Freeze drying--principles and practice for successful scale-up to manufacturing.

Freeze Drying involves transfer of heat and mass to and from the product under preparation, respectively, thus it is necessary to scale these transport phenomena appropriately from pilot plant to manufacturing-scale units to maintain product quality attributes. In this manuscript we describe the principal approach and tools utilized to successfully transfer the lyophilization process of a labile pharmaceutical product from pilot plant to manufacturing. Based on pilot plant data, the lyophilization cycle was tested during limited scale-up trials in manufacturing to identify parameter set-point values and test process parameter ranges. The limited data from manufacturing were then used in a single-vial mathematical model to determine manufacturing lyophilizer heat transfer coefficients, and subsequently evaluate the cycle robustness at scale-up operating conditions. The lyophilization cycle was then successfully demonstrated at target parameter set-point values.

Stability and compatibility of tirofiban hydrochloride during simulated Y-site administration with other drugs.

The stability and compatibility of tirofiban hydrochloride injection during simulated Y-site administration with various other drugs were studied. Tirofiban hydrochloride, dobutamine, epinephrine hydrochloride, furosemide, midazolam hydrochloride, and propranolol hydrochloride injections were each prepared from their respective concentrates in both 0.9% sodium chloride injection and 5% dextrose injection at both the minimum and maximum concentrations normally administered. The high-concentration solutions of midazolam hydrochloride and furosemide were used as is. Morphine sulfate was diluted in 5% dextrose injection only. Nitroglycerin premixed infusions, atropine sulfate injection, and diazepam injection were used as is. Tirofiban hydrochloride solutions were combined 1:1 with each of the secondary drug solutions in separate glass containers. Samples were stored for four hours at room temperature under ambient fluorescent light and were assayed for drug content and degradation by high-performance liquid chromatography and for pH, appearance, and turbidity. All mixtures except those containing diazepam remained clear and colorless, with no visual or turbidimetric indication of physical instability. Mixing of tirofiban hydrochloride and diazepam solutions resulted in immediate precipitation. all remaining mixtures remained clear. There was no significant loss of any of the drugs tested, no increase in known degradation products, and no appearance of unknown drug-related peaks. The pH of all test solutions remained constant. Tirofiban hydrochloride injection 0.05 mg/mL was stable for at least four hours when combined 1:1 in glass containers with atropine sulfate, dobutamine, epinephrine hydrochloride, furosemide, midazolam hydrochloride, morphine sulfate, nitroglycerin, and propranolol hydrochloride at the concentrations studied. Tirofiban hydrochloride was incompatible with diazepam.

Compatibility of tirofiban HCl with dopamine HCl, famotidine, sodium heparin, lidocaine HCl and potassium chloride during simulated Y-site administration.

OBJECTIVE: To study the compatibility of tirofiban HCl injection 0-05 mg/ml with dopamine HCl, famotidine, sodium heparin, lidocaine HCl and potassium chloride infusion solutions during simulated Y-site administration. METHOD: Tirofiban HCl, dopamine HCl, famotidine, lidocaine HCl and potassium chloride infusions were each prepared from their respective concentrates as per current clinical preparation instructions in both 0.9% sodium chloride and 5% dextrose solutions at both the minimum and maximum concentrations normally administered. Sodium heparin premixed infusion solutions in 5% dextrose and 0-45% sodium chloride were used as-is. Tirofiban HCl solutions were combined 1:1 (simulated Y-site administration) with the dopamine HCl, famotidine, sodium heparin, lidocaine HCl and potassium chloride solutions in separate glass containers and polyvinylchloride Y-site infusion lines. Samples were held for 4 h at room temperature under ambient fluorescent light and were assayed for changes in drug content, degradation, pH, appearance and turbidity. Activity of sodium heparin solutions was measured using an aPTT coagulation assay. RESULTS: All mixtures remained clear and colourless with no visual indication of instability, i.e. precipitation. Clarity of solutions was confirmed by turbidometric analysis. There was no significant loss of drug, increase in known degradates, or appearance of unknown drug-related peaks as determined by HPLC. The activity of heparin in heparin-containing solutions remained unchanged. The pH of all test-solutions remained constant. CONCLUSION: Tirofiban HCl injection 0.05 mg/ml can be co-infused by Y-site administration with dopamine HCl, famotidine, sodium heparin, lidocaine HCl and potassium chloride injection solutions.

