Low-force powder compression physics relevant to plug formation.

The objective of this study was to simulate powder plug formation and explore the low-force powder compression physics of the process. A single-ended saw-tooth waveform was used to make powder plugs, representing no. 1 size capsules, at constant punch speeds of 1, 10, and 100 mm/sec on a tablet compaction simulator. Plugs of different heights (4, 8, and 12 mm) were made in a prelubricated die from three materials: Avicel PH 102, anhydrous lactose, and Starch 1500. The compression data were fit to Heckel's pressure-density relationship, Kawakita's pressure-volume relationship, and Shaxby-Evans's exponential relationship. Heckel analysis of this low-pressure range data revealed "apparent yield pressures" of 25-70 MPa, which were dependent upon the material type, machine speed, and plug height. Shaxby-Evans's relationship was found to hold in that the axial load transmission decreased exponentially with increased plug height/diameter ratio. A dramatic decrease in the coefficient of lubrication, R, with increase in plug height was attributed to poor axial load transmission through the length of the plug. Kawakita's pressure-volume relationship fit the plug formation data very well, and it was evident from this model (Kawakita constant, a) that Avicel PH 102 had the largest available volume for reduction. The plug formation process can be simulated using a programmable tablet compaction simulator. Overall, the data analysis demonstrated that the compression models available for tableting that were used in this study can also be applied to the powder plug formation process with appropriate interpretation.

Comparison of melatonin products against USP's nutritional supplements standards and other criteria.

OBJECTIVE: To evaluate and compare the quality of a sample of melatonin products, as measured by the United States Pharmacopeial Convention (USP) General Tests and Assays for Nutritional Supplements (other than Microbial Limits) and certain other tests. DESIGN: Five immediate-release, two sublingual, and two controlled-release products were randomly gathered from a health food store, groceries, and pharmacies in the Baltimore-Washington metropolitan area. MAIN OUTCOME MEASURES: Weight variation, disintegration (not applicable for controlled-release products), and drug dissolution, based on USP standards. Twelve-hour dissolution profiles were obtained from the controlled-release products. All tablets were also evaluated for friability following the USP procedure and for hardness following unofficial procedures. RESULTS: All products passed the weight variation test. Two products showed excessive friability. Three immediate-release products failed both the disintegration and the dissolution tests. One of the three products demonstrated a threefold difference in hardness. One controlled-release product released 90% of melatonin in four hours in the dissolution test; the other released 90% of its content in 12 hours. CONCLUSION: Some products showed evidence of poor formulation and/or poor quality control as indicated by excessive friability, failure to disintegrate and dissolve, and excessive variation in hardness. In vitro release profiles of the two controlled-release products were substantially different. The poor quality of some supplements should be a concern to consumers and health care providers.

The impact of formulation and process changes on in vitro dissolution and the bioequivalence of piroxicam capsules.

The purpose of this research was to determine the effect of major compositional changes on the bioavailability of piroxicam from immediate-release formulations filled in hard gelatin capsules. The capsules were manufactured according to a 2(5-1) + star point (resolution V) experimental design to investigate the effects of sodium lauryl sulfate level, magnesium stearate level, lactose/microcrystalline cellulose ratio, piroxicam particle size, and lubricant blending time. Sodium lauryl sulfate level, lactose level, and piroxicam particle size were the most important main effects affecting dissolution. Lubricant level and lubricant blending time were either not significant (5% level) or were among the lowest ranking of factors affecting dissolution in standardized pareto analysis. Three of these formulations exhibiting slow, medium, and fast dissolution were compared to a single lot of the Innovator (commercial) product in a small bioavailability study. The slow formulation did not meet the USP dissolution specification for piroxicam capsules. Compositionally, the experimental formulations represented major changes in piroxicam particle size, level of filler, and level of sodium lauryl sulfate. Sixteen healthy volunteers received each formulation (20 mg) in a four-way crossover design. The three Maryland manufactured formulations were bioequivalent with the commercial product and were also bioequivalent among themselves. The major changes incorporated into these formulations did not result in major differences in bioavailability. The dissolution profiles which discriminated between the formulations in vitro did not accurately represent the in vivo bioavailability results. The results of this study are part of the research database that supports SUPAC-IR, an FDA guidance that provides relaxed testing and filing requirements for scale-up and post-approval changes to immediate-release oral solid dosage forms.

Identification of formulation and manufacturing variables that influence in vitro dissolution and in vivo bioavailability of propranolol hydrochloride tablets.

The purpose of this study was to evaluate the effect of formulation and processing changes on the dissolution and bioavailability of propranolol hydrochloride tablets. Directly compressed blends of 6 kg (20,000 units) were prepared by mixing in a 16-qt V blender and tablets were compressed on an instrumented Manesty D3B tablet press. A half-factorial (2(5-1), Resolution V) design was used to study the following variables: filler ratio (lactose/dicalcium phosphate), sodium starch glycolate level, magnesium stearate level, lubricant blend time, and compression force. The levels and ranges of the excipients and processing changes studied represented level 2 or greater changes as indicated by the Scale-up and Post Approval Changes (SUPAC-IR) Guidance. Changes in filler ratio, disintegrant level, and compression force were significant in affecting percent drug released (Q) in 5 min (Q5) and Q10. However, changes in magnesium stearate level and lubricant blend time did not influence Q5 and Q10. Hardness was found to be affected by changes in all of the variables studied. Some interaction effects between the variables studied were also found to be significant. To examine the impact of formulation and processing variables on in vivo absorption, three batches were selected for a bioavailability study based on their dissolution profiles. Thirteen subjects received four propranolol treatments (slow-, medium-, and fast-dissolving formulations and Inderal 80 mg) separated by 1 week washout according to a randomized crossover design. The formulations were found to be bioequivalent with respect to the log Cmax and log AUC0-infinity. The results of this study suggest that (i) bioavailability/bioequivalency studies may not be necessary for propranolol and perhaps other class 1 drugs after level 2 type changes, and (ii) in vitro dissolution tests may be used to show bioequivalence of propranolol formulations with processing or formulation changes within the specified level 2 ranges examined.