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. The aim of the present investigation was to test the hypothesis that the solid-state physical instability of LEVO precedes the chemical instability leading to product failure. The failure mode was hypothesized to be the dehydration of the crystal hydrate, when exposed to certain humidity and temperature conditions, followed by the oxidation of the API through vacated channels. It was previously reported by the authors that LEVO degradation occurred in the presence of oxygen at a low relative humidity (RH). Furthermore, powder X-ray diffractometry shows changes in the crystal lattice of LEVO initially and through the dehydration stages. Storage of LEVO at RT and 40 °C at 4-6% RH for 12 days shows a decrease in d-spacing of the (00 l) planes. Based on a structure solution from the powder data of the dehydrated material, the basic packing motif persists to varying degrees even when fully dehydrated along with disordering. Therefore, the crystal structure changes of LEVO depend on RH and temperature and are now explicable at the structural level for the first time. This exemplifies the dire need for "new prior knowledge" in generic product development.

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. The dissolution behavior of the pure polymorphs and the resulting granules was determined using in-situ fiber optic UV testing system. An XRPD quantitation method using Excel full pattern fitting was developed to determine the concentration of each constituent (amorphous, α and γ indomethacin and PEG) in samples collected from each functioning zone and in granules. RESULTS: Analysis of in-process samples and granules revealed that higher temperature (≥130°C) and shear stress accelerated the process induced phase transitions from amorphous and/or the α form to γ indomethacin during heating stage. However, rapid cooling resulted in an increased percentage of the α form allowing isolation of the meta-stable form. CONCLUSIONS: By determining the conditions that either prevent or facilitate process induced transformations of IMC polymorphs during melt granulation, a design space was developed to control the polymorph present in the resulting granules. This represents the conditions necessary to balance the thermodynamic relationships between the polymorphs of the IMC system and the kinetics of the possible transformations as a function of the processing stresses.

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. ΔH of the endotherm showed strong heating rate dependence. Variable temperature XRPD (25-160 °C) revealed structure loss in GNE068-PC, suggesting the endotherm to be an "apparent melt". In addition, gentle grinding of GNE068-PC in a mortar led to a marked decrease in XRPD peak intensities, indicating a "soft" crystalline lattice. Computational analysis of XRPD data revealed the presence of two noncrystalline contributions, one of which was associated with GNE068-A. The second was a variable component that could be modeled as diffuse scattering from local disorder within the associated crystal structure, suggesting a mesomorphous system. Owing to the dominance of the noncrystalline diffuse scattering in GNE068-PC and the observed lattice deformation, the mesomorphous phase exhibited properties consistent with a conformationally disordered mesophase. Because of the intimate association of the residual solvent (ethyl acetate) with the lattice long-range order, loss of solvent on heating through the glass transition temperature of the local disorder caused irrecoverable loss of the long-range order. This precluded the observation of characteristic thermodynamic mesophase behavior above the glass transition temperature.

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 glutamate­glutamate interactions and providing further insight into glutamate­water interactions. In particular we have characterised the solution structure using three different water potentials, finding little difference between the structural features they predict. We find key differences in the bonding motifs for the two different carboxyl groups, both in the glutamate­glutamate and glutamate­water interactions. Finally, we have examined the hydration structure of the sodium ions in the solution, showing that 10% of the ions are fully hydrated by water, despite the high glutamate concentration.

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. Pair Distribution Functions (PDFs) of the components in the dispersion were determined from the PXRD data, and the pure curves of the components were also extracted from PXRD data using the Pure Curve Resolution Method (PCRM) and compared against experimentally obtained results. RESULTS: Molecular-level mixing over the complete range of concentration was verified for nifedipine-PVP and felodipine-PVP. For felodipine-PAA, drug-polymer immiscibility was verified for samples containing 30 to 70% polymer, while IR results suggest at least some level of mixing for samples containing 10 and 90% polymer. For ketoconazole-PVP system, partial miscibility is suspected, whereby the presence of one-phase amorphous solid dispersion system could only be unambiguously verified at higher concentrations of polymer. CONCLUSIONS: The three techniques mentioned complement each other in establishing drug-polymer miscibility in amorphous solid dispersion systems. In particular, IR spectroscopy and PXRD are sensitive to changes in local chemical environments and local structure, which makes them especially useful in elucidating the nature of miscibility in binary mixtures when DSC results are inconclusive or variable.