Influence of viscosity on WIN 39996 as a contrast agent for gastrointestinal magnetic resonance imaging.

RATIONALE AND OBJECTIVES: The authors discuss the influence of viscosity on the imaging properties of WIN 39996 suspension. WIN 39996 suspension is a magnetically susceptible iron ferrite that provides negative (darkening) contrast enhancement in magnetic resonance imaging of the gastrointestinal tract. METHODS: The viscosity of WIN 39996 suspension was altered by various stress conditions (1 week to 4.5 months storage at temperatures of 5 degrees to 70 degrees C) or by various amounts of xanthan gum. Magnetic resonance imaging was performed in vitro on phantoms and in vivo on the gastrointestinal tract of anesthetized dogs. RESULTS: The results indicated that in vitro and in vivo imaging efficacies of WIN 39996 suspension depended on the viscosity, irrespective of the means by which the viscosity was altered. Specifically, the imaging quality was suitable at viscosities > or = 36.6 cp for in vitro imaging, and > 25 cp for in vivo imaging. The lower in vivo viscosity limit for magnetic resonance imaging compared with the in vitro limit may be due to gastrointestinal peristaltic activities continuously mixing the WIN 39996 suspension to prevent gravitational settling, and the enhancement of signal blackening by intraluminal WIN 39996 that was above and below the plane of image. CONCLUSIONS: It is speculated that the imaging quality of WIN 39996 suspension depends on the degree of dispersion of the magnetically susceptible iron ferrite in the WIN 39996 suspension, and that a minimum viscosity is needed to ensure such dispersion.

Optimization of an oral magnetic particle formulation as a gastrointestinal contrast agent for magnetic resonance imaging.

RATIONALE AND OBJECTIVES: Magnetically susceptible iron oxide (MSIO) contrast agents for magnetic resonance imaging (MRI) of the gastrointestinal (GI) tract are limited because they produce magnetic susceptibility artifacts. To determine whether oral magnetic particles (WIN 39996) can be an effective MRI contrast agent without producing induced image artifacts, we optimized a liquid formulation of WIN 39996. METHODS: A range of concentrations (25-250 micrograms iron/mL) and viscosities (1-600 cP) was imaged in a phantom at 1.5 T using conventional spin-echo and gradient-recalled echo pulse sequences. Some formulations also contained titanium. RESULTS: All concentrations of WIN 39996 at 1 cP produced susceptibility artifacts. For formulations in the 150 to 600 cP range, the 125 to 150 micrograms/mL concentrations produced signal blackening and magnetic susceptibility image distortion comparable to an air control. Concentrations greater than 150 micrograms/mL were unacceptable because they produced significant susceptibility artifacts, while concentrations less than 125 micrograms/mL were undesirable because they produced insufficient signal blackening. CONCLUSIONS: These preliminary in-vitro studies suggest that an optimized liquid formulation of WIN 39996 can be produced that yields excellent negative contrast without producing image artifacts.

Liquid oral magnetic particles as a gastrointestinal contrast agent for MR imaging: efficacy in vivo.

Recent in vitro studies suggested there is an optimal range of concentration and viscosity for a liquid formulation of oral magnetic particles (WIN 39996) for magnetic resonance (MR) imaging of the gastrointestinal (GI) tract. To determine whether this formulation is also effective in vivo and whether differing viscosity and administration regimen affect GI distribution of the contrast agent, a range of concentrations of iron (75, 150, and 200 micrograms/mL) and viscosities (1, 150, and 600 cp) were imaged in dogs at 1.5 T with conventional spin-echo and fat-saturation pulse sequences. The effects of dose regimen (single vs divided dose) and subject position (supine vs right lateral decubitus) were also studied. The 75 and 200 micrograms/mL concentrations were unacceptable for MR imaging, while 150 micrograms/mL was effective. The GI distribution of the contrast agent was affected jointly by viscosity, subject position, and dose regimen. The 150 micrograms/mL formulation produced excellent GI contrast enhancement in vivo for both 150- and 600-cp viscosities. The choice of optimal viscosity may depend on the preferred administration regimen.

Test method for evaluation of loss of prime in metered-dose aerosols.

