Mechanistic Insights into Propylparaben Sorption on Polyvinyl Chloride.

The mechanism of loss of propylparaben potency from formulations when in contact with polyvinyl chloride has been determined. It is caused by the adsorption of propylparaben onto polyvinyl chloride surfaces. The adsorption kinetics is best described using a pseudo-second order model based on non-linear fit. The rate of adsorption increases with increasing bulk concentration of propylparaben. Adsorption equilibrium isotherm was fitted to three isotherm models: Langmuir, Freundlich, and Temkin, using non-linear fit. The Freundlich and Temkin models show the best fit, indicating a multi-layer adsorption. Using this case study, we present a methodology to provide mechanistic insights into the compatibility data between pharmaceutical ingredients and product contact materials when sorption is involved.

Evaluation of the Pharmacokinetics and Safety of AMG 986 Tablet and Capsule Formulations in Healthy Adult Subjects: A Phase I, Open-Label, Randomized Study.

BACKGROUND AND OBJECTIVE: AMG 986 is a first-in-class, novel apelin receptor small molecule agonist initially developed for the treatment of heart failure. The current phase I study was conducted to evaluate the pharmacokinetics and safety of a single-dose 200-mg capsule formulation of AMG 986 relative to the tablet formulation in 12 healthy subjects. METHODS: In a two-period, two-way crossover design, eligible subjects were randomized 1:1 to tablet/capsule or capsule/tablet treatment sequences; each treatment sequence lasted for approximately 6 days and comprised six subjects. RESULTS: Following a single oral dose of AMG 986, the geometric mean maximum observed concentration (Cmax) values were 9670 ng/mL and 6920 ng/mL and the geometric mean area under the curve from time zero to 120 h (AUC0-120h) values were 68,000 ng*h/mL and 59,900 ng*h/mL for the tablet and capsule, respectively. The geometric least squares means (90% confidence interval [90% CI]) for the ratios of capsule/tablet were 0.88 (90% CI 0.81-0.96) and 0.72 (90% CI 0.57-0.91) for AUC0-120h and Cmax, respectively. AMG 986 had an acceptable safety profile; all adverse events were grade 1 or 2 in severity. CONCLUSION: There was a modest 12% decrease in AUC0-120h and a 28% decrease in Cmax with the AMG 986 capsule versus the tablet. These differences are not considered to be clinically relevant, suggesting the capsule formulation can be used in subsequent clinical studies of AMG 986.

The application of machine learning algorithms in understanding the effect of core/shell technique on improving powder compactability.

This study systemically investigated the application of core/shell technique to improve powder compactability. A 28-run Design-of-Experiment (DoE) was conducted to evaluate the effects of the type of core and shell materials and their concentrations on tensile strength and brittleness index. Six machine learning algorithms were used to model the relationships of product profile outputs and raw material attribute inputs: response surface methodology (RSM), Support Vector Machine (SVM), and four different types of artificial neural networks (ANN), namely, Backpropagation Neural Network (BPNN), Genetic Algorithm Based BPNN (GA-BPNN), Mind Evolutionary Algorithm Based BPNN (MEA-BPNN), and Extreme Learning Machine (ELM). Their predictive and generalization performance were compared with the training dataset as well as an external dataset. The results indicated that the core/shell technique significantly improved powder compactability over the physical mixture. All machine learning algorithms being evaluated provided acceptable predictability and capability of generalization; furthermore, the ANN algorithms were shown to be more capable of handling convoluted and non-linear patterns of dataset (i.e. the DoE dataset in this study). Using these models, the relationship of product profile outputs and raw material attribute inputs were disclosed and visualized.

Humidity induced phase transformation of poloxamer 188 and its effect on physical stability of amorphous solid dispersion of AMG 579, a PDE10A inhibitor.

Poloxamer 188, a commonly used emulsifying and solubilizing agent, was found to be the cause of crystallization of an investigational drug, AMG 579, from its amorphous solid dispersion at accelerated storage conditions. Investigation of this physical stability issue included thorough characterization of poloxamer 188 at non-ambient conditions. At 40°C, poloxamer 188 becomes deliquescent above relative humidity of 75%. Upon returning to ambient conditions, the deliquescent poloxamer 188 loses water and re-solidifies. The reversible phase transformation of poloxamer 188 may cause physical and chemical stability issues and this risk should be assessed when selecting it as an excipient for formulation development.

Conformational isomerism in solid state of AMG 853--structure studies using solid-state nuclear magnetic resonance and X-ray diffraction.

