Simultaneous XRD-DSC identifies correct drug-polymer solubility and miscibility for enantiotropic solid forms.

Thermodynamic properties, including solubility and miscibility, which are highly correlated with amorphous solid dispersion physical stability were identified for the complex solid forms of bromopropamide using simultaneous X-ray diffraction (XRD)-differential scanning calorimetry (DSC). The most stable solid form of bromopropamide was crystallized and its crystal structure was solved. The crystallized material was characterized using simultaneous XRD-DSC measurements, which allowed dual analyses of a single sample.

A threefold superstructure of the anti-epileptic drug phenytoin sodium as a mixed methanol solvate hydrate.

Phenytoin sodium, a salt of 5,5-diphenylimidazolidine-2,4-dione, or phenytoin, is commercially available in various dosage forms for its anti-epileptic properties to treat and prevent seizures. The title compound, poly[aquatris(μ-4,4-diphenyl-2,5-dioxoimidazolidin-1-ido)trimethanoltrisodium(I)], [Na(CHNO)(CHO)(HO)], a methanol solvate and hydrate of phenytoin sodium, forms a modulated crystal structure that consists of a supercell made up of three close-to-identical repeat units. Each of the basic fragments consists of one phenytoin anion, a sodium cation, and either a methanol, or a methanol and a water molecule coordinated to the sodium ion, yielding a formula unit of Na(CHNO)(CHOH)(HO) for each of the three segments (x, y = 0 or 1; x + y = 1 or 2).

New Insights on Solid-State Changes in the Levothyroxine Sodium Pentahydrate during Dehydration and its Relationship to Chemical Instability.

Levothyroxine sodium pentahydrate (LEVO) tablets have been on the US market since the mid-twentieth century and remain the most highly prescribed product. Unfortunately, levothyroxine sodium tablets have also been one of the most highly recalled products due to potency and dissolution failures on stability. In 2008, the assay limits were tightened, yet the recalls did not decline, which highlights the serious quality concerns remaining to be elucidated.

Polymorphic Transformation of Indomethacin during Hot Melt Extrusion Granulation: Process and Dissolution Control.

Purpose: To study and elucidate the effect of the intensity and duration of processing stresses on the possible solid-state changes during a hot melt extrusion granulation process.

Methods: Blends of α-indomethacin and PEG 3350 (w/w 4:1) were granulated using various screw sizes/designs on the melt extruder under different temperature regimes. Differential Scanning Calorimetry and X-ray Powder Diffraction were employed for characterization.

Open DeveloperSpace: An Enabling Infrastructure for Stakeholders to Generate New Access Solutions.

The DeveloperSpace, one of the core components of GPII, is a self-sustainable infrastructure and collaborative environment, where developers, implementers, consumers, prosumers and other directly and indirectly involved actors (e.g. teachers, caregivers, clinicians) may interact with and play a role in its viability and the development of new access solutions.

Correlation of Structural and Macroscopic Properties of Starches with Their Tabletability Using the SM(2) Approach.

The effects of PURE-DENT® and SPRESS® starch properties on their compression behavior was characterized using "SM(2) " approach (structural properties, macroscopic properties, and multivariate analysis). Moisture sorption rate constants, moisture content, amylose and amylopectin degradation enthalpy, percent crystallinity, amylose-amylopectin ratio, and cross-linking degree were used to profile starch structural properties. Particle density, particle size distribution, and Heckel compression descriptors [yield pressure (YP) of plastic deformation, and elastic recovery] were used as macroscopic descriptors.

Identification of a potential conformationally disordered mesophase in a small molecule: experimental and computational approaches.

GNE068, a small organic molecule, was obtained as an amorphous form (GNE068-A) after isolation from ethanol and as a partially disordered form (GNE068-PC) from ethyl acetate. On subsequent characterization, GNE068-PC exhibited a number of properties that were anomalous for a two phase crystalline-amorphous system but consistent with the presence of a solid state phase having intermediate order (mesomorphous). Modulated DSC measurements of GNE068-PC revealed an overlapping endotherm and glass transition in the 135-145 °C range.

Effect of water vapor sorption on local structure of poly(vinylpyrrolidone).

The effect of water vapor sorption on the local structure of poly(vinylpyrrolidone) (PVP), was investigated using high-quality X-ray powder diffraction (XRPD). To examine the effects on molecular scale structure due to polymer chain length and water sorption, different molecular weights of PVP were studied at ambient temperature and different controlled relative humidities. Sorption of water determined gravimetrically on drying and changes to the glass-transition temperature (T(g)) measured by modulated differential scanning calorimetry (mDSC) were found to be consistent with previous reports.

Structure and bonding of aqueous glutamic acid from classical molecular dynamics simulations.

Using classical molecular dynamics we have studied the solution structure of (1:1:29) glutamate with sodium counter ions and water. We provide a structural description of the system, focusing on glutamate–glutamate interactions and providing further insight into glutamate–water interactions. In particular we have characterised the solution structure using three different water potentials, finding little difference between the structural features they predict.

Evaluation of drug-polymer miscibility in amorphous solid dispersion systems.

Purpose: To evaluate drug-polymer miscibility behavior in four different drug-polymer amorphous solid dispersion systems, namely felodipine-poly(vinyl pyrrolidone) (PVP), nifedipine-PVP, ketoconazole-PVP, and felodipine-poly(acrylic acid) (PAA).