A new test method is described for assessing the loss of prime in metered-dose aerosols. Two representative metered-dose valve designs and two storage positions were used to assess the utility of this test method at three different sites. Loss of prime, defined as a valve delivery 15% below the mean, was detected in three of the four test configurations. The first significant loss of prime in this study was observed at the two-week time point for valves without drain tanks stored in the upright position. Onset of loss of prime was shown to be dependent on valve design as well as storage position, thus alternate valves or storage conditions should yield different results. This test method appeared to be reproducible over the three test sites, with a slight variation in results attributed to differences in storage conditions and agitation during sample handling. This test method intentionally excluded agitation which is in sharp contrast to the normal "shake well before use" instruction to the patient. Following one priming actuation, all of the valves returned to their mean valve delivery.

Particle-size distribution of bitolterol mesylate solution delivered by four compressed-air nebulizer devices.

The particle-size distribution of bitolterol mesylate solution delivered by four types of compressed-air nebulizers was determined. Before nebulization, bitolterol mesylate solution 0.2% w/v was diluted to 0.0833% w/v with 0.9% sodium chloride solution. The following commercially available nebulizers were tested: DeVilbiss Nebulizer Model 645, Hudson 1720 (Updraft) Hand Held Nebulizer, Bard Inspiron 002220 Mini-Neb Nebulizer, and Bunn Mini Mist Set model 0140-041. The particle-size distribution of nebulized solutions was determined with a cascade impactor contained in an in vitro apparatus designed to simulate use by a patient. Assays of bitolterol mesylate in the cascade impactor apparatus were done by high-performance liquid chromatography. Only slight differences were found in the particle-size distributions among the four types of nebulizers; the calculated average particle size ranged from 3.0 to 3.6 micron. All nebulizers tested showed satisfactory, comparable particle-size distributions and performance with bitolterol mesylate solution.

Stability of some bronchodilator solutions during ultrasonic nebulization.

The effect of ultrasonic nebulization on the stability of isoetharine hydrochloride and isoproterenol hydrochloride solutions was studied. Commercially available solutions of isoetharine hydrochloride 1%, isoproterenol hydrochloride 1%, and isoproterenol hydrochloride 0.5% were diluted to 0.25%, 0.125%, and 0.125%, respectively. The solutions were nebulized for 10 or 15 minutes using three ultrasonic nebulizers at 0, 3, 6, 8, and 24 hours. Before and after nebulization, the solutions were assayed for intact drug by chemical assay and by thin-layer chromatography (TLC). The nebulized mist was also collected and assayed. The extent of drug degradation from ultrasonic nebulization was calculated as the apparent percent loss of active drug. Results of the chemical and TLC analyses for samples from two nebulizers showed no substantial chemical degradation of isoetharine hydrochloride or isoproterenol hydrochloride in any solution. Chemical assay was not performed for the third nebulizer, but results of TLC analysis showed no substantial degradation of either drug in any solution. Under the simulated-use conditions of this study, solutions of isoetharine hydrochloride and isoproterenol hydrochloride were stable when nebulized ultrasonically.

Mass transport properties of co(polyether)polyurethane membranes II: permeability and sorption characteristics.

A series of co(polyether)polyurethane polymers containing polyethylene glycol 600, 1000, or 1540 was synthesized, purified by reprecipitation, and cast into clear, tough, flexible membranes using the solution method. Hydration and membrane swelling increased with increasing polyethylene glycol molecular weight. Paroxypropione, 5-nitrosalicylic acid, sulfaguanidine, and phenylbutazone were used as penetrants of a 1 mM donor concentration. Transport rates through the 1540 and 1000 copolymer membranes were in decreasing order: paroxypropione greater than 5-nitrosalicylic acid greater than sulfaguanidine greater than phenylbutazone; however, through the 600 copolymer membrane the rates were paroxypropione greater than 5-nitrosalicylic acid approximately sulfaguanidine. Phenylbutazone did not penetrate during the experiment. Good agreement was obtained between apparent diffusion coefficients calculated by both the time lag and nonsteady-state methods. Boundary layer effects were examined by variations in stirring speeds. Evidence that diffusion may occur primarily through the aqueous region of the hydrated membranes is presented.

Mass transport properties of co(polyether)polyurethane membranes I: Preparation and characterization.

A series of polyurethane copolymers containing polyethylene glycol 600, 1000, or 1540 was synthesized, purified by reprecipitation, and cast into clear, tough, flexible membranes using the solution method. The weight average molecular weight of each polymer was estimated by gel permeation chromatography. The ability of the various polymers to absorb water was measured and increased with the increasing molecular weight of the polyethylene-glycol. The ability of the copolymer membranes to hold a pH gradient decreased with increasing polyethylene glycol molecular weight.