Drug-Polymer Interactions in Acetaminophen/Hydroxypropylmethylcellulose Acetyl Succinate Amorphous Solid Dispersions Revealed by Multidimensional Multinuclear Solid-State NMR Spectroscopy.

The bioavailability of insoluble crystalline active pharmaceutical ingredients (APIs) can be enhanced by formulation as amorphous solid dispersions (ASDs). One of the key factors of ASD stabilization is the formation of drug-polymer interactions at the molecular level. Here, we used a range of multidimensional and multinuclear nuclear magnetic resonance (NMR) experiments to identify these interactions in amorphous acetaminophen (paracetamol)/hydroxypropylmethylcellulose acetyl succinate (HPMC-AS) ASDs at various drug loadings. At low drug loading (<20 wt %), we showed that 1H-13C through-space heteronuclear correlation experiments identify proximity between aromatic protons in acetaminophen with cellulose backbone protons in HPMC-AS. We also show that 14N-1H heteronuclear multiple quantum coherence (HMQC) experiments are a powerful approach in probing spatial interactions in amorphous materials and establish the presence of hydrogen bonds (H-bond) between the amide nitrogen of acetaminophen with the cellulose ring methyl protons in these ASDs. In contrast, at higher drug loading (40 wt %), no acetaminophen/HPMC-AS spatial proximity was identified and domains of recrystallization of amorphous acetaminophen into its crystalline form I, the most thermodynamically stable polymorph, and form II are identified. These results provide atomic scale understanding of the interactions in the acetaminophen/HPMC-AS ASD occurring via H-bond interactions.

A Case of Torsion of the Gallbladder Suspected with SPECT-CT: Review and Recommendations.

Torsion or volvulus of the gallbladder is a rare situation that rapidly progresses to gangrene and linked with a poor prognosis, even death, if unrecognized and untreated. An interesting and rare case of gallbladder volvulus in which diagnosis was obtained by comparing CT images and HIDA scan with SPECT-CT is presented. Relevant literature is reviewed, and recommendations are outlined.

Mass Transport Analysis of the Enhanced Buffer Capacity of the Bicarbonate-CO2 Buffer in a Phase-Heterogenous System: Physiological and Pharmaceutical Significance.

The bicarbonate buffer capacity is usually considered in a phase-homogeneous system, at equilibrium, with no CO2 transfer between the liquid buffer phase and another phase. However, typically, an in vitro bicarbonate buffer-based system is a phase-heterogeneous system, as it entails continuously sparging (bubbling) the dissolution medium with CO2 in a gas mixture, at constant ratio, to maintain a constant partial pressure of CO2 (g) and CO2(aq) molarity at a prescribed value, with CO2 diffusing freely between the gas and the aqueous phases. The human gastrointestinal tract is also a phase-heterogeneous system, with CO2 diffusing across the mucosal membrane into the mesenteric arterial blood, which serves as a sink for CO2 from the intestinal lumen. In this report, a mass transport analysis of the apparent buffer capacity of a phase-heterogeneous bicarbonate-CO2 system is developed. It is shown that, most significantly, a phase-heterogeneous bicarbonate-CO2 system can have a much higher buffer capacity than a phase-homogeneous system such that the buffer capacity is dependent on the bicarbonate concentration. It is double that of a phase-homogeneous system at the pH = p Ka for a monoprotic buffer at the same concentration. This buffer capacity enhancement increases hyperbolically with pH above the p Ka, thus providing a much stronger buffering to keep the pH in the physiologically neutral range. The buffer capacity will be dependent on the bicarbonate molarity (which in vivo will depend on the bicarbonate secretion rate) and not the pH of the luminal fluid. Further, there is no conjugate acid accumulation as a result of bicarbonate neutralization, since the resulting carbonic acid (H2CO3) rapidly dehydrates producing CO2 and H2O. The mass transport analysis developed in this report is further supported by in vitro experimental results. This enhanced bicarbonate buffer capacity in a phase-heterogeneous system is of physiological significance as well as significant for the dissolution and absorption of ionizable drugs.