Materials And Methods: Amorphous solid dispersion samples were prepared at different drug-to-polymer ratios and analyzed using differential scanning calorimetry (DSC), mid-infrared (IR) spectroscopy, and powder X-ray diffractometry (PXRD). To help with interpretation of the IR spectra, principal components (PC) analysis was performed.

Novel methods for the assessment of miscibility of amorphous drug-polymer dispersions.

A typical approach to miscibility analysis of amorphous drug-excipient dispersions involves measuring the glass transition temperature, T(g), using differential scanning calorimetery (DSC). Recently, we discussed two computational methods for the miscibility analysis of amorphous dispersions using X-ray powder diffraction (XRPD). Those methods could be used to qualify an amorphous dispersion as miscible or phase separated, with the implication that miscible dispersions are more stable towards recrystallization.

Toward understanding the evolution of griseofulvin crystal structure to a mesophase after cryogenic milling.

The purpose of this research is to investigate the response of crystalline griseofulvin to mechanically induced stress through cryogenic milling. Crystalline griseofulvin was subjected to cryogenic milling for two different lengths of time. Following cryo-milling, the samples were immediately analyzed by differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD).

Characterization of amorphous API:Polymer mixtures using X-ray powder diffraction.

Recognizing limitations with the standard method of determining whether an amorphous API-polymer mixture is miscible based on the number of glass transition temperatures (T(g)) using differential scanning calorimetry (DSC) measurements, we have developed an X-ray powder diffraction (XRPD) method coupled with computation of pair distribution functions (PDF), to more fully assess miscibility in such systems. The mixtures chosen were: dextran-poly(vinylpyrrolidone) (PVP) and trehalose-dextran, both prepared by lyophilization; and indomethacin-PVP, prepared by evaporation from organic solvent. Immiscibility is detected when the PDF profiles of each individual component taken in proportion to their compositions in the mixture agree with the PDF of the mixture, indicating phase separation into independent amorphous phases.

Assessment of defects and amorphous structure produced in raffinose pentahydrate upon dehydration.

The progressive conversion of crystalline raffinose pentahydrate to its amorphous form by dehydration at 60 degrees C, well below its melting temperature, was monitored by X-ray powder diffraction over a period of 72 h. The presence of defects within the crystal structure and any amorphous structure created was determined computationally by a total diffraction method where both coherent long-range crystalline order and incoherent short-range disorder components were modeled as a single system. The data were analyzed using Rietveld, pair distribution function (PDF), and Debye total diffraction methods.

New solid-state chemistry technologies to bring better drugs to market: knowledge-based decision making.

Modern drug development demands constant deployment of more effective technologies to mitigate the high cost of bringing new drugs to market. In addition to cost savings, new technologies can improve all aspects of pharmaceutical development. New technologies developed at SSCI, Inc.

Solution structure of the aqueous model peptide N-methylacetamide.

Classical molecular dynamics simulations of aqueous N-methylacetamide (NMA) have been performed across a concentration range at 308 K. This peptidic fragment molecule is a useful model for investigating water/peptide hydrogen bond competition. The simulations predict considerable NMA self-association even at low concentrations with a concentration-dependent increase in the ratio of branched to linear clusters.

Analysis of amorphous and nanocrystalline solids from their X-ray diffraction patterns.

Purpose: The purpose of this paper is to provide a physical description of the amorphous state for pharmaceutical materials and to investigate the pharmaceutical implications. Techniques to elucidate structural differences in pharmaceutical solids exhibiting characteristic X-ray amorphous powder patterns are also presented.

Materials And Methods: The X-ray amorphous powder diffraction patterns of microcrystalline cellulose, indomethacin, and piroxicam were measured with laboratory XRPD instrumentation.

On pattern matching of X-ray powder diffraction data.

We introduce a novel pattern matching algorithm optimized for X-ray powder diffraction (XRPD) data and useful for data from other types of analytical techniques (e.g., Raman, IR).

Adsorption and structure of hydrocarbons in MCM-41: a computational study.

The adsorption of linear, branched, and cyclic hydrocarbons in MCM-41 is studied using Configurational Bias Monte Carlo simulations. A new computational model for MCM-41 is proposed which, although simple, is able to predict adsorption isotherms which are in agreement with the scarce experimental data. The structure of the adsorbed phase is analyzed and found to be similar to that of studies using small, hard spheres trapped in pores.

Modeling of transmitted X-ray intensity variation with sample thickness and solid fraction in glycine compacts.

The previous paper in this series introduced an X-ray diffraction quantitation method for the polymorphic content in tablets made of pure components. Before the method could be transferred, further studies were required to explain the commonly observed X-ray intensity variation in analyzing compacts. The literature typically attributes the variation to partial amorphization under compression and/or to preferred orientation, without much viable explanation or compelling evidence.

Quantitative determination of polymorphic composition in intact compacts by parallel-beam X-ray powder diffractometry.

This paper details the development of a method using parallel-beam X-ray powder diffractometry as a novel means of determining polymorphic composition in intact compacts. Two polymorphic systems, chlorpropamide and glycine, were selected. The polymorphic components were weighed, mixed, and compressed using a Carver press with 3/8-in.