Investigation of an additional resonance peak in the (19) F solid-state nuclear magnetic resonance (NMR) spectrum of AMG 853, a dual antagonist of DP and CRTH2 previously in clinical development for asthma, has led to the identification of two conformational isomers coexisting in the crystal lattice in a continuous composition range between 89.7%:10.3% and 96.5%:3.5%. These two isomers differ in the chloro-flurorophenyl moiety orientation-the aromatic ring is flipped by 180° in these two isomers. The level of the minor isomer is directly measured through integration of the two peaks in the (19) F solid-state NMR spectrum. The values obtained from the NMR data are in excellent agreement with the degree of disorder of the fluorine atom in the crystal structure, refined using both single-crystal and high-resolution powder X-ray diffraction data.

Structural studies of a non-stoichiometric channel hydrate using high resolution X-ray powder diffraction, solid-state nuclear magnetic resonance, and moisture sorption methods.

Structural investigations of a nonstoichiometric hydrate, AMG 222 tosylate, a DPP-IV inhibitor in clinical development for type II diabetes, were performed using a multitechnique approach. The moisture sorption isotherm is in good agreement with a simple Langmuir model, suggesting that the hydrate water is located in well-defined crystallographic sites, which become vacant during dehydration. Crystal structures of AMG 222 tosylate at ambient and dry conditions were determined from high-resolution X-ray diffraction using the direct space method. On the basis of these crystal structures, hydrated water is located in channels formed by the drug framework. Upon dehydration, an isostructural dehydrate is formed with the channels remaining void and accessible to water for rehydration. Kitaigorodskii packing coefficients of the solid between relative humidity of 0% and 90% indicate that the equilibrium form of AMG 222 tosylate is the fully hydrated monohydrate.

Crystal structure study and investigation of solid-state cyclization for AMG 222, a channel hydrate.

In this study, we investigate the solid-state structure and stability of AMG 222 (5-(2-[2-(2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-propyl)-5-(1H-tetrazol-5-yl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2,8 dicarboxylic acid bisdimethylamide), a small molecule DPP-IV inhibitor. Crystal structure of AMG 222 has been solved from single crystal X-ray analysis. Crystallographic data are as follows: monoclinic, P2(1) (no. 4), a=9.0327(5)Å, b=18.6177(8)Å, c=21.4927(10)Å, ß=90.126(3)°, V=3614.4(3)Å(3), Z=4. Based on single crystal structure, AMG 222 is a pentahydrate with the water molecules sitting in channels formed by the drug framework. There are three distinct crystal structures of AMG 222 between 0 and 95% relative humidity (RH), namely the anhydrate, hemihydrate, and pentahydrate forms. Solid-state stability of the GMP batch showed a high level of cyclized degradation product. It was postulated that the degradation was promoted by increased amorphous content generated as a result of excessive drying that was employed to remove residual crystallization solvent. Material produced using a modified procedure using a humidified nitrogen purge had lower amorphous content and lower levels of cyclic degradation when compared to the GMP batch.

Structure- and property-based design of aminooxazoline xanthenes as selective, orally efficacious, and CNS penetrable BACE inhibitors for the treatment of Alzheimer's disease.

A structure- and property-based drug design approach was employed to identify aminooxazoline xanthenes as potent and selective human ß-secretase inhibitors. These compounds exhibited good isolated enzyme, cell potency, and selectivity against the structurally related aspartyl protease cathepsin D. Our efforts resulted in the identification of a potent, orally bioavailable CNS penetrant compound that exhibited in vivo efficacy. A single oral dose of compound 11a resulted in a significant reduction of CNS Aß40 in naive rats.

Enhancing and sustaining AMG 009 dissolution from a matrix tablet via microenvironmental pH modulation and supersaturation.

The objective of this study was to investigate the combined effect of pH modifiers and nucleation inhibitors on enhancing and sustaining the dissolution of AMG 009 tablet via supersaturation. Several bases and polymers were added as pH modifiers and nucleation inhibitors, respectively, to evaluate their impact on the dissolution of AMG 009 tablets. The results indicate that sodium carbonate, among the bases investigated, enhanced AMG 009 dissolution the most. HPMC E5 LV, among the nucleation inhibitors tested, was the most effective in sustaining AMG 009 supersaturation. The release of AMG 009 went from 4% for tablets which did not contain both sodium carbonate and HPMC E5 LV to 70% for the ones that did, resulting in a 17.5-fold increase in the extent of dissolution. The effect of compression force and disintegrant on the dissolution of tablets were also evaluated. The results indicate that compression force had no effect on AMG 009 release. The addition of disintegrating agents, on the other hand, decreased the dissolution of AMG 009.

Improved pharmacokinetics of AMG 517 through co-crystallization. Part 1: comparison of two acids with corresponding amide co-crystals.