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(µ3-4,4-diphenyl-2,5-dioxoimidazolidin-1-ido)trimethanoltrisodium(I)], [Na3(C15H11N2O2)3(CH4O)3(H2O)1.08]n, 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(C15H11N2O2)(CH3OH)x(H2O)y for each of the three segments (x, y = 0 or 1; x + y = 1 or 2). Modulation along the b axis is introduced due to the presence or absence of water or methanol molecules at sodium and by the alternating torsion angles of one of the two phenytoin phenyl rings. Individual segments within the asymmetric unit are linked by covalent Na-O and Na-N bonds, with each sodium ion coordinated to one anionic amide N atom and three keto O atoms. The Na-N and one of the Na-O bonds connect (C15H11N2O2)·Na units along the modulation direction, creating an infinite [(C15H11N2O2)·Na]n chain that is further stabilized by intramolecular N-H...O hydrogen bonding parallel to [010]. The second Na-O bond connects this chain with a symmetry-equivalent copy of itself created by a screw-axis operation, yielding double strands of [(C15H11N2O2)·Na]n chains. Two of these double strands, propagating in opposite directions, constitute the content of the unit cell. Neighboring double strands are connected with each other to form layers perpendicular to the a axis, tethered together via O-H...O hydrogen bonds involving the water and methanol molecules. In addition to modulation, each of the repeat units also exhibits disorder of the modulated segments. Phenyl rings of each repeat unit are rotationally disordered, and sodium-coordinated methanol and water molecules are also positionally disordered and/or partially occupied. The solvated structure reported here, while not matching the patterns reported for any of the known forms of phenytoin sodium, does provide a first insight into the complications and complexities involved in resolving the structure of anhydrous phenytoin sodium.

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. Throughout the dehydration process, when crystalline material was observed, the average long-range crystal structure remained isostructural with the original pentahydrate material. Although the space group symmetry remained unchanged by dehydration, the c-axis of the crystal unit cell exhibited an abrupt discontinuity after approximately 2 h of drying (loss of one to two water molecules). Analysis of diffuse X-ray scattering revealed an initial rapid build up of defects during the first 0.5 h with no evidence of any amorphous material. From 1-2 h of drying out to 8 h where the crystalline structure is last observed, the diffuse scattering has both amorphous and defect contributions. After 24 h of drying, there was no evidence of any crystalline material remaining. It is concluded that the removal of the first two waters from raffinose pentahydrate created defects, likely in the form of vacancies, that provided the thermodynamic driving force and disorder for subsequent conversion to the completely amorphous state.

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.

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. Water-mediated NMA contacts are a feature of this regime, manifested by an unexpected increase in the number of short NMA oxygen contacts arising from water bridge motifs. In contrast, bulk water structure is significantly disrupted by the addition of even small quantities of NMA. With increases in NMA concentration water molecules become progressively more isolated, forming dimers and trimers hydrogen-bonded to NMA. The mixture in this concentration regime may therefore offer a minimal model system for certain structural properties of interior water buried in protein cavities and hydrogen-bonded to mainchain peptide groups.

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). The algorithm is based on hierarchical clustering with a similarity metric that compares peak positions using the full peak profile. It includes heuristics developed from years of experience manually matching XRPD data, and preprocessing algorithms that reduce the effects of common problems associated with XRPD (e.g., preferred orientation and poor particle statistics). This algorithm can find immediate application in automated polymorph screening and salt selection, common tasks in the development of pharmaceuticals.

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. The structural and macroscopic properties were correlated qualitatively [principal component analysis (PCA)] and quantitatively [standard least square regression (SLSR)] with the tablet mechanical strength (TMS). These analyses revealed that the differences correlated with amylose-amylopectin content, particle density, compression mechanisms, and TMS between the starch grades. Univariate analysis proved lacking; however, PCA identified the particle size, moisture content, percent crystallinity, amylose-amylopectin ratio, and YP of plastic deformation and elastic recovery as the main factors influencing the starch TMS. SLSR quantified the positive influence of Fourier transform infrared spectra absorbance ratio at 1022-1003 and YP of the immediate elastic recovery, and the negative contribution of amylopectin content on the TMS. Therefore, starch amylose and amylopectin content, crystallinity, and lower elastic recovery are mainly responsible for better TMS.

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. In this study, changes in intensity in compacts analyzed in transmission geometry were found to be primarily a function of sample thickness and solid fraction. A theoretical model was developed to describe the X-ray powder diffraction (XRPD) intensity as a function of solid fraction, mass absorption coefficient, and thickness. The model was tested on two sets of glycine compacts: one with varying thickness at constant solid fraction, and the other with various solid fractions at a given thickness. The results show that the model predicts the XRPD intensity at any given sample thickness and solid fraction. With this model, the intensity variation of compacts made under different compression conditions can be normalized, making the method transferable to various tablet geometries and facilitating the analysis over expected ranges of formulation and process variation.

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. concave tooling. The compacts were then analyzed using parallel-beam X-ray powder diffractometry in transmission geometry. The data were processed using the profile-fitting module in the Shimadzu XRD-6000 software V 4.1 (for NT 4.0/98). The integrated intensity ratio of a selected peak for each crystal form was used for quantitation of each polymorph. Excellent linear correlation was observed for both polymorphic systems. The convex shape of the compact surface had no effect on the XRD patterns. Since parallel-beam X-ray diffractometry is not sensitive to the shape of the sample surface, it provides a simple method for quantifying polymorphs in intact compacts. Further work to extend this to formulated tablets is ongoing. The relatively larger variation in one of the peaks in the chlorpropamide study was found to be consistent with the computational analysis of the slip behavior of the stable polymorph. This method provides the first reported non-invasive X-ray diffraction pattern quantitation of crystal forms in intact compacts.