Characterization of Phase Separation Propensity for Amorphous Spray Dried Dispersions.

A generalized screening approach, applying isothermal calorimetry at 37 °C 100% RH, to formulations of spray dried dispersions (SDDs) for two active pharmaceutical ingredients (APIs) (BMS-903452 and BMS-986034) is demonstrated. APIs 452 and 034, with similar chemotypes, were synthesized and promoted during development for oral dosing. Both APIs were formulated as SDDs for animal exposure studies using the polymer hydroxypropylmethlycellulose acetyl succinate M grade (HPMCAS-M). 452 formulated at 30% (wt/wt %) was an extremely robust SDD that was able to withstand 40 °C 75% RH open storage conditions for 6 months with no physical evidence of crystallization or loss of dissolution performance. Though 034 was a chemical analogue with similar physical chemical properties to 452, a physically stable SDD of 034 could not be formulated in HPMCAS-M at any of the drug loads attempted. This study was used to develop experience with specific physical characterization laboratory techniques to evaluate the physical stability of SDDs and to characterize the propensity of SDDs to phase separate and possibly crystallize. The screening strategy adopted was to stress the formulated SDDs with a temperature humidity screen, within the calorimeter, and to apply orthogonal analytical techniques to gain a more informed understanding of why these SDDs formulated with HPMCAS-M demonstrated such different physical stability. Isothermal calorimetry (thermal activity monitor, TAM) was employed as a primary stress screen wherein the SDD formulations were monitored for 3 days at 37 °C 100% RH for signs of phase separation and possible crystallization of API. Powder X-ray diffraction (pXRD), modulated differential scanning calorimetry (mDSC), Fourier transform infrared spectroscopy (FTIR), and solid state nuclear magnetic resonance (ssNMR) were all used to examine formulated SDDs and neat amorphous drug. 452 SDDs formulated at 30% (wt/wt %) or less did not show phase separation behavior upon exposure to 37 °C 100% RH for 3 days. 034 SDD formulations from 10 through 50% (wt/wt %) all demonstrated thermal traces consistent with exothermic phase separation events over 3 days at 37 °C 100% RH in the TAM. However, only the 15, 30, and 50% containing 034 samples showed pXRD patterns consistent with crystalline material in post-TAM samples. Isothermal calorimetry is a useful screening tool to probe robust SDD physical performance and help investigate the level of drug polymer miscibility under a humid stress. Orthogonal analytical techniques such as pXRD, ssNMR, and FTIR were key in this SDD formulation screening to gain physical understanding and confirm or refute whether physical changes occur during the observed thermal events characterized by the calorimetric screening experiments.

Correlation of Phosphorus Cross-Linking to Hydration Rates in Sodium Starch Glycolate Tablet Disintegrants Using MRI.

Understanding the behavior of tablet disintegrants is valuable in the development of pharmaceutical solid dosage formulations. In this study, high-resolution magnetic resonance imaging has been used to understand the hydration behavior of a series of commercial sodium starch glycolate (SSG) samples, providing robust estimates of tablet disintegration rate that could be correlated with physicochemical properties of the SSGs, such as the extent of phosphorus (P) cross-linking as obtained from infra-red spectroscopy. Furthermore, elemental analysis together with powder X-ray diffraction has been used to quantify the presence of carboxymethyl groups and salt impurities, which also contribute to the disintegration behavior. The utility of Fast Low Angle SHot magnetic resonance imaging has been demonstrated as an approach to rapidly acquire approximations of the volume of a disintegrating tablet and, together with a robust voxel analysis routine, extract tablet disintegration rates. In this manner, a complete characterization of a series of SSG grades from different sources has been performed, showing the variability in their physicochemical properties and demonstrating a correlation between their disintegration rates and intrinsic characteristics. The insights obtained will be a valuable aid in the choice of disintegrant source as well as in managing SSG variability to ensure robustness of drug products containing SSG.

Polarization ellipse and Stokes parameters in geometric algebra.