The dissolution and pharmacokinetics (PK) of two carboxylic acid co-crystals (cinnamic acid and benzoic acid) with the corresponding amide co-crystals (cinnamamide and benzamide) of AMG 517 were investigated. Powder and intrinsic dissolution studies were performed in fasted simulated intestinal fluid (FaSIF). Suspension formulations in 1% polyvinylpyrrolidone K25 in water were administered orally at 100 mg/kg to rats. The four co-crystals were found to have faster intrinsic and powder dissolution rates in FaSIF than the free base. This correlated with a 2.4- to 7.1-fold increase in the area under the concentration-time curve in rat PK investigations. When contrasting the acid to its corresponding amide co-crystal, cinnamamide shows improvement over cinnamic acid, while benzamide and benzoic acid perform similarly.

Calculation of effective penetration depth in X-ray diffraction for pharmaceutical solids.

The use of the glancing incidence X-ray diffraction configuration to depth profile surface phase transformations is of interest to pharmaceutical scientists. The Parratt equation has been used to depth profile phase changes in pharmaceutical compacts. However, it was derived to calculate 1/e penetration at glancing incident angles slightly below the critical angle of condensed matter and is, therefore, applicable to surface studies of materials such as single crystalline nanorods and metal thin films. When the depth of interest is 50-200 microm into the surface, which is typical for pharmaceutical solids, the 1/e penetration depth, or skin depth, can be directly calculated from an exponential absorption law without utilizing the Parratt equation. In this work, we developed a more relevant method to define X-ray penetration depth based on the signal detection limits of the X-ray diffractometer. Our definition of effective penetration depth was empirically verified using bilayer compacts of varying known thicknesses of mannitol and lactose.

Multiple approaches to pharmaceutical polymorphism investigation--a case study.

Polymorph screening of Compound A, an investigational drug, revealed two anhydrous polymorphs (Forms I and II) and two monohydrates (Forms III and IV) of this pharmaceutical solid. The physiochemical properties of the four forms were characterized by thermal analysis, hot-stage microscopy, equilibrium solubility and intrinsic dissolution rate measurements, and X-ray powder diffraction. Inter-conversion relationship of the four forms was fully elucidated. Thermodynamic stability relationship was inferred from melting data for Form I and Form II and evaluated by van't Hoff plot for Form III and Form IV. Form I and Form III were found to be the more stable anhydrous and hydrate form, respectively. Anhydrous Form I was selected for further pharmaceutical development.

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.

Quantification of compaction-induced crystallinity reduction of a pharmaceutical solid using 19F solid-state NMR and powder X-ray diffraction.

(19)F solid-state nuclear magnetic resonance (NMR) was investigated as an analytical technique to quantify the amorphous phase in a fluorine-containing pharmaceutical candidate. The crystallinity of Compound 1 was calculated using two (19)F T(1) relaxation-based methods. The first method employs both the pure amorphous and the crystalline reference standards while the second method is model independent and utilizes a single standard. The (19)F solid-state NMR results were confirmed with powder X-ray diffraction methods. From X-ray diffraction data, two linear calibration curves were obtained from blends of crystalline and amorphous Compound 1: one is based on the total integrated intensity of selected diffraction peaks and the other on the total intensity of the amorphous halo at 2theta positions that have no interference from crystalline diffraction peaks. The crystallinity of Compound 1 after compaction calculated by both (19)F solid-state NMR methods was in excellent agreement with the results from the X-ray calibration curves. (19)F solid-state NMR was shown to be a powerful technique in determining the amount of amorphous phase present in a pharmaceutical solid.

Crystal structure, crystal morphology, and surface properties of an investigational drug.

In this study we investigated the correlations between the single crystal structure, the crystal habit and morphology, and surface energetics of an investigational pharmaceutical compound. Crystal structures of both the anhydrous form (Form A) and monohydrate form (Form B) have been solved from single crystal X-ray analysis. The external morphology of Form A solid was predicted by molecular modeling using attachment energies to be thick plate-like with two dominant faces (100) and (002). The external morphology of Form B was predicted to be needle-like with a dominant face (101 ). The predicted morphologies were confirmed by optical micrographs and the Miller indices of the dominant faces were complemented by X-ray powder diffraction (XRPD) method. Contact angle measurements showed that the anhydrous form has better wettability as predicted from crystal structure and morphology.

On the identification of slip planes in organic crystals based on attachment energy calculation.

Knowledge of slip or cleavage planes can facilitate the fundamental understanding of mechanical properties of organic crystals important to pharmaceutical operations, such as tableting and milling. Slip/cleavage planes were frequently assigned based on attachment energy calculation. These crystallographic planes can also be identified by visualization of crystals characterized by stacking layers of high molecular density and often strengthened by two-dimensional hydrogen bonding network. Using 14 organic crystals exhibiting such layered structures, predicted slip planes by attachment energy calculation employing three force fields, Dreiding, cvff, and COMPASS, were compared to those identified by crystal structure visualization. Overall, slip/cleavage planes in <50% crystals were successfully predicted by attachment energy calculation. Thus predicted slip/cleavage planes by attachment energy calculation may not be always accurate and should be treated with caution.

