The objectives of this study were to establish a rational basis for choosing parameters for conducting the tensile strength and indentation hardness test on pharmaceutical compacts, to describe the changes in tableting indices based on the different parameters, to develop a method to spherically crystallize ibuprofen, and to compare the mechanical and micromeritic properties of spherically crystallized ibuprofen and naproxen to the starting materials. This work described the importance of establishing the appropriate test parameters for tensile strength and indentation hardness tests so that reliable and predictive tableting indices could be determined. The fracture strength for diametral compression of ibuprofen compacts was determined for two modes of stress application, constant stress rate and constant strain rate. The tensile strength for diametral compression of ibuprofen and naproxen compacts was determined using a constant strain rate (0.05 to 16 mm/min). The static indentation hardness (Meyer hardness) of ibuprofen and naproxen compacts was determined at varying solid fractions and indentor depth of penetration. Results from these studies were used to establish an appropriate rate of stress application during diametral compression and an appropriate depth of penetration for indentation hardness testing in order to calculate tableting indices. The tableting indices calculated from the aforementioned properties were: the brittle fracture index (BFI), the best case bonding index (BIb), the worst case bonding index (BIw), the brittle/viscoelastic bonding index (bBIv), and the viscoelastic index (VI). In addition, changes in compactibility between the starting materials and their spherically crystallized products were assessed through the analysis of Athy-Heckel profiles. A comparison of micromeritic properties included particle size, porosity, surface area, bulk density, tap density, true density, and flowability as measured by the Carr Index. The spherically crystallized products of ibuprofen and naproxen were shown to be free flowing, less compressible, and more compactible than the starting materials. The spherically crystallized ibuprofen product was optimized for improved tensile strength, bonding index, and minimal particle size using response surface experimental design methodology. Key process factors in the quasi-emulsion solvent diffusion method employed to spherically crystallize ibuprofen were: the amount of additive, hydroxypropylmethyl cellulose, added to the nonsolvent, the agitation rate during the crystallization process, and the amount of agglomerating solvent. Naproxen was spherically crystallized using a solvent change method adopted from the open literature. Thermal analysis and x-ray powder diffraction analysis showed that both ibuprofen and naproxen spherically crystallized products were the same highly crystalline form as the starting materials. The relative contribution of the different micromeritic properties to the changes in the mechanical properties was exemplified by the change in BFI. (Abstract shortened by UMI.)
In the past four years three guidances have been prepared for the pharmaceutical industry which dealt with different aspects of extended-release dosage forms. This dissertation focused on one main issue from each of the three guidances. The first issue addressed pharmaceutical equivalence requirements. The second issue examined how multiple changes in formulation and process variables affect in vitro dissolution test result. The third issue concentrated on in vitro-in vivo correlation (IVIVC) as a predictor of in vivo performance across release mechanisms. A metoprolol tartrate extended-release capsule formulation was developed using fluid bed multiprocessor equipment with Wurster insert. Sugar spheres were drug-layered with metoprolol tartrate, seal-coated with Opadry (hydroxypropyl methylcellulose) and film-coated with Surelease (ethylcellulose). This dosage form was compared to a reference metoprolol tartrate matrix tablet dosage form which was formulated using Methocel K100LV (hydrodroxypropyl methylcellulose) as a hydrophilic polymer to retard the release. The mechanisms of release between both dosage forms differ. In the case of the tablet (reference) product, release is a function of the square root of time and the release rate can be controlled by the tablet porosity, addition of soluble solids, and the ratio of drug to carrier. The mechanism and kinetics of drug delivery from the capsule (test) formulation depend on the nature of the film and can be controlled by film porosity and thickness. For insoluble membranes made of ethylcellulose, drug release depends primarily on diffusion and partitioning of the drug into the membrane. Dissolution tests using different media, agitation speeds and methods were performed on both formulations to determine how the differences in dosage forms in terms of appearance or type (multiparticulate vs single unit) and release mechanism affect in vitro release. An in vitro-in vivo correlation (IVIVC) between plasma concentration and dissolution rate for matrix tablet formulation of the same drug was used to predict the in vivo performance of the capsule formulation. A clinical study was conducted using the capsule formulation and the bioavailability parameters derived from this study were compared to those predicted from the matrix tablet IVIVC. Both formulations released drug similarily under different dissolution testing conditions (f2>75). While the extent of release from both formulations was similar in vivo, the rate of release was not. This finding was also reflected in the predictions made using the matrix tablet IVIVC. The area under the curve (AUC) was adequately predicted (error<3%) whereas, the maximum concentration (Cmax) which is a bioavailability parameter that reflects rate in addition to extent of absorption was not well predicted(error>20%). The results demonstrate: (1) the f2 criteria used to determine in vitro profile similarity between formulations may not be suitable when the dosage forms being compared differ in release mechanisms, and/or (2) the IVIVC is formulation and mechanism dependent. The differences found in the in vivo absorption rates of these two formulations reflect differences in the dynamics of stomach emptying and intestinal transport between a multiparticulate dosage form compared to a monolithic matrix tablet dosage form.
Remifentanil (ULTIVA) is an ultra short-acting opioid which has recently been approved for use during surgical procedures requiring opioid analgesia. After i.v. administration, it is rapidly metabolized by non-specific esterases in the blood and other tissues to less active metabolites. Total body clearance of remifentanil in man is 41.2 mL/min/kg, the Vd is 390 mL/kg and the elimination half-life is 10-48 minutes. In dogs, the clearance is 63 mL/min/kg, Vdss is 222 mL/kg and the elimination half-life is 5.7 minutes. Esmolol is an ultra short-acting beta-blocker administered intravenously during surgical procedures to decrease heart rate and blood pressure in patients at risk of cardiovascular complications. It is also metabolized by non-specific esterases in the blood and other tissues to form an inactive acid metabolite and methanol. It is likely both drugs will be administered together in patients with cardiac disease during surgical procedures. The goal of this study was to evaluate a possible drug interaction between remifentanil and esmolol following concomitant administration. This was accomplished by comparing pharmacokinetic and pharmacodynamic parameters of remifentanil after administration alone and in combination with esmolol. In the first study, remifentanil (treatment I, 25 mug/kg/min) and remifentanil plus esmolol (treatment II, (25 mug/kg/min and 200 mug/kg/min, respectively)) were infused for 20 minutes into male Sprague-Dawley rats in a random parallel design. Arterial blood samples were collected over the course of the study, extracted with methylene chloride, and analyzed (off-site) by a validated GC-MS assay. Additionally, cardiovascular measurements were continuously collected from 15 minutes pre-dose until about 20 minutes after end of infusion. Compartmental modeling was performed to determine the pharmacokinetic parameters. In a follow-up study, remifentanil (treatment I, 15 mug/kg/mL) and remifentanil plus esmolol (treatment II, (15 mug/kg/min and 600 mug/kg/min, respectively)) were infused into male Sprague-Dawley rats in a random two-way cross-over design. Blood samples (using limited sampling strategy) were collected and analyzed as before. EEG data were collected continuously over the course of the study. Bayesian estimation was used to determine the pharmacokinetic parameters. Pharmacodynamic parameters were obtained by modeling EEG spectral edge, using a pharmacokinetic-pharmacodynamic link model. Comparison of the pharmacokinetic and pharmacodynamic parameters between treatments I and II in both studies did not detect any significant (p < 0.05) differences. This indicates that at the doses tested, the co-administration of esmolol did not cause a significant change in the pharmacokinetics or pharmacodynamics of remifentanil no drug-drug interaction.
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