Insights into the Control of Drug Release from Complex Immediate Release Formulations.

The kinetics of water transport into tablets, and how it can be controlled by the formulation as well as the tablet microstructure, are of central importance in order to design and control the dissolution and drug release process, especially for immediate release tablets. This research employed terahertz pulsed imaging to measure the process of water penetrating through tablets using a flow cell. Tablets were prepared over a range of porosity between 10% to 20%. The formulations consist of two drugs (MK-8408: ruzasvir as a spray dried intermediate, and MK-3682: uprifosbuvir as a crystalline drug substance) and NaCl (0% to 20%) at varying levels of concentrations as well as other excipients. A power-law model is found to fit the liquid penetration exceptionally well (average R2>0.995). For each formulation, the rate of water penetration, extent of swelling and the USP dissolution rate were compared. A factorial analysis then revealed that the tablet porosity was the dominating factor for both liquid penetration and dissolution. NaCl more significantly influenced liquid penetration due to osmotic driving force as well as gelling suppression, but there appears to be little difference when NaCl loading in the formulation increases from 5% to 10%. The level of spray dried intermediate was observed to further limit the release of API in dissolution.

Development of an ultra-high-performance liquid chromatography-charged aerosol detection/UV method for the quantitation of linear polyethylenimines in oligonucleotide polyplexes.

Linear polyethylenimines are polycationic excipients that have found many pharmaceutical applications, including as a delivery vehicle for gene therapy through formation of polyplexes with oligonucleotides. Accurate quantitation of linear polyethylenimines in both starting solution and formulation containing oligonucleotide/polyethylenimine polyplexes is critical. Existing methods using spectroscopy, matrix-assisted laser desorption/ionization mass spectrometry time-of-flight, or nuclear magnetic resonance are either complex or suffer from low selectivity. Here, the development and performance of a simple analytical method is described whereby linear polyethylenimines are resolved by ultra-high-performance liquid chromatography and quantified using either a charged aerosol detector or an ultraviolet detector. For formulated oligonucleotide/polyethylenimine polyplexes, sample preparation through decomplexation/digestion by trifluoroacetic acid was necessary to eliminate separation interference. The method can be used not only to support formulation development but also to monitor the synthesis/purification and characterization of linear polyethylenimines.

Assessing the Impact of Different Light Sources on Product Quality During Pharmaceutical Drug Product Manufacture - Fluorescent Versus Light-Emitting Diode Light.

Pharmaceutical scientists are often asked to assess the impact of modifications to the illumination in the manufacturing and product packaging environment on product quality. To assess the impact of switching light sources, four model compounds were exposed to standard fluorescent light, LED, and "yellow light" and the extent of drug photodegradation was determined. Photodegradation under LED light is generally reduced compared to fluorescent light and is often predictable if the UV-Vis absorption spectrum of the active pharmaceutical ingredient (API) and the spectral power distribution emitted by the various light sources overlap. However, lack of noticeable spectral overlap does not ensure absence of API photodegradation and may require additional assessment for selection of appropriate lighting conditions. A detailed evaluation of the API and solid formulation absorbance was performed to assess degradation risk for Compound A and Vitamin D3 when exposed to LED light. The light budget was established for Compound A, spanning all stages of the manufacturing process, under different illumination conditions to enable a complex supply chain. The results also demonstrate that while LEDs used in manufacturing areas are generally "better" compared to fluorescent lights, they are not replacing yellow lights for compounds sensitive to visible light.

Mechanistic understanding of abnormal reverse phase chromatographic behavior of basic analytes in the presence of sodium dodecyl sulfate.