Crystal structure and surface properties of an investigational drug--a case study.

In this study we investigate the correlations between the single crystal structure, the crystal habitat and morphology, and surface energetics of an investigational pharmaceutical compound. Crystal structure of this investigational pharmaceutical solid has been solved from single crystal X-ray analysis. Crystallographic data are as follows: triclinic, P1 (no. 1), a = 6.1511 (8) A, b = 13.5004 (18) A, c = 17.417 (2) A, alpha = 68.259 (2) degrees, beta = 80.188 (2) degrees, gamma = 82.472 (2) degrees, V = 1320.2 (3) A(3), Z = 2. The external morphology of this crystalline solid was predicted by molecular modelling using attachment energies to be thin-plate like with a dominant face (001). The predicted morphology was confirmed by scanning electron micrographs (SEM) and the Miller Index of the dominant face was complemented by X-ray powder diffraction (XRPD) method. The microscopic layering structures of crystals and surface stability of the dominant faces were investigated using atomic force microscopy (AFM). Contact angle measurement showed that the surface of the dominant face is hydrophilic as predicted from crystal structure.

Structure determination of enalapril maleate form II from high-resolution X-ray powder diffraction data.

The crystal structure of polymorphic Form II of enalapril maleate, a potent angiotensin-converting enzyme inhibitor, was determined from high-resolution X-ray diffraction data using the direct space method. Enalapril maleate Form II crystallizes in space group P2(1)2(1)2(1), Z = 4, with unit cell parameters a = 33.9898(3) A, b = 11.2109(1) A, c = 6.64195(7) A, and V = 2530.96(5) A(3). By treating the molecules as rigid bodies and using the bond lengths and angles obtained from the X-ray single crystal structures of Form I, which were solved almost 20 years ago, the total degrees of freedom of enalapril maleate were reduced from 25 to 12. This reduction in total degrees of freedom allowed the simulated annealing to complete within a reasonable computation time. In the crystal structure of Form II, the crystal packing, hydrogen-bonding pattern, and conformation of enalapril maleate resemble those in the structure of Form I. The crystal packing and conformation of enalapril maleate in the two polymorphic forms may explain the similarity of the thermal properties, (13)C nuclear magnetic resonance, Fourier transform infrared, and Raman spectra of Forms I and II. In both structures, the conformations of the main peptide chains, which are considered responsible for binding the active angiotensin-converting enzyme sites, remain largely unchanged. Lattice energy calculation showed that Form II is slightly more stable than Form I by 3.5 kcal/mole.

Ab initio structure determination of rofecoxib from powder diffraction data using molecular packing analysis method and direct space method.

Crystal structures of a COX-II inhibitor, rofecoxib (Vioxx) were solved ab initio from X-ray powder diffraction pattern using both molecular packing analysis and direct space methods. The X-ray powder pattern was indexed into a tetragonal cell. Packing energies were generated and analyzed in eight most frequently found tetragonal space groups. The two space groups with the lowest total energy, P4(1)2(1)2 and P4(3)2(1)2, were used for direct space method with a Monte-Carlo/Simulated Annealing searching algorithm. Structural solutions obtained from direct space method were evaluated using molecular packing energy analysis. The structures solved ab initio from this work were compared to the single crystal structure deposited in the Cambridge Structural Database.

Structure rationalization and topology prediction of two-distinct-component organic crystals: the role of volume fraction and interface topology.

We consider here small-length-scale crystal structures with two clearly different molecular components (e.g., hydrophobic and hydrophilic). Using a perspective developed by studies on large-length-scale block copolymers and liquid crystals, we focus on the crystalline interface between the two components. We examine four types of two-component crystals: aromatic ammonium carboxylates, aromatic oligo(ethylene oxides), cyclohexylammonium carboxylates, and ether-thioether compounds. Of the 111 crystal structures found in the Cambridge Structure Database (CSD), 108 adopt one of the five generic topologies found in diblock copolymers: spheres, columns, perforated layers, layers, and bicontinuous structures. As in diblock copolymers, a key factor controlling the interfacial topology is shown to be the volume ratio of the two components. When the volume fraction of one component is less than 30% of the whole, more than five-sixths of the examined crystal structures are of columnar or spherical type. For volume fractions between 40 and 50% more than three-quarters are of lamellar or bicontinuous type. We use this model to predict the topologies of small-length-scale two-component crystals. We predict the crystal topolgies of six new crystal structures: three are predicted to be columnar, and the other three, lamellar or bicontinuous. The crystal structures of these systems were then determined by single-crystal X-ray methods. Five of the structures form in topologies consistent with the predictions: three in columns and two in layers. The remaining one forms as a perforated layer instead of the predicted columnar structure. Such predictive accuracy is consistent with the statistics of the CSD investigation.