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. The XRPD results show that the position of the high- and low-angle halos for PVP change with the sorption of water. The corresponding characteristic scattering distances display a strong correlation with the measured water content and to T(g). Chemometric analysis was also performed to extract water content information from XRPD data and obtained results are correlated with the values measured gravimetrically, which lends support for the apparent clustering of water in PVP drawn by other techniques.

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. The methods were limited by the need for reference XRPD patterns of both the amorphous drug and excipient. In this work, we propose two additional computational approaches that overcome that limitation and can be used to quantify the degree of miscibility in an amorphous dispersion. The first approach is based on the use of a Pure Curve Resolution Method to extract unknown amorphous references as well as qualify miscibility. The second method, based on Alternate Least Squares, can then be used to quantify the degree of miscibility by determining the nearest neighbor (NN) coordination number for the active pharmaceutical ingredient (API) and excipient. It is proposed that the NN coordination number is related to physical stability.

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). The DSC thermograms of cryo-milled griseofulvin showed a complex exothermic event at around 65 degrees C for the 30min cryo-milled sample and around 75 degrees C for the 60min cryo-milled sample. A glass transition event was not observed for the cryo-milled samples. This is in direct contrast to the X-ray amorphous griseofulvin sample prepared through the quench melt method The XRPD patterns of cryo-milled griseofulvin show a loss of the crystalline Bragg peaks and a corresponding increase in diffuse scattering (halos). The disordered griseofulvin material produced through cryo-milling appears X-ray amorphous, yet different from the amorphous phase produced using the quench melt method. Both X-ray amorphous materials have distinctive DSC thermograms and X-ray powder patterns. These findings suggest that the evolution of the griseofulvin crystal structure during cryo-milling is not simply a crystal-to-amorphous transition but a transition to an intermediate mesophase.

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. A lack of agreement of the PDF profiles indicates that the mixture with a unique PDF is miscible. In agreement with DSC measurements that detected two independent T(g) values for the dextran-PVP mixture, the PDF profiles of the mixture matched very well indicating a phase separated system. From the PDF analysis, indomethacin-PVP was shown to be completely miscible in agreement with the single T(g) value measured for the mixture. In the case of the trehalose-dextran mixture, where only one T(g) value was detected, however, PDF analysis clearly revealed phase separation. Since DSC can not detect two T(g) values when phase separation produces amorphous domains with sizes less than approximately 30 nm, it is concluded that the trehalose-dextran system is a phase separated mixture with a structure equivalent to a solid nanosuspension having nanosize domains. Such systems would be expected to have properties intermediate to those observed for miscible and macroscopically phase separated amorphous dispersions. However, since phase separation has occurred, the solid nanosuspensions would be expected to exhibit a greater tendency for physical instability under a given stress, that is, crystallization, than would a miscible system.

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. include solid form development of an active pharmaceutical ingredients. (APIs) are PatternMatch software and capillary-based crystallisation techniques that not only allow for fast and effective solid form screening, but also extract maximum property information from the routine screening data that is generally available. These new technologies offer knowledge-based decision making during solid form development of APIs and result in more developable API solid forms.

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. Analysis of the data were carried out using a combination of direct methods, such as pair distribution functions (PDF), and indirect material modeling techniques including Rietveld, total scattering, and amorphous packing. RESULTS: The observation of X-ray amorphous powder patterns may indicate the presence of amorphous, glassy or disordered nanocrystalline material in the sample. Rietveld modeling of microcrystalline cellulose (Avicel PH102) indicates that it is predominantly disordered crystalline cellulose Form Ibeta with some amorphous contribution. The average crystallite size of the disordered nanocrystalline cellulose was determined to be 10.9 nm. Total scattering modeling of ground samples of alpha, gamma, and delta crystal forms of indomethacin in combination with analysis of the PDFs provided a quantitative picture of the local structure during various stages of grinding. For all three polymorphs, with increased grinding time, a two-phase system, consisting of amorphous and crystalline material, continually transformed to a completely random close packed (RCP) amorphous structure. The same pattern of transformation was detected for the Form I polymorph of piroxicam. However, grinding of Form II of piroxicam initially produced a disordered phase that maintained the local packing of Form II but over a very short nanometer length scale. The initial disordered phase is consistent with continuous random network (CRN) glass material. This initial disordered phase was maintained to a critical point when a transition to a completely amorphous RCP structure occurred. CONCLUSIONS: Treating X-ray amorphous powder patterns with different solid-state models, ranging from disordered nanocrystalline to glassy and amorphous, resulted in the assignment of structures in each of the systems examined. The pharmaceutical implications with respect to the stability of the solid are discussed.

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. The adsorption of mixtures is investigated, and the adsorption hierarchy is discussed. The structure of the adsorbed mixture is revealed and shows that all components of the mixture exhibit structure, even if they are only adsorbed in small quantities. Finally, the model is modified to include surface roughness and the effect on the adsorption isotherms and structure of the adsorbed phase is discussed.