Poly(vinylpyridine-co-vinylpyridine N-oxide) Excipients Mediate Rapid Dissolution and Sustained Supersaturation of Posaconazole Amorphous Solid Dispersions.

The chemical structure of excipients molecularly mixed in an amorphous solid dispersion (ASD) has a significant impact on properties of the ASD including dissolution behavior, physical stability, and bioavailability. Polymers used in ASDs require a balance between hydrophobic and hydrophilic functionalities to ensure rapid dissolution of the amorphous dispersion as well as sustained supersaturation of the drug in solution. This work demonstrates the use of postpolymerization functionalization of poly(vinylpyridine) excipients to elucidate the impact of polymer properties on the dissolution behavior of amorphous dispersions containing posaconazole. It was found that N-oxidation of pyridine functionalities increased the solubility of poly(vinylpyridine) derivatives in neutral aqueous conditions and allowed for nanoparticle formation which supplied posaconazole into solution at concentrations exceeding those achieved by more conventional excipients such as hydroxypropyl methylcellulose acetate succinate (HPMCAS) or Eudragit E PO. By leveraging these functional modifications of the parent poly(vinylpyridine) excipient to increase polymer hydrophilicity and minimize the effect of polymer on pH, a new polymeric excipient was optimized for rapid dissolution and supersaturation maintenance for a model compound.

Structural Modifications of Polyethylenimine to Control Drug Loading and Release Characteristics of Amorphous Solid Dispersions.

Crystalline drugs with low solubility have the potential to benefit from delivery in the amorphous form. The polymers used in amorphous solid dispersions (ASDs) influence their maximum drug loading, solubility, dissolution rate, and physical stability. Herein, the influence of hydrophobicity of crosslinked polyethylenimine (PEI) is investigated for the delivery of the BCS class II nonsteroidal anti-inflammatory drug flufenamic acid (ffa). Several synthetic variables for crosslinking PEI with terephthaloyl chloride were manipulated: solvent, crosslinking density, reactant concentration, solution viscosity, reaction temperature, and molecular weight of the hyperbranched polymer. Benzoyl chloride was employed to cap amine groups to increase the hydrophobicity of the crosslinked materials. Amorphous deprotonated ffa was present in all ASDs; however, the increased hydrophobicity and reduced basicity from benzoyl functionalization led to a combination of amorphous deprotonated ffa and amorphous neutral ffa in the materials at high drug loadings (50 and 60 wt %). All ASDs demonstrated enhanced drug delivery in acidic media compared to crystalline ffa. Physical stability testing showed no evidence of crystallization after 29 weeks under various relative humidity conditions. These findings motivate the broadening of polymer classes employed in ASD formation to include polymers with very high functional group concentrations to enable loadings not readily achieved with existing polymers.

High Bulk-Density Amorphous Dispersions to Enable Direct Compression of Reduced Tablet Size Amorphous Dosage Units.

Amorphous solid dispersions (ASDs) are an attractive option to improve the bioavailability of poorly water-soluble compounds. However, the material attributes of ASDs can present formulation and processability challenges, which are often mitigated by the addition of excipients albeit at the expense of tablet size. In this work, an ASD manufacturing train combining co-precipitation and thin film evaporation (TFE) was used to generate high bulk-density co-precipitated amorphous dispersion (cPAD). The cPAD/TFE material was directly compressed into tablets at amorphous solid dispersion loadings up to 89 wt%, representing a greater than 60% reduction in tablet size relative to formulated tablets containing spray dried intermediate (SDI). This high ASD loading was possible due to densification of the amorphous dispersion during drying by TFE. Pharmacokinetic performance of the TFE-isolated, co-precipitated dispersion was shown to be equivalent to an SDI formulation. These data highlight the downstream advantages of this novel ASD manufacturing pathway to facilitate reduced tablet size via high ASD loading in directly compressed tablets.

Densifying Co-Precipitated Amorphous Dispersions to Achieve Improved Bulk Powder Properties.

PURPOSE: Precipitation of amorphous solid dispersions has gained traction in the pharmaceutical industry given its application to pharmaceuticals with varying physicochemical properties. Although preparing co-precipitated amorphous dispersions (cPAD) in high-shear rotor-stator devices allows for controlled shear conditions during precipitation, such aggressive mixing environments can result in materials with low bulk density and poor flowability. This work investigated annealing cPAD after precipitation by washing with heated anti-solvent to improve bulk powder properties required for downstream drug product processing. METHODS: Co-precipitation dispersions were prepared by precipitation into pH-modified aqueous anti-solvent. Amorphous dispersions were washed with heated anti-solvent and assessed for bulk density, flowability, and dissolution behavior relative to both cPAD produced without a heated wash and spray dried intermediate. RESULTS: Washing cPAD with a heated anti-solvent resulted in an improvement in flowability and increased bulk density. The mechanism of densification was ascribed to annealing over the wetted Tg of the material, which lead to collapse of the porous co-precipitate structure into densified granules without causing crystallization. In contrast, an alternative approach to increase bulk density by precipitating the ASD using low shear conditions showed evidence of crystallinity. The dissolution rate of the densified cPAD granules was lower than that of the low-bulk density dispersions, although both samples reached concentrations equivalent to that of the spray dried intermediate after 90 min dissolution. CONCLUSIONS: Hot wash densification was a tenable route to produce co-precipitated amorphous dispersions with improved properties for downstream processing compared to non-densified powders.

Dissolution Behavior of Weakly Basic Pharmaceuticals from Amorphous Dispersions Stabilized by a Poly(dimethylaminoethyl Methacrylate) Copolymer.

Amorphous solid dispersions (ASDs) are a well-documented formulation approach to improve the rate and extent of dissolution for hydrophobic pharmaceuticals. However, weakly basic compounds can complicate standard approaches to ASDs due to pH-dependent solubility, resulting in uncontrolled drug release in gastric conditions and unstabilized supersaturated solutions prone to precipitation at neutral pH. This work examines the release mechanisms of amorphous dispersions containing model weakly basic pharmaceuticals posaconazole and lumefantrine from a basic poly(dimethylaminoethyl methacrylate) copolymer (Eudragit EPO) and compares their dissolution behavior with ASDs stabilized by acidic and neutral polymers to understand potential benefits to release from a basic polymeric stabilizer. It was found that dissolution of Eudragit EPO ASDs resulted in supersaturation under gastric conditions, which could be sustained upon adjustment to neutral pH. However, the dissolution behavior of Eudragit EPO ASDs was sensitive to the initial pH of the gastric media. For lumefantrine, elevated initial gastric pH resulted in precipitation of amorphous nanoparticles; for posaconazole, elevated gastric pH led to crystallization of the pharmaceutical from solution. This sensitivity to gastric pH was found to originate from the impact of Eudragit EPO on gastric pH and the solubility of each pharmaceutical in the first stage of dissolution. In total, these data illustrate benefits and liabilities for the use of Eudragit EPO for ASDs containing weak pharmaceutical bases to guide the design of robust pharmaceutical formulations.

Assessing the Role of Light Absorption in Laser Lithotripsy by Isotopic Substitution of Kidney Stone Materials.

Understanding the chemical characteristics of kidney stones and how the stone composition affects their fragmentation is key to improving clinical laser lithotripsy. During laser lithotripsy, two mechanisms may be responsible for stone fragmentation: a photothermal mechanism and/or microexplosion mechanism. Herein, we carry out an isotopic substitution of crystal H2O with D2O in calcium oxalate monohydrate and struvite stones to alter their optical properties to study the relationship between the absorption of the stones, at the wavelength of the Ho:YAG (2.12 µm) laser, and the fragmentation behavior. Changing the absorption of the stones at 2.12 µm changes the extent of fragmentation, whereas changing the absorption of the bulk medium has a negligible effect on fragmentation, leading to the conclusion that kidney stone ablation is dominated by a photothermal mechanism.

Inhibiting or Accelerating Crystallization of Pharmaceuticals by Manipulating Polymer Solubility.

Polymers play a central role in controlling the crystallization of pharmaceuticals with effects as divergent as amorphous form stabilization and the acceleration of crystallization. Here, using pyrazinamide and hydrochlorothiazide as model pharmaceuticals, it is demonstrated that the same functional group interactions are responsible for these opposing behaviors and that whether a polymer speeds or slows a crystallization can be controlled by polymer solubility. This concept is applied for the discovery of polymers to maintain drug supersaturation in solution: the strength of functional group interactions between drug and polymer is assessed through polymer-induced heteronucleation, and soluble polymers containing the strongest-interacting functional groups with drug are shown to succeed as precipitation inhibitors.

Effect of Polymer Hydrophobicity on the Stability of Amorphous Solid Dispersions and Supersaturated Solutions of a Hydrophobic Pharmaceutical.

Amorphous solid dispersions of pharmaceuticals often show improved solubility over crystalline forms. However, the crystallization of amorphous solid dispersions during storage, or from elevated supersaturation once dissolved, compromise the solubility advantage of delivery in the amorphous phase. To combat this phenomenon, polymer additives are often included in solid dispersions to inhibit crystallization; however, the optimal properties for polymer to stabilize against crystallization are not fully understood, and furthermore, it is not known how inhibition of precipitation from solution is related to the propensity of a polymer to inhibit crystallization from the amorphous phase. Here, polymers of varied hydrophobicity are employed as crystallization inhibitors in supersaturated solutions and amorphous solid dispersions of the BCS Class II pharmaceutical ethenzamide to investigate the chemical features of polymer that lead to long-term stability for a hydrophobic pharmaceutical. A postpolymerization functionalization strategy was employed to alter the hydrophobicity of poly( N-hydroxyethyl acrylamide) without changing physical properties such as number-average chain length. It was found that supersaturation maintenance for ethenzamide is improved by increasing the hydrophobicity of dissolved polymer in aqueous solution. Furthermore, amorphous solid dispersions of ethenzamide containing a more hydrophobic polymer showed superior stability compared to those containing a less hydrophobic polymer. This trend of increasing polymer hydrophobicity leading to improved amorphous stability is interpreted by parsing the effects of water absorption in amorphous solid dispersions using intermolecular interaction strengths derived from global structural analysis. By comparing the structure-function relationships, which dictate stability in solution and amorphous solid dispersions, the effect of hydrophobicity can be broadly understood for the design of polymers to impart stability throughout the application of amorphous solid dispersions.

Polymer-Mineral Composites Mimic Human Kidney Stones in Laser Lithotripsy Experiments.

Despite the widespread use of laser lithotripsy to fragment kidney stones in vivo, there is a lack of robust artificial stone models to replicate the behavior of human stones during lithotripsy procedures. This need for accurate stone models is particularly important as novel laser technologies are introduced in the field of lithotripsy. In this work, we present a method to prepare composite materials that replicate the properties of human kidney stones during laser lithotripsy. Their behavior is understood through the lens of near-IR spectroscopy and helps to elucidate the mechanism of laser lithotripsy in kidney stone materials.

Probing the Interplay between Amorphous Solid Dispersion Stability and Polymer Functionality.

Amorphous solid dispersions containing a polymeric component often impart improved stability against crystallization for a small molecule relative to the pure amorphous form. However, the relationship between side chain functionalities on a polymer and the ability of a polymer to stabilize against crystallization is not well understood. To shed light on this relationship, a series of polymers were functionalized from a parent batch of poly(chloromethylstyrene- co-styrene) to investigate the effect of functionality on the stability in amorphous solid dispersions without altering the physical parameters of polymers, such as the average molecular weight or backbone chain chemistry. The kinetics of the crystallization of the nonsteroidal anti-inflammatory drug nabumetone from amorphous solid dispersions containing each functionalized polymer were interpreted on the basis of two interactions: hydrogen bonding between the drug and the polymer and the solubility of the polymer in the amorphous drug. It was found that hydrogen bonding between functionalized polymers and nabumetone can impart stability against crystallization, but only if the polymer shows significant solubility in amorphous nabumetone. Methylation of a protic functionality can improve the ability of a polymer to inhibit nabumetone crystallization by increasing the solubility in the drug, even when the resulting polymer lacks hydrogen bonding functionalities to interact with the pharmaceutical. Furthermore, factors, such as the glass transition temperature of pure polymers, were uncorrelated with isothermal nucleation rates. These findings inform a framework relating polymer functionality and stability deconvoluted from the polymer chain length or backbone chemistry with the potential to aid in the design of polymers to inhibit the crystallization of hydrophobic drugs from amorphous solid dispersions.

The covalent interaction between dihydrogen and gold: A rotational spectroscopic study of H2-AuCl.

The pure rotational transitions of H2-AuCl have been measured using a pulsed-jet cavity Fourier transform microwave spectrometer equipped with a laser ablation source. The structure was found to be T-shaped, with the H-H bond interacting with the gold atom. Both 35Cl and 37Cl isotopologues have been measured for both ortho and para states of H2. Rotational constants, quartic centrifugal distortion constants, and nuclear quadrupole coupling constants for gold and chlorine have been determined. The use of the nuclear spin-nuclear spin interaction terms Daa, Dbb, and Dcc for H2 were required to fit the ortho state of hydrogen, as well as a nuclear-spin rotation constant Caa. The values of the nuclear quadrupole coupling constant of gold are χaa=-817.9929(35) MHz, χbb=504.0(27) MHz, and χcc=314.0(27). This is large compared to the eQq of AuCl, 9.63 312(13) MHz, which indicates a strong, covalent interaction between gold and dihydrogen.

Influence of Chemical Functionality on the Rate of Polymer-Induced Heteronucleation.

Polymer-induced heteronucleation can dramatically increase the nucleation rate of pharmaceuticals. However, directly comparing the heteronucleation rates of different polymer functionalities is often convoluted with changing physical or structural aspects of heteronuclei. Here, we report a methodology for comparing nucleation efficiencies of different functionalities on polymer heteronuclei of uniform topology with the goal of identifying those functionalities that best accelerate nucleation of a model pharmaceutical. It was found that the previously employed design for additives to speed acetaminophen crystallization underperforms a modified framework that accounts for the effect of competitive solvent binding. These findings are informed by a survey of interactions from the CSD and not only serve to aid in the controlled crystallization of pharmaceuticals, but also provide insight into the mechanism of heteronucleation.

A Study of the Monohydrate and Dihydrate Complexes of Perfluoropropionic Acid Using Chirped-Pulse Fourier Transform Microwave (CP-FTMW) Spectroscopy.

This work reports the first known spectroscopic observation of the monohydrate and dihydrate complexes of perfluoropropionic acid (PFPA). The spectra have been observed using a chirped-pulse Fourier transform microwave (CP-FTMW) spectrometer in the 7750 to 14,250 MHz region. The structures of the species have been confirmed with the aid of ab initio quantum chemical calculations. Rotational constants A, B, and C have been determined and reported for both species along with centrifugal distortion constants ΔJ, ΔJK, ΔK, δJ, δK for H2O-PFPA and ΔJ, ΔJK, and δJ for (H2O)2-PFPA. Effects due to large amplitude motions were not observable in these experiments. Structures of the complexes have been determined using a combination of experimental second moment values and ab initio results. The complexation of the -OH of one or two water molecules has been found to occur in the plane of the carboxylic acid group forming a six- or eight-member ring.

The position of deuterium in HOD-NNO as determined by structural and nuclear quadrupole coupling constants.

Rotational spectra of the weakly bound H2O-N2O complex and its HOD-N2O isotopologue in a supersonic jet are reported. Rotational constants of the singly substituted deuterium in water and each singly substituted nitrogen-15 are presented. Combinations of isotopic data and high level ab initio calculations place the water in a similar position to those of the isoelectronic H2O-CO2 complex, with a slight tilt of the OH towards the NNO axis. The deuterium nuclear quadrupole coupling constant places the deuterium on the O-H axis quasi-parallel to the NNO axis.