In this paper, we use geometric algebra to describe the polarization ellipse and Stokes parameters. We show that a solution to Maxwell's equation is a product of a complex basis vector in Jackson and a linear combination of plane wave functions. We convert both the amplitudes and the wave function arguments from complex scalars to complex vectors. This conversion allows us to separate the electric field vector and the imaginary magnetic field vector, because exponentials of imaginary scalars convert vectors to imaginary vectors and vice versa, while exponentials of imaginary vectors only rotate the vector or imaginary vector they are multiplied to. We convert this expression for polarized light into two other representations: the Cartesian representation and the rotated ellipse representation. We compute the conversion relations among the representation parameters and their corresponding Stokes parameters. And finally, we propose a set of geometric relations between the electric and magnetic fields that satisfy an equation similar to the Poincaré sphere equation.

Solution-mediated phase transformation of salts during dissolution: investigation using haloperidol as a model drug.

Soluble salts can undergo solution-mediated phase transformation to a lower solubility form due to pH gradients in the gastrointestinal tract. Therefore, dissolution rate rather than solubility may be the best predictor of bioavailability for such compounds. The purpose of this project was to examine the kinetics of the conversion of a basic compound, haloperidol, and its salt forms using a flow-through dissolution apparatus and rotating disk method in neutral conditions. The effects of buffer concentration, salt form, dissolution apparatus, and hydrodynamics were examined. Raman microscopy was used to characterize solids after dissolution. Haloperidol mesylate and haloperidol chloride showed a decrease in dissolution rate with time in the dissolution media. Haloperidol mesylate and haloperidol chloride dissolution rates also decreased with increasing buffer capacity. Raman microscopy confirmed phase conversion from the salt forms to the free base form in phosphate buffer. Hydrodynamics did not affect the time course of the solution-mediated phase transformation of salt forms. Dissolution and precipitation appear to be a function of pH close to the surface of the dissolving solid. In situations where equilibrium solubility of salts cannot be assessed experimentally, dissolution experiments are useful for examining the extent and duration of the dissolution rate enhancement.

Oblique superposition of two elliptically polarized lightwaves using geometric algebra: is energy-momentum conserved?

In this paper, we use Clifford (geometric) algebra Cl(3,0) to verify if electromagnetic energy-momentum density is still conserved for oblique superposition of two elliptically polarized plane waves with the same frequency. We show that energy-momentum conservation is valid at any time only for the superposition of two counter-propagating elliptically polarized plane waves. We show that the time-average energy-momentum of the superposition of two circularly polarized waves with opposite handedness is conserved regardless of the propagation directions of the waves. And, we show that the resulting momentum density of the superposed waves generally has a vector component perpendicular to the momentum densities of the individual waves.

Toward an in vivo dissolution methodology: a comparison of phosphate and bicarbonate buffers.

The purpose of this research was to evaluate the difference between the pharmaceutical phosphate buffers and the gastrointestinal bicarbonates in dissolution of ketoprofen and indomethacin, to illustrate the dependence of buffer differential on biopharmaceutical properties of BCS II weak acids, and to recommend phosphate buffers equivalent to bicarbonates. The intrinsic dissolution rates of ketoprofen and indomethacin were experimentally measured using a rotating disk method at 37 degrees C in USP SIF/FaSSIF and various concentrations of bicarbonates. Theoretical models including an improved reaction plane model and a film model were applied to estimate the surrogate phosphate buffers equivalent to the bicarbonates. Experimental results show that the intrinsic dissolution rates of ketoprofen and indomethacin in USP and FaSSIF phosphate buffers are 1.5-3.0 times that in the 15 mM bicarbonates. Theoretical analysis demonstrates that the buffer differential is largely dependent on the drug pK(a) and second on solubility, and weakly dependent on the drug diffusivity. Further, in accordance with the drug pK(a), solubility and diffusivity, a simple phosphate surrogate was proposed to match an average bicarbonate value (15 mM) of the upper gastrointestinal region. Specifically, phosphate buffers of 13-15 mM and 3-4 mM were recommended for ketoprofen and indomethacin, respectively. For both ketoprofen and indomethacin, the intrinsic dissolution using the phosphate surrogate buffers closely approximated the 15 mM bicarbonate buffer. This work demonstrates the substantial difference between pharmaceutical phosphates and physiological bicarbonates in determining the drug intrinsic dissolution rates of BCS II weak acids, such as ketoprofen and indomethacin. Surrogate phosphates were recommended in order to closely reflect the in vivo dissolution of ketoprofen and indomethacin in gastrointestinal bicarbonates, which has significant implications for defining buffer systems for BCS II weak acids in developing in vitro bioequivalence dissolution methodology.

Use of a glutaric acid cocrystal to improve oral bioavailability of a low solubility API.

PURPOSE: The bioavailability of a development candidate active pharmaceutical ingredient (API) was very low after oral dosing in dogs. In order to improve bioavailability, we sought to increase the dissolution rate of the solid form of the API. When traditional methods of forming salts and amorphous material failed to produce a viable solid form for continued development, we turned to the non-traditional approach of cocrystallization. METHODS: A crystal engineering approach was used to design and execute a cocrystal screen of the API. Hydrogen bonding between the API and pharmaceutically acceptable carboxylic acids was identified as a viable synthon for associating multiple components in the solid state. A number of carboxylic acid guest molecules were tested for cocrystal formation with the API. RESULTS: A cocrystal containing the API and glutaric acid in a 1:1 molecular ratio was identified and the single crystal structure is reported. Physical characterization of the cocrystal showed that it is unique regarding thermal, spectroscopic, X-ray, and dissolution properties. The cocrystal solid is nonhygroscopic, and chemically and physically stable to thermal stress. Use of the cocrystal increased the aqueous dissolution rate by 18 times as compared to the homomeric crystalline form of the drug. Single dose dog exposure studies confirmed that the cocrystal increased plasma AUC values by three times at two different dose levels. CONCLUSIONS: APIs that are non-ionizable or demonstrate poor salt forming ability traditionally present few opportunities for creating crystalline solid forms with desired physical properties. Cocrystals are an additional class of crystalline solid that can provide options for improved properties. In this case, a crystalline molecular complex of glutaric acid and an API was identified and used to demonstrate an improvement in the oral bioavailability of the API in dogs.

Use of a physiologic bicarbonate buffer system for dissolution characterization of ionizable drugs.

PURPOSE: The aim of this study was to examine if sparging with CO2(g) could be used to establish stable biorelevant bicarbonate buffers, in aqueous medium, for use in dissolution characterization of low-solubility ionizable drugs. METHODS: Preparation of the bicarbonate-containing dissolution medium was monitored by use of a commercially available fiberoptic probe to measure the concentration of dissolved CO2(aq). Intrinsic dissolution measurements at 100 rpm, 37 degrees C for indomethacin and dipyridamole were performed using a rotating disk and UV detection at pH 6.8 and 5.0 in a USP dissolution vessel apparatus. RESULTS: Indomethacin dissolution at pH 6.8 was significantly impacted by the concentration of CO2(g) in the sparging gas. Dipyridamole flux at pH 6.8 was independent of buffer species or buffer concentrations studied. However, dipyridamole dissolution at pH 5 was also a strong function of the concentration of CO2(g) in the sparging gas. CONCLUSIONS: Stable bicarbonate biorelevant buffers could be established to perform intrinsic dissolution rate determinations for indomethacin and dipyridamole as long a continuous gas sparging of CO2(g) was used. Depending of the pH of the dissolution medium, the intrinsic dissolution rates of both indomethacin and dipyridamole were affected by the bicarbonate concentration. Sparging with CO2(g) to create physiologic buffers has a unique advantage over conventional buffers in that gas sparging serves as a continuous source of bicarbonate buffer species. This advantage was demonstrated by performing dissolution experiments at pH values typically associated with the fed state (pH 5) and applying relatively low CO2(g) pressures, resulting in bicarbonate concentrations less than 0.5 mM. It was demonstrated that CO2(g) sparging at a pH consistent with the fed state created an in-situ bicarbonate buffer at low concentrations, which had a significant impact on the dissolution of a basic drug such as dipyridamole.