In Vitro Screening Methods To Assess the Potential of In Vivo Precipitation of Injectable Formulations upon Intravenous Administration.

In vivo precipitation of injectable formulations upon intravenous administration is a major concern in formulation development. In this work, two in vitro screening tools, static dilution and dynamic injection, are developed to assess the potential of in vivo precipitation of active pharmaceutical ingredients from injectable formulations upon intravenous administration. Nine model injectable formulations are studied. These include marketed formulations as well as formulations from Merck programs. Results from these models are compared with reports of precipitation from product labels, the Physicians Desk Reference, and literature reports. Good correlation is observed between results from the static dilution and dynamic injection models. The in vitro data correlates well with precipitation reported during clinical evaluations and animal experiments. The importance of protein in dilution medium, prototype formulations for screening studies, and optical microscopy for studying phase behavior is demonstrated. This work demonstrates the utility of using these models as a valuable screen during injectable formulation development. LAY ABSTRACT: In vivo precipitation of injectable formulations upon intravenous administration is a major concern in formulation development. Although animal models are routinely used for this purpose, they require strict protocol and are expensive. Furthermore, their results are far from ideal. This work describes the development of two in vitro screening tools, static dilution and dynamic injection, to assess the potential of in vivo precipitation of active pharmaceutical ingredients from injectable formulations upon intravenous administration. The utility of using these models as a valuable screen during injectable formulation development is demonstrated through the use of several model compounds.

Risk assessment and physicochemical characterization of a metastable dihydrate API phase for intravenous formulation development.

(1S,5R)-2-{[(4S)-azepan-4-ylamino]carbonyl}-7-oxo-2,6-diazabicyclo[3.2.0] heptane-6-sulfonic acid (Compound 1) is a ß-lactamase inhibitor for intravenous administration. The objective of this preformulation study was to determine the most appropriate form of the API for development. Compound 1 can exist as an amorphous solid and four distinct crystalline phases A, B, C, and D in the solid state. Slurry experiments along with analysis of physicochemical properties were used to construct a phase diagram and select the most suitable form of the API for development. In aqueous formulations, the dihydrate form of the API was predominant and, due to the more favorable solubility and dissolution profile required for preclinical and clinical studies, a metastable form of the API was selected, and the risks associated with developing this form were evaluated.

Exploring the formation of multiple layer hydrates for a complex pharmaceutical compound.

The pharmaceutical compound A, 3-{2-oxo-3-[3-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)propyl]imidazolidin-1-yl}-3(S)-(6-methoxypyridin-3-yl)propionic acid, is known to exist in five different crystalline forms that differ in the hydration state ranging from the anhydrous desolvate over hemihydrate, dihydrate, and tetrahydrate forms to the pentahydrate. The formation of the higher hydrates and the concomitant lattice expansion leads to undesirable tablet cracking at higher humidities. In this work, particle-based simulation techniques are used to explore the hydrate formation of compound A as a function of humidity. It is found that a simulation strategy employing Monte Carlo simulations in the isobaric-isothermal and Gibbs ensembles and transferable force fields, which are not parametrized against any experimental data for compound A, is able to yield satisfactory crystal structures for the anhydrate and pentahydrate and to predict the existence of all five hydrates.

Mechanochromism of piroxicam accompanied by intermolecular proton transfer probed by spectroscopic methods and solid-phase changes.

Structural and solid-state changes of piroxicam in its crystalline form under mechanical stress were investigated using cryogenic grinding, powder X-ray diffractometry, diffuse-reflectance solid-state ultraviolet-visible spectroscopy, variable-temperature solid-state (13)C nuclear magnetic resonance spectroscopy, and solid-state diffuse-reflectance infrared Fourier transform spectroscopy. Crystalline piroxicam anhydrate exists as colorless single crystals irrespective of the polymorphic form and contains neutral piroxicam molecules. Under mechanical stress, these crystals become yellow amorphous piroxicam, which has a strong propensity to recrystallize to a colorless crystalline phase. The yellow color of amorphous piroxicam is attributed to charged piroxicam molecules. Variable-temperature solid-state (13)C NMR spectroscopy indicates that most of the amorphous piroxicam consists of neutral piroxicam molecules; the charged species comprise only about 8% of the amorphous phase. This ability to quantify the fractions of charged and neutral molecules of piroxicam in the amorphous phase highlights the unique capability of solid-state NMR to quantify mixtures in the absence of standards. Other compounds of piroxicam, which are yellow, are known to contain zwitterionic piroxicam molecules. The present work describes a system in which proton transfer accompanies both solid-state disorder and a change in color induced by mechanical stress, a phenomenon which may be termed mechanochromism of piroxicam.

Dehydration kinetics of piroxicam monohydrate and relationship to lattice energy and structure.

The dehydration kinetics of piroxicam monohydrate (PM) is analyzed by both model-free and model-fitting approaches. The conventional model-fitting approach assuming a fixed mechanism throughout the reaction is found to be too simplistic. The model-free approach allows for a change of mechanism and activation energy, Ea, during the course of a reaction and is therefore more realistic. The complexity of the dehydration of PM is illustrated by the dependence of Ea on both the heating conditions, isothermal or nonisothermal, and on the fraction of conversion, alpha (0 < or = alpha < or = 1). Under both isothermal and nonisothermal conditions, Ea increases with alpha for 0 < or = alpha < or = 0.25, followed by an approximately constant value of Ea during further dehydration. In the constant-Ea region, isothermal dehydration follows the two-dimensional phase boundary model (R2), whereas nonisothermal dehydration follows a mechanism intermediate between two- and three-dimensional diffusion that cannot be described by any of the common models. Structural studies suggest that the complex hydrogen-bond pattern in PM is responsible for the observed dehydration behavior. Ab initio calculations provide an explanation for the changes in the molecular and crystal structures accompanying the reversible change in hydration state between anhydrous piroxicam Form I and PM. This work also demonstrates the utility of model-free analysis in describing complex dehydration kinetics.

Solid-state properties of warfarin sodium 2-propanol solvate.

The goal of the present work was to understand the effect of relative humidity (RH) and temperature on the molecular structure, crystal structure, and physical properties of warfarin sodium 2-propanol solvate (W). After previous determination of the crystal structure of W, which corresponds to a 1:1 2-propanol solvate, the present work shows that W has a critical RH (60% < RH(0) < or = 68%), below which minimal uptake of water occurs, due to surface adsorption, but above which gradual and continuous uptake of water occurs, due to deliquescence. Deliquescence begins at the surface and proceeds inward into the bulk of the crystal. Single crystal X-ray diffractometry indicates no change in the crystal and molecular structure of W during the initial stages of deliquescence. Studies of the unit cell and volume computations of W show that water can neither find space to enter the crystal lattice, nor can replace 2-propanol. Thus, water does not exchange with 2-propanol within the lattice, contrary to previous reports. Storage of single crystals of W at 120 degrees C for 23 h produces shrinkage cracks along the needle (b) axis, which are interpreted as a reduction in d-spacing of the 00l planes. Thus, under thermal stress, W crystals undergo amorphization with concurrent loss of 2-propanol, which may proceed via an intermediate crystalline phase. The phase changes of W, which depend on RH and temperature, are explained at the molecular level.

Crystal structure of neotame anhydrate polymorph G.

PURPOSE: To determine the crystal structure of the neotame anhydrate polymorph G and to evaluate X-ray powder diffractometry (XRPD) with molecular modeling as an alternative method for determining the crystal structure of this conformationally flexible dipeptide. METHODS: The crystal structure of polymorph G was determined by single crystal X-ray crystallography (SCXRD) and also from the X-ray powder diffraction (XRPD) pattern using molecular modeling (Cerius2, Powder Solve module). RESULTS: From SCXRD, polymorph G crystals are orthorhombic with space group of P2(1)2(1)2(1) with Z = 4, unit cell constants: a = 5.5999(4), b = 11.8921(8), c = 30.917(2) A, and one neotame molecule per asymmetric unit. The XRPD pattern of polymorph G, analyzed by Cerius2 software, led to the same P2(1)2(1)2(1) space group and almost identical unit cell dimensions. However, with 13 rigid bodies defined, Cerius2 gives a conformation of the neotame molecule, which is different from that determined by SCXRD. CONCLUSIONS: For neotame anhydrate polymorph G, the unit cell dimensions calculated from XRPD were almost identical to those determined by SCXRD. However, the crystal structure determined by XRPD closely resembled that determined by SCXRD, only when the correct conformation of the neotame molecule had been chosen before detailed analysis of the XRPD pattern.