In the process of dissolution method development for Merck proprietary compound A, a basic analyte, abnormal chromatographic behavior involving peak splitting and retention time shifting in the presence of sodium dodecyl sulfate (SDS) in the sample solution was observed. A mechanistic study was conducted and the level and type of surfactant, along with the pKa of the analyte, were determined to be the critical variables in the degree of effect seen. Chromatographically, the effect was further impacted by the injection volume used, the pH and identity of the mobile phase buffer and the amount of system volume between the autosampler and the column. A simple resolution using a basic mobile phase pH was identified to be an effective way to eliminate abnormal chromatographic behavior and produce robust and reproducible analysis.

Incomplete Loading of Sodium Lauryl Sulfate and Fasted State Simulated Intestinal Fluid Micelles Within the Diffusion Layers of Dispersed Drug Particles During Dissolution.

Poorly water soluble drug candidates have been common in developmental pipelines over the last several decades. This has fueled considerable research around understanding how bile salt and model micelles can improve drug particle dissolution rates and human drug exposure levels. However, in the pharmaceutical context only a single mechanism of how micelles load solute has been assumed, that being the direct loading mechanism put forth by Cussler and coworkers (Am Inst Chem Eng J. 1976;22(6):1006-1012) 40 years ago. In this model, micelles load at the particle surface and will be loaded to their equilibrium loading values. More recently, Kumar and Gandhi and coworkers (Langmuir. 2003;19:4014-4026) developed a comprehensive theory of micelle solubilization which also features an indirect loading mechanism which they argue should operate in ionic surfactant systems. In this mechanism, micelles cannot directly load at the solute particle surface and thus may not reach equilibrium loading values within the particle diffusion layer. In this work, we endeavor to understand if the indirect micelle loading mechanism represents a plausible description in the pharmaceutical context. The overall data in SLS and FaSSIF systems obtained here, as well as several other previously published datasets, can be described by the indirect micelle loading mechanism. Implications for pharmaceutical development of poorly soluble compounds are discussed.

Direct determination of amino acids by hydrophilic interaction liquid chromatography with charged aerosol detection.

A chromatographic analytical method for the direct determination of amino acids by hydrophilic interaction liquid chromatography (HILIC) was developed. A dual gradient simultaneously varying the pH 3.2 ammonium formate buffer concentration and level of acetonitrile (ACN) in the mobile phase was employed. Using a charged aerosol detector (CAD) and a 2(nd) order regression analysis, the fit of the calibration curve showed R(2) values between 0.9997 and 0.9985 from 1.5mg/mL to 50µg/mL (600ng to 20ng on column). Analyte chromatographic parameters such as the sensitivity of retention to the water fraction in the mobile phase values (mHILIC) were determined as part of method development. A degradation product of glutamine (5-pyrrolidone-2-carboxylic acid; pGlu) was observed and resolved chromatographically with no method modifications. The separation was used to quantitate amino acid content in acid hydrolysates of various protein samples.

Sequential elution liquid chromatography can significantly increase the probability of a successful separation by simultaneously increasing the peak capacity and reducing the separation disorder.

This paper demonstrates that sequential elution liquid chromatography (SE-LC), an approach in which two or more elution modes are employed in series for the separation of two or more groups of compounds, can be used to separate not only weak acids (or weak bases) from neutral compounds, but weak acids and weak bases from neutral compounds (and each other) by the sequential application of either of two types of an extended pH gradient prior to a solvent gradient. It also details a comparison, based on peak capacity and separation disorder, of the probability of success of this approach with the unimodal elution approach taken by conventional column liquid chromatography. For an HPLC peak capacity of 120 and samples of moderate complexity (e.g., 12 components), the probability of success (Rs≥1) increases from 37.9% (HPLC) to 85.8% (SE-LC). Different columns were evaluated for their utility for SE-LC using the following criteria: (1) the prediction of the elution order of the groups based on the degree of ionization of the compounds; and (2) the closeness of the peak shape to the ideal Gaussian distribution. The best columns overall were the Zorbax SB-AQ and Waters XBridge Shield columns, as they provided both between-class and within-class separations of all compounds, as well as the lowest degree of tailing of 4-ethylaniline using the pH 2 to pH 8 